3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH

Abstract

The invention is directed to a formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

Description

FIELD OF THE INVENTION

The present invention is directed to novel 3-pyrimidinyl-4-yl-oxazolidin-2-one compounds, compositions containing these compounds, the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity and in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

BACKGROUND OF THE INVENTION

Isocitrate dehydrogenase (IDH) is a key family of enzymes found in cellular metabolism. They are NADP⁺/NAD⁺ and metal dependent oxidoreductases of the enzyme class EC 1.1.1.42. The wild type proteins catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate generating carbon dioxide and NADPH/NADH in the process. They are also known to convert oxalosuccinate into alpha-ketoglutarate. Mutations in IDH1 (cytosolic) and IDH2 (mitochondrial) have been identified in multiple cancer types including, but not limited to, glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma. (See L. Deng et al., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J. Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010; Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol., 2008). The mutations have been found at or near key residues in the active site: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 and R172 for IDH2. (See L. Deng et al., Nature, 2009, 462, 739; L. Sellner et al., Eur. J. Haematol., 2011, 85, 457).

These mutant forms of IDH are shown to have a neomorphic activity (also known as a gain of function activity), reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG). (See P. S. Ward et al., Cancer Cell, 2010, 17, 225) In general, production of 2-HG is enantiospecific, resulting in generation of the D-enantiomer (also known as R enantiomer or R-2-HG). Normal cells have low native levels of 2-HG, whereas cells harboring these mutations in IDH1 or IDH2 show significantly elevated levels of 2-HG. High levels of 2-HG have been detected in tumors harboring the mutations. For example, high levels of 2-HG have been detected in the plasma of patients with mutant IDH containing AML. (See S. Gross et al., J. Exp. Med., 2010, 207(2), 339). High levels of 2-HG are highly associated with tumorigenesis.

Mutant IDH2 is also associated with the rare neurometabolic disorder D-2-hydroxyglutaric aciduria type II (D-2-HGA type II). Germline mutations were found at R140 in IDH2 in 15 pateints having D-2-HGA type II. Patients having this disorder also have consistently increased levels of D-2-HG in their urine, plasma and cerebrospinal fluid. (See Kranendijk, M. et al., Science, 2010, 330, 336). Finally, patients with Ollier Disease and Mafucci Syndrome (two rare disorders that predispose to cartilaginous tumors) have been shown to be somatically mosaic for IDH1 and 2 mutations and exhibit high levels of D-2-HG. (See Amary et al., Nature Genetics, 2011 and Pansuriya et al., Nature Genetics, 2011).

Thus, there is a need for small molecule inhibitors of mutant IDH proteins having a neomorphic activity for the treatment of diseases and disorders associated with these proteins.

SUMMARY OF THE INVENTION

In one aspect, this invention provides for a compound of formula (I)

or a pharmaceutically acceptable salt thereof wherein R¹, R^2a, R^2b and R³-R⁷ are defined below.

In a second aspect, this invention provides for a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In a third aspect, this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of a mutant IDH protein having a neomorphic activity such as reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphic activity). Suitably, this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of mutant IDH1 having a neomorphic activity, such as 2-HG neomorphic activity, and/or mutant IDH2 having a neomorphic activity, such as 2-HG neomorphic activity. This invention further provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R172S, R172G, and R172W.

In a fourth aspect, this invention provides for a method of treating a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of an effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In one embodiment, the disease or disorder is a cell proliferation disorder, such as cancer. In another embodiment, the cancer is brain cancer, such as glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (pNET); leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome, and chronic myelogenous leukemia (CML); skin cancer, including melanoma; prostate cancer; thyroid cancer; colon cancer; lung cancer; sarcoma, including central chondrosarcoma, central and periosteal chondroma; and fibrosarcoma. In another embodiment the disease or disorder is D-2-hydroxyglutaric aciduria.

In a fifth aspect the invention provides for a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent.

These and other aspects of the present invention are described further in the following.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein:
R¹ is hydrogen, methyl or ethyl;
R^2a is hydrogen, methyl or C_1-3 haloalkyl;
R^2b is OH, halo, C_1-6 alkoxy, C_1-3 haloalkyl, NH₂, NH(CH₃) or N(CH₃)₂;
R³ and R⁴ are each independently hydrogen, methyl or ethyl or R³ and R⁴ are joined together forming cyclopropyl, cyclobutyl or oxetanyl;
R⁵ and R⁶ are each independently hydrogen, deuterium, halo, —C(O)OCH₃, C_1-3 alkyl or C_1-3 haloalkyl;

R⁷ is

wherein:

• • ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms;
  • ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
  • X is N or CH;
  • each R⁸ is independently hydrogen, halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy or C_1-3 haloalkoxy;
  • n is 1 or 2;
  • R⁹ is hydrogen, halo, C_1-3 haloalkyl, optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR^9a, —SO₂R^9a, —C(O)NHR^9a, CH₂R^9b or CHCH₃R^9b, provided that when X is N, R⁹ is hydrogen, C_1-3 haloalkyl, optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO₂R^9a or —C(O)NHR^9a, wherein:
    • said C_1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and
    • said C_3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C_1-6 alkyl, C_1-6 haloalkyl, C_1-3 alkoxy, and C_1-3 haloalkoxy;
  • R^9a is optionally substituted C_1-6 alkyl, C_1-6 haloalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic,
  • wherein:
    • said C_1-6 alkyl is optionally substituted with one C_3-6 cycloalkyl,
    • said C_3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH₂OH, —NRR, cyano, C_1-3 alkyl, C_1-3 haloalkyl, and C_1-3 alkoxy, and
    • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C_1-6 alkyl, C_1-6 haloalkyl, C_1-3 alkoxy, and C_1-3 haloalkoxy;
  • R^9b is optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
    • said C_3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH₂OH, —NRR, —NRC(O)CH₃, 4 to 6 membered heterocyclic, cyano, halo, C_1-3 alkyl, C_1-3 haloalkyl, and C_1-3 alkoxy, and
    • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C_1-6alkyl, C_1-6 haloalkyl, C_1-3 alkoxy, and C_1-3 haloalkoxy; and

each R is independently selected from the group consisting of H, C_1-3 alkyl and C_3-6 cycloalkyl.

“Alkyl” refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms. For example, C_1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

“Alkoxy” refers to any alkyl moiety attached through an oxygen bridge (i.e. a —O—C_1-3 alkyl group wherein C_1-3 alkyl is as defined herein). Examples of such groups include, but are not limited to, methoxy, ethoxy, and propoxy.

“Aryl” refers to a hydrocarbon ring system having an aromatic ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl rings refer to naphthyl and to rings wherein phenyl is fused to a C_5-7 cycloalkyl or C_5-7 cycloalkenyl ring as defined herein. Aryl groups may be optionally substituted with one or more substituents as defined in formula (I).

“Cycloalkyl” refers to a saturated hydrocarbon ring system having the specified number of carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring systems. For example, C_3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbon atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Cycloalkenyl” refers to an unsaturated hydrocarbon ring system having the specified number of carbon atoms and having a carbon-carbon double bond within the ring. For example, C_5-7 cycloalkenyl refers to a cycloalkenyl group having from 5 to 7 carbon atoms. In certain embodiments, cycloalkenyl groups have one carbon-carbon double bond within the ring. In other embodiments, cycloalkeneyl groups have more than one carbon-carbon double bond within the ring. Cycloalkenyl rings are not aromatic. Cycloalkenyl groups may be optionally substituted with one or more substituents as defined in formula (I).

“Halo” refers to the halogen radicals fluoro, chloro, bromo, and iodo.

“Haloalkyl” refers to an alkyl group wherein at least one hydrogen atom attached to a carbon atom within the alkyl group is replaced with halo. The number of halo substituents includes, but is not limited to, 1, 2, 3, 4, 5, or 6 substituents. Haloalkyl includes, but is not limited to, monofluoromethyl, difluoroethyl, and trifluoromethyl.

“Haloalkoxy” refers to a haloalkyl moiety attached through an oxygen bridge (i.e. a —O—C_1-3 haloalkyl group wherein C_1-3 haloalkyl is as defined herein). An example of a haloalkoxy group is trifluoromethoxy.

“Heteroaryl” refers to an aromatic ring system containing from 1 to 5 heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups are monocyclic ring systems or are fused bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms. Bicyclic heteroaryl rings have from 8 to 10 member atoms. Bicyclic heteroaryl rings include those ring systems wherein a heteroaryl ring is fused to a phenyl ring. Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, trazinyl, tetrazinyl, tetrzolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl and the like.

“Heteroatom” refers to a nitrogen, oxygen, or sulfur atom.

“Heterocyclic” refers to a 3 to 11 membered saturated or unsaturated monocyclic or bicyclic ring containing from 1 to 4 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. Heterocyclic includes ring systems wherein a sulfur atom is oxidized to form SO or SO₂. Heterocyclic groups may be optionally substituted with one or more substituents as defined in formula (I). Heterocyclic groups are monocyclic, spiro, or fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings have 3 to 7 ring atoms. Examples of monocyclic heterocyclic groups include oxtanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran-1,1-dioxide, 1,4-diazepanyl, and the like. Fused heterocyclic ring systems have from 8 to 11 ring atoms and include groups wherein a heterocyclic ring is fused to a phenyl ring, a heteroaryl ring or another heterocyclic ring. Examples of fused heterocyclic rings include 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[1,3]dioxyl, octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl and the like. Examples of bridged heterocyclic groups include 3,8-diaza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[4.2.0]octanyl and the like. Examples of spiro heterocyclic groups include 4,7-diaza-spiro[2.5]octanyl and the like.

“5-6 membered heterocylic” refers to a heterocyclic group as defined above, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.

“Optionally substituted” indicates that a group, such as an alkyl, cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may be unsubstitued or the group may be substituted with one or more substituents as defined in formula (I).

“Oxo” refers to a C═O group.

“Pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of compounds of the invention which are suitable for use in medicine are those where in the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.

“Substituted” in reference to a group such as alkyl, phenyl, benzyl, heteroaryl, and heterocyclic, indicates that one or more hydrogen atoms attached to an atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation, for example, by hydrolysis, rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) atoms within the group may be substituted. In addition, a single atom within the group may be substituted with more than one substituent as long as such substitution is accordance with the permitted valence of the atom. Suitable substituents are defined for each substituted or optionally substituted group.

The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to formula (I) may be prepared. These salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Solvates, including pharmaceutically acceptable solvates, of the compounds of formula (I) may also be prepared. “Solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

The compounds of formula (I), including salts and solvates thereof, may exist in crystalline forms, non-crystalline forms, or mixtures thereof. The compound or salt or solvate thereof may also exhibit polymorphism, i.e. the capacity of occurring in different crystalline forms. These different crystalline forms are typically known as “polymorphs”. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, all of which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing a compound of formula (I).

The invention also includes various isomers of the compounds of formula (I). “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereosiomers). With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

Any asymmetric atom (e.g., carbon or the like) of a compound of formula (I) can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

The invention includes unlabeled forms as well as isotopically labeled forms of compounds of formula (I). Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹F, ³²F, ³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as ³H and ¹⁴C, or those into which non-radioactive isotopes, such as ²H and ¹³C are present. Such isotopically labelled compounds are useful in metabolic studies (with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., ²H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Representative Embodiments

Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide for further embodiments.

In one embodiment of the present invention R¹ is hydrogen.

In another embodiment of the present invention R^2a is hydrogen or methyl. Suitably R^2a is methyl.

In another embodiment of the present invention R^2b is OH, fluoro, methoxy, t-butoxy, CHF₂, CF₃, NH₂ or NH(CH₃). Suitably R^2b is OH, fluoro or NH₂.

In another embodiment of the present invention R³ and R⁴ are each hydrogen.

In another embodiment of the present invention R⁵ is hydrogen or halo. Suitably R⁵ is hydrogen, fluoro or chloro. More suitably R⁵ is hydrogen or fluoro.

In another embodiment of the present invention R⁶ is hydrogen, halo, methyl, CH₂F, CHF₂, or CF₃. Suitably R⁶ is hydrogen, fluoro, chloro, methyl, CH₂F, CHF₂, or CF₃. More suitably R⁶ is hydrogen or methyl.

In another embodiment of the present invention R⁵ is hydrogen and R⁶ is hydrogen, halo, methyl, CH₂F, CHF₂, or CF₃. Suitably R⁶ is hydrogen, fluoro, chloro, methyl, CH₂F, CHF₂, or CF₃. More suitably R⁶ is hydrogen or methyl.

In another embodiment of the present invention R⁶ is hydrogen and R⁵ is hydrogen or halo. Suitably R⁵ is hydrogen, fluoro or chloro. More suitably R⁵ is hydrogen or fluoro.

In another embodiment R⁵ and R⁵ are both hydrogen.

In another embodiment R⁷ is

In another embodiment R⁷ is

In another embodiment R⁸ is hydrogen, fluoro, chloro or methyl and n is 1. In another embodiment each R⁸ is independently fluoro or chloro and n is 2.

In another embodiment R⁹ is hydrogen, halo, C_1-3 haloalkyl, optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl. Suitably R⁹ is hydrogen, halo, CF₂H, CF₃, CF₂CH₃, C(CH₃)₂F, C_1-6 alkyl optionally substituted with one substituent selected from the group consisting of: OH, phenyl and phenoxy, or C_3-6 cycloalkyl optionally substituted with one substituent selected from the group consisting of: cyano, C_1-3 alkyl, and C_1-3 alkoxy. Suitably R⁹ is hydrogen, halo, CF₂H, CF₃, CF₂CH₃, C(CH₃)₂F, C_1-3 alkyl optionally substituted with one substituent selected from the group consisting of: OH, phenyl and phenoxy group, or cyclopropyl optionally substituted with one substituent selected from the group consisting of: cyano, C_1-3 alkyl, and C_1-3 alkoxy.

In another embodiment R⁹ is phenyl or 2,3-dihydro-1H-indenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH₂OH, C_1-4 alkyl, C_1-4 haloalkyl and C_1-3 haloalkoxy.

In another embodiment R⁹ is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH₂OH, C_1-4 alkyl, C_1-4 haloalkyl and C_1-3 haloalkoxy. Suitably R⁹ is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH₂OH, C_1-4 alkyl, CF₂H, CF₃, C(CH₃)₂CF₃, OCF₃, —OCH₂CF₃, and —OCHF₂. Suitably R⁹ is phenyl substituted in the para position with chloro, fluoro, methyl, cyano, CF₃ or isopropyl. Suitably R⁹ is phenyl substituted in the para position with chloro, CF₃ or isopropyl.

In another embodiment R⁹ is optionally substituted heteroaryl. Suitably R⁹ is optionally substituted pyrazolyl, pyridinyl, indolyl or isoquinolinyl. Suitably R⁹ is pyrazolyl or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C_1-6 alkyl and C_1-6 haloalkyl, for example, fluoro, methyl and CF₃ or C(CH₃)₂CF₃.

In another embodiment R⁹ is −OR^9a wherein R^9a is optionally substituted C_1-6 alkyl, C_1-6 haloalkyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heterocyclic. Suitably R^9a is tetrahydrofuranyl, CF₃, CHF₂, CHCF₃, C_1-6 alkyl optionally substituted with one cyclopropyl, or phenyl optionally substituted with one halo.

In another embodiment R⁹ is —SO₂R^9a wherein R^9a is C_1-6 alkyl.

In another embodiment R⁹ is —C(O)NHR^9a wherein R^9a is optionally substituted C_3-6 cycloalkyl. Suitably R⁹ is —C(O)NHR^9a wherein R^9a is cyclopentyl.

In another embodiment R⁹ is CH₂R^9b wherein R^9b is optionally substituted heterocyclic. Suitably R^9b is optionally substituted 5 to 6 membered heterocyclic. Suitably R^9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, halo, CH₂OH, —NRR, cyano, C_1-3 alkyl, C_1-3 haloalkyl, and C_1-3 alkoxy. Suitably R^9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH₂OH, fluoro, NH₂, N(CH₃)₂, NHCH₃, methyl, and CF₃.

In another embodiment of the present invention each R is independently selected from the group consisting of: H, C_1-3 alkyl.

Another embodiment of the present invention is a compound according to formula (II).

Another embodiment of the present invention is a compound according to formula (III).

wherein R^2b is OH, NH₂ or fluoro.

Another embodiment of the present invention is a compound according to formula (IV).

wherein R^2b is OH or NH₂. Suitably R^2b is OH. Suitably R^2b is NH₂.

Another embodiment of the present invention is a compound according to formula (IV), wherein:

R^2b is OH;

R⁵ is hydrogen or fluoro;

R⁶ is hydrogen, chloro, methyl or CH₂F;

R⁷ is

R⁸ is hydrogen, methyl or fluoro;
n is 1 or 2; and

R⁹ is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C_1-4 alkyl, CF₂H, and CF₃, or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF₃ and C(CH₃)₂CF₃; Suitably R⁵ is hydrogen and R⁶ is chloro, methyl or CH₂F or R⁶ is hydrogen and R⁵ is fluoro. Suitably R⁵ is hydrogen and R⁶ are both hydrogen.

Another embodiment of the present invention is a compound according to formula (V).

Another embodiment of the present invention is a compound according to formula (V) wherein:

R⁵ is hydrogen or fluoro;
R⁶ is hydrogen;

R⁷ is

R⁸ is hydrogen or methyl;
n is 1; and
R⁹ is phenyl optionally substituted with one chloro.

Preferred compounds of the invention include:

• (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
• (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
• (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
• (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
• (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and
• (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one.

General Synthetic Procedures

The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

The compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of formula (I).

Those skilled in the art will recognize if a stereocenter exists in the compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.

wherein R² is CH₂R^2aR^2b

Non-commercial aminoacids can be prepared following the procedures of Scheme 1. Conversion of ketone 1 to the corresponding imidazolidine-2,4-dione 2 followed by hydrolysis provides aminoacid 3.

wherein R² is CH₂R^2aR^2b

When aminoalcohol, precursor of oxazolidinone, is not commercially available, it can be prepared from aminoacid 3 following the procedures of Scheme 2. When R³=R⁴, protected aminoester 5 is treated with an appropriate Grignard reagent to give protected aminoalcohol 6 which goes through basic or acidic deprotection step. When R³=R⁴, protected aminoacid 8 is converted into Weinreb amide 9 which is treated with different Grignard reagents sequentially to provide protected aminoalcohol 10. Either basic or acidic deprotection of 10 gives 11. Insertion of CO unit into 7 or 11 to provide oxazolidinone 12 is accomplished with several reagents, including (but not limited to) triphosgene, Et₂CO₃ or N-N′-darbonyldiimidazole, as shown in Scheme 2.

wherein R² is CH₂R^2aR^2b

Oxazolidinone 12 is coupled with dihalogen-pyrimidine 13 in the presence of NaH and the resulting 14 is treated with primary amine 15 under several different reaction conditions as shown in Scheme 3 to provide 16.

wherein R² is CH₂R^2aR^2b

Alternately intermediate 14 can be prepared by coupling the amino alcohol 11 and dihalogen-pyrimidine 13 in the presence of a base such as diisopropylethyl amine resulting in intermediate 17 which can be treated with triphosgene in the presence of a base such as 2,6-lutidine resulting in intermediate 14.

wherein R² is CH₂R^2aR^2b

Intermediate 14 can undergo modification of functional groups on R¹, R², R³ or R⁴ prior to transformation to compound 16 as described in Scheme 3.

Methods of Use

The compounds of the present invention are inhibitors of a mutant IDH protein having a neomorphic activity and are therefore useful in the treatment of diseases or disorders associated with such proteins including, but not limited to, cell proliferation disorders, such as cancer.

Examples of a mutant IDH protein having a neomorphic activity are mutant IDH1 and mutant IDH2. A neomorphic activity associated with mutant IDH1 and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HG neomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity). Mutations in IDH1 associated with 2-HG neomorphic activity, specifically R-2-HG neomorphic activity, include mutations at residues 97, 100, and 132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. Mutations in IDH2 associated with 2-HG neoactivity, specifically R-2-HG neomorphic activity, include mutations at residues 140 and 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.

Cell-proliferation disorders associated with a mutant IDH protein having a neomorphic activity include, but are not limited to, cancer. Examples of such cancers include Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primaiy; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; steosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor.

In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is brain cancer, such as astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma); oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma); ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma; primitive neuroectodermal tumor, schwannoma, meningioma, meatypical meningioma, anaplastic meningioma; and pituitary adenoma. In another embodiment, the brain cancer is glioma, glioblastoma multiforme, paraganglioma, or suprantentorial primordial neuroectodermal tumors (sPNET).

In another embodiment the cancer associated with a mutant IDH protein having a neomorphic acitvity is leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), MDS.MPN including chronic myelomonocytic leukemia, post MDS AML, post MPN AML, post MDS/MPN AML, del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.

In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is skin cancer, including melanoma.

In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is prostate cancer, thyroid cancer, colon cancer, or lung cancer.

In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is sarcoma, including central chondrosarcoma, central and periosteal chondroma, and fibrosarcoma.

In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is cholangiocarcinoma.

Another disease or disorder associated with a mutant IDH protein having R-2-HG neomorphic activity is D-2-hydroxyglutaric aciduria.

Another disease or disorder associated with a mutant IDH protein having R-2-HG neomorphic activity is Diller disease and Mafucci syndrome.

As used herein the term “neomorphic activity” refers to a gain of novel activity of a protein that the wild-type protein does not have or does not exhibit to a significant degree. For example, a neomorphic activity associated with a mutant form of IDH1 and IDH2 is the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG). The wild type form of IDH1 and IDH2 does not have the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG) or if it does have this ability, it does not produce significant (i.e. harmful or disease causing) amounts of 2-HG.

As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

As used herein, the term “therapeutically effective amount” in reference to a compound of the invention means an amount of the compound sufficient to treat the subject's disease or condition, but low enough to avoid serious sides effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A therapeutically effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of the concurrent therapy; the desired therapeutic effect; and like factors and can be routinely determined by the skilled artisan.

As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

The compounds of the present invention may be administered by any suitable route including oral and parenteral administration. Parenteral administration is typically by injection or infusion and includes intravenous, intramuscular, and subcontaneous injection or infusion.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half life which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the subject being treated, the medical history of the subject being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual subject's response to the dosing regimen or over time as the individual subject needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration, to a human weighing approximately 70 kg would range from about 5 mg to about 500 mg of a compound of formula (I).

One embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having a neomorphic activity comprising administration of a therapeutically effective amount of a compound of formula (I) to a subject in need of treatment thereof. In one embodiment, the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder. In another embodiment, the cell proliferation disorder is cancer. In another embodiment, the cancer is a cancer associated with mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is R-2-HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

Another embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity comprising administration of a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for the use of a compound of formula (I) in therapy. In a further embodiment the therapy is a disease or disorder associated with a mutant form of IDH having a neomorphic activity. In another embodiment the therapy is a cell proliferation disorder associated with a mutant form of IDH having a neomorphic activity. In another embodiment the therapy is cancer. In another embodiment the therapy is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is R-2-HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

Another embodiment of the present invention provides for the use of a compound of formula (I) in therapy wherein the therapy is D-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having a neomorphic activity. In one embodiment the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder. In another embodiment, the cell proliferation disorder is cancer. In another embodiment the cancer is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is R-2-HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Oilier Disease, or Mafucci Syndrome.

Compositions

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a therapeutically effective amount of a compound of the invention can be extracted and then given to a subject, such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a therapeutically effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from about 5 mg to 500 mg of a compound of formula (I).

As used herein the term “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable material, composition or vehicle that, for example, are involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must, of course, be of sufficiently high purity to render it pharmaceutically acceptable.

The compound of the invention and the pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention, once administered to the subject, from one organ or portion of the body to another organ or another portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable carriers and excipients in appropriate amounts for the use in the invention. In addition, there are a number of resources available to the skilled artisan, which describe pharmaceutically acceptable carriers and excipients and may be useful in selecting suitable pharmaceutically acceptable carriers and excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives, (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch) gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

The compounds of the invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanacrylates and cross-linked or amphipathic block copolymers of hydrogels.

In another aspect, the invention is directed to a liquid oral dosage form. Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of the invention. Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution; while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound of the invention in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or other natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.

In another aspect, the invention is directed to parenteral administration. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Combinations

The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s). The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).

In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or disorder associated with a mutant form of IDH. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic agent may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is administered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is administered with a compound of formula (I).

The invention also provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected from: vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxic agents.

Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369), Brivanib Alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No, WO 02/066470), pasireotide (also known as SOM230, and described in PCT Publication No, WO 02/010192), and sorafenib (sold under the tradename Nexavar®).

Examples of topoisomerase II inhibitors, include but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), and teniposide (also known as VM-26, sold under the tradename Vumon®).

Examples of alkylating agents, include but are not limited to, temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexylen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexylen®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, and sold under the tradename Thioplex®.

Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename Ienoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), and mitomycin C (sold under the tradename Mutamycin®).

Examples of anti-metabolites include, but are not limited to, claribine (2-chlorodeoxyadenosine, sold under the tradename Ieustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™) methotrexate (also known as amethopterin, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), and pentostatin (sold under the tradename Nipent®).

Examples of retinoids include, but are not limited to, alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), and bexarotene (sold under the tradename Targretin®).

Examples of other cytotoxic agents include, but are not limited to, arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®).

INTERMEDIATES AND EXAMPLES

The following examples are intended to be illustrative only and not limiting in any way. Unless otherwise noted, the following Intermediates and Examples were purified vial silica gel column chromatograph using RediSep® Rf columns from Teledyne Isco, Inc. Abbreviations used are those conventional in the art or the following:

ACN acetonitrile
BI NAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
BSA bovine serum albumin

C Celsius

d doublet
dd doublet of doublets
DAST diethylaminosulfur trifluoride
DEAD diethyl azodicarboxylate

DIPEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide
DTT dithiothreitol
EtOAc ethyl acetate
EtOH ethanol
g gram
h hour(s)
hr hour(s)
HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HEPES 4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acid
HPLC high pressure liquid chromatography
IPA isopropyl alcohol
kg kilogram
L liter
LC liquid chromatography LCMS liquid chromatography and mass spectrometry
MeOH methanol
MS mass spectrometry
m multiplet
min minutes
mL milliliter(s)
μM micromolar
m/z mass to charge ratio
nm nanometer
nM nanomolar
N normal
NADPH nicotinamide adenine dinucleotide phosphate

NMP N-methylpyrrolidone

NMR nuclear magnetic resonance
PdCl₂(dppf).CH₂Cl₂ 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex
psi pounds per square inch
rac racemic
Rt retention time
s singlet
sat. saturated
SFC supercritical fluid chromatography
t triplet
tR rentention time
TCEP tris(2-carboxyethyl)phosphine
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography

Instrumentation

LCMS:

Unless otherwise noted, LCMS data (also reported herein as simply MS) were recorded using a Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C18 1.8-micron, 2.1×50 mm; gradient: 5-95% acetonitrile in water with 0.05% TFA over a 1.8 min period; flow rate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 50° C.). All masses reported are those of the protonated parent ions unless recorded otherwise.

High Resolution Mass Spectrometry (HRMS):

HRMS Method A: ESI-MS data were recorded using a Synapt G2 HDMS (TOF mass spectrometer, Waters) with electrospray ionization source. The resolution of the MS system was approximately 15000. Leucine Enkephalin was used as lock mass (internal standards) infused from lockspary probe. The compound was infused into the mass spectrometer by UPLC (Acquity, Waters) from sample probe. The separation was performed on Acquity UPLC BEH C18 1×50 mm column at 0.2 mL/min flow rate with the gradient from 5% to 95% in 3 min. Solvent A was Water with 0.1% Formic Acid and solvent B was Acetonitrile with 0.1% Formic Acid. The mass accuracy of the system has been found to be <5 ppm with lock mass.

HRMS Method B: LC-MS/ESI-MS data were recorded on an Acquity G2 Xevo QT of −Rs(FWHM)>20000 Accuracy<5 ppm. The separation was performed on Acquity CSH 1.7 μm 2.1×50 mm-50° C. column Eluent A: Water+3.75 mM ammonium acetate. Eluent B: Acetonitrile. Gradient: from 2 to 98% B in 4.4 min-flow 1.0 mL/min.

HRMS Method C: Same as HRMS method B, except Gradient: from 40 to 98% B in 3.4 min-flow 1.0 mL/min.

HRMS Method D: LC-MS/ESI-MS data were recorded on an Acquity LCTp T of −Rs(FWHM)>12000<5 ppm. The separation was performed on Acquity BEHC18 1.7 μm 2.1×50 mm-50° C. column Eluent A: Water+0.1% Formic Acid+3.75 mM Am acetate. Eluent B: Acetonitrile+0.04% formic+3.75 mM Am Acetate+5% Water. Gradient: from 0.2 to 98% B in 4.4 min-flow 1.0 mL/min.

HRMS methods A, B, C and D are referred to throughout as HRMS (A), HRMS (B), HRMS (C) and HRMS (D) respectively.

Intermediates

Intermediate 1: benzyl ((2R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate

A solution of (2S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid (500 mg, 1.0 mmol) in 10 ml of THF and isobutyl chloroformate (167 mg, 1.2 mmol, 1.2 equiv) at −25° C. was added N-methylmorpholine (124 mg, 1.2 mmol, 1.2 equiv), the mixture was stirred at same temperature for 10 min and filtered. The filtrate was cooled to −20° C. and to it was added NaBH₄, followed by 2 ml of water immediately afterwards. The reaction mixture was stirred at same temperature for 5 min. then graduately warm to room temperature for 25 min, poured it into water (10 ml) and extracted with EA (2×20 ml), the combines organic phases were washed with water, brine and dried over Na₂SO₄. The solvent was removed to yield the desired product as the clear oil. No further purification was required for next step. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.16 (m, 5H), 5.25 (d, J=8.0 Hz, 1H), 5.02 (s, 1H), 4.04 (ddd, J=12.0, 8.9, 2.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.59 (dddd, J=32.3, 14.6, 8.2, 4.3 Hz, 2H), 1.10 (s, 9H), 1.09-1.06 (m, 3H).

Intermediate 2: (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

Method A: A solution of benzyl ((2R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (134 mg, 0.45 mmol in 5 mL of THF) was pre-cooled to 0° C.) under nitrogen was treated with potassium tert-butoxide (153 mg, 1.4 mmol, 3.0 equiv), it was stirred at same temperature for 2 hours, 5 mL of water was added, it was extracted with EtOAc (2×20 mL), the combined organic layers were washed with water, brine, dried over Na₂SO₄, the solvent was removed to yield the desired product as a yellow oil, no further purification was required for next step. ¹H NMR (400 MHz, CDCl₃) δ 4.33 (t, J=8.7 Hz, 1H), 4.07 (dd, J=8.9, 5.5 Hz, 1H), 3.67-3.58 (m, 1H), 3.58-3.49 (m, 1H), 1.13 (s, 9H), 1.02 (d, J=6.0 Hz, 3H).

Method B: (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol hydrochloride (19.77 g, 100 mmol) was dissolved in DCM (200 mL) at 0° C., and added triethylamine (69.7 ml, 500 mmol). Solution was treated over 90 mins with a solution of triphosgene (12.76 g, 43.0 mmol) in DCM (100 mL) [keep the reaction mixture below 5° C.]. The reaction mixture was stirred at 0° C. for 30 mins before allowing to warm to room temperature and stirring overnight. The reaction mixture was treated with aqueous saturated NH₄Cl (200 mL), water (50 mL) and stirred vigorously at room temperature for 1 h. Separated the organics, extracted the aqueous with DCM (500 mL), combined the organics and washed them with 1N HCl (3×150 mL), and aqueous saturated NH4Cl, dried (MgSO4) and concentrated to dryness (careful not to leave under vacuum or heat excessively) to give a pale brown oil. TLC shows mostly product with some small by-product peaks at higher Rf and some baseline materials. Subjected to flash column chromatography on silica with neat heptanes, 20% Et2O/heptanes, 50% Et2O/heptanes, neat Et2O, and 30% EtOAc/Et2O. TLC: neat ether, stain with cupric ammonium sulfate (heat hard for 1 minute to see the blue product stain); product Rf=0.34. Product off mostly with neat Et2O. One of the cleanest single fractions was concentrated to dryness to give 2.02 g of a very pale yellow/brown oil which crystallized upon standing. The remainder of the product fractions were combined and concentrated to dryness to give 15.2 g as a pale brown oil, which was seeded with crystals of the initial batch to give a pale brown crystalline solid. Overall yield ˜90%. ¹H NMR (400 MHz, CDCl₃) δ 5.28 (br s, 1H); 4.44 (t, 1H); 4.13-4.09 (m, 1H); 3.7-3.57 (m, 2H); 1.23 (s, 9H); 1.11 (d, 3H).

Intermediate 3: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Method A: A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (86 mg, 0.46 mmol) and 2,4-difluoropyrimidine (79 mg, 0.55 mmol, 1.2 equiv) in 3 ml of DMF was cooled to 0° C. under N2 before adding NaH (60%, 28 mg, 0.69 mmol, 1.5 equiv) slowly. The reaction mixture was stirred at 0° C. for 45 min., then gradually warmed to room temperature, and stirred at room temperature overnight. The reaction was quenched with 5 ml of water, and extracted with EtOAc (2×10 ml). The solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) provided the desired product as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J=5.8, 2.1 Hz, 1H), 8.14 (dd, J=5.8, 3.8 Hz, 1H), 4.85-4.63 (m, 2H), 4.56-4.30 (m, 2H), 1.26 (s, 9H), 1.05 (d, J=6.5 Hz, 3H).

Method B: A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.602 g, 40.1 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4-difluoropyrimidine (2.507 mL, 29.4 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the reaction mixture to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 2 h. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence although minimal increase in temperature. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil [8.33 g] which was purified by silica gel chromatography (initial ramp DCM/heptane 5 to 100%, then EtOAc/DCM 0% to 20%, product off with ˜5% EtOAc/DCM). Combined and concentrated the pure product fractions to dryness to give a white solid which was placed under high vacuum for 4 h. ¹H NMR (400 MHz, CDCl₃) δ 8.5 (dd, 1H), 8.15 (dd, 1H); 4.77-4.66 (m, 2H); 4.53-4.42 (m, 2H); 1.26 (s, 9H); 1.05 (d, 3H). MS m/z 284.1 (M+H)⁺.

Intermediate 4: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.28 g, 32 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4,5-trifluoropyrimidine (3.76 g, 28 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the rm to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 6 h. Sampled reaction mixture and quenched with water, extracted into EtOAc; TLC and LCMS show significant product but remaining oxazolidinone sm. Cooled reaction mixture to 0° C. and added an additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmed to room temperature and left stirring for 3 h at rt. Still faint residual sm seen by TLC of sample, but quenched reaction mixture at this point. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil. Crude was purified by silica gel chromatography (initial neat DCM, then ramp to 20% EtOAc/DCM). Pure product fractions were combined and concentrated to dryness to give a colourless oil which was placed under high vacuum. Upon standing the oil converted into a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=3, 1 Hz, 1H); 4.73-4.68 (m, 1H); 4.62-4.52 (m, 2H); 4.34-4.28 (m, 1H); 1.20 (s, 9H); 1.11 (d, 3H). MS m/z 302.1 (M+H)⁺.

Intermediate 5: (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (1.0 g, 3.35 mmol) in 20 ml of DCM was cooled in an ice bath, and treated with 8.16 mL of TFA. The mixture was stirred at same temperature for 4 hours, and allowed to warm to room temp and stir 16 h. The reaction was poured into 10 mL water. The DCM was removed in vacuo. The aqueous was basified by slow addition of saturated NaHCO3 solution, then extracted with (2×30 mL) EtOAc. The organics were washed with 30 mL brine, and dried over Na2SO4. Filtered and concentrated to give the desired alcohol, (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (0.56 g, 70% yield) as a white solid. HRMS (B) tR=0.80 min; MS m/z 228.4 (M+H)⁺.

Intermediate 6: (R)-methyl 3-(2-fluoropyrimidin-4-yl)-2-oxooxazolidine-4-carboxylate

A solution of (R)-methyl 2-oxooxazolidine-4-carboxylate (200 mg, 1.4 mmol) and 2,4-fluoropyrimidine (176 mg, 1.5 mmol, 1.1 equiv) in DMF (3 mL) was treated with NaH (60%, 66.2 mg, 1.2 mmol, 1.2 equiv), then the resulting mixture was stirred at 0° C. for 45 minutes, then room temperature for 12 h. The reaction mixture was diluted with EtOAc (20 mL), washed with sat. NH₄Cl (15 mL) and 4% aqueous NaCl (2×100 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10% to 50%) to provide

(R)-methyl 3-(2-fluoropyrimidin-4-yl)-2-oxooxazolidine-4-carboxylate (240 mg, white waxy solid) in 71% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=5.8, 2.0 Hz, 1H), 8.07 (dd, J=5.7, 3.7 Hz, 1H), 5.18 (dd, J=9.4, 3.7 Hz, 1H), 4.68 (t, J=9.4 Hz, 1H), 4.45 (dd, J=9.3, 3.7 Hz, 1H), 3.78 (s, 3H).

Intermediate 7: 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol

To a chilled (0° C.) solution of 2-amino-4,4,4-trifluoro-3-methylbutanoic acid (736 mg, 4.30 mmol) in THF (9 mL) was added aluminum (III) lithium hydride (2.26 mL, 9.03 mmol, 4M) dropwise. After addition complete, the reaction was allowed to stir at ambient temperature for 1 hour. Cool to 0° C. and quench w/sat. Na₂SO₄ soln, added EtOAc (50 mL), Na₂SO₄, filtered, conc. in vacuo afforded material that was a mixture of the title compound and the starting material acid in a 3:2 ratio which was used crude in the next step. ¹H NMR (400 MHz, CDCl₃) δ 3.71 (dd, J=10.7, 3.7 Hz, 1H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.45 (ddd, J=10.7, 8.0, 4.8 Hz, 2H), 3.28 (ddd, J=8.2, 5.3, 2.9 Hz, 1H), 3.06 (td, J=7.3, 3.6 Hz, 1H), 2.44-2.20 (m, 2H), 2.04-1.54 (m, 1H), 1.21-1.08 (m, 7H). ¹⁹F NMR (376 MHz, CDCl₃) δ −68.33 (s), −70.12 (s).

Intermediate 8: 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

To a solution of 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol (580 mg, 3.69 mmol) in DCM (13 ml) was added triethylamine (1.132 ml, 8.12 mmol) and added dropwise a solution of triphosgene (329 mg, 1.107 mmol) in 1 mL in DCM (3 ml) over 10 min. The reaction mixture was washed with sat. NH₄Cl solution (13 ml) dry, and concentrated in vacuo. Afforded 450 mg (lt yellow solid). Used crude in the next step. ¹H NMR (400 MHz, CDCl₃) δ 5.91 (d, J=13.3 Hz, 1H), 4.61-4.34 (m, 1H), 4.22-4.00 (m, 2H), 3.05 (q, J=7.3 Hz, 1H), 2.54-2.14 (m, 1H), 1.34 (t, J=7.3 Hz, 1H), 1.17 (d, J=7.1 Hz, 2H), 1.09 (d, J=7.1 Hz, 1H). MS 183.0507 m/z.

Intermediate 9: 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

A solution of 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (270 mg, 1.474 mmol) and 2,4-difluoropyrimidine (171 mg, 1.474 mmol, 1 eq) in DMF (4 mL) was treated with NaH (60%, 88 mg, 2.212 mmol, 1.5 eq), then the resulting mixture was stirred at 0° C. for 10 minutes, then room temperature for 1 h. The reaction mixture was quenched with sat. Na₂SO₄ (15 mL) diluted with EtOAc (20 mL), washed and 4% aqueous NaCl (3×20 mL), dried over Na₂SO₄, concentrated in vacuo. Flash column chromatography (silica, 120 g, 15 m) 5% EtOAc/DCM to provide 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (100 mg, white solid). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J=5.8, 2.1 Hz, 1H), 8.20 (dd, J=5.8, 3.7 Hz, 1H), 5.04-4.84 (m, 1H), 4.68 (dd, J=9.5, 2.6 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 3.34 (ddddd, J=13.3, 9.3, 7.1, 3.9, 1.6 Hz, 1H), 1.29 (d, J=7.3 Hz, 3H). MS 279.0631 m/z.

Intermediate 10: (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one

Step 1

To a round bottom flask was added NaH (0.54 g, 13.5 mmol, 57% despersion in mineral oil) to a solution of 2,4,6-trichloropyrimidine (1.22 ml, 10.6 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (1.8 g, 9.61 mmol) in DMF (32 mL) at 0° C. (ice bath) under a bubbler. The yellow suspension was then stirred at 0° C. for 15 min and then the ice bath was removed and reaction mixture allowed to stir 1 hr at room temperature. Reaction mixture was diluted with EtOAc and then carefully quenched with brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 6.28 mmol, 65% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.04 (d, J=6.55 Hz, 3H) 1.26 (s, 9H) 4.38-4.48 (m, 2H) 4.64-4.75 (m, 2H) 8.22 (s, 1H). LCMS m/z 334.1 (M+H)⁺, Rt 1.10 min.

Step 2

To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1 g, 2.99 mmol) was added DCM (7.5 mL) followed by the addition of TFA (7.5 mL). The resulting homogenous reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Residue dissolved in DCM and neutralized with a saturated solution of NaHCO₃. The phases were partioned, the aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a white foam of (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (737 mg, 2.65 mmol, 89% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (d, J=6.46 Hz, 3H) 4.47 (dd, J=9.37, 8.53 Hz, 1H) 4.55 (quin, J=5.69 Hz, 1H) 4.63 (dd, J=9.49, 2.79 Hz, 1H) 4.89 (ddd, J=8.19, 4.96, 2.79 Hz, 1H) 8.24 (s, 1H). LCMS m/z 278.0 (M+H)⁺, Rt 0.66 min.

Step 3

To a round bottom flask was added (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (364 mg, 1.31 mmol) followed by the addition of DCM (10.8 mL). The reaction mixture was then cooled to 0° C. in a (ice/water bath) under nitrogen. To this cold solution was added tetrafluoroboric acid (0.20 mL, 1.31 mmol, 50% aqueous solution) followed by the addition of trimethylsilyldiazomethane (1.96 mL, 3.93 mmol, 2 M in hexanes) divided into 3 portions added 20 min apart. A second addition of trimethylsilyldiazomethane in hexanes (1.96 mL, 3.93 mmol, 2 M in hexanes) again divided into 3 portions added 20 min apart was added. Reaction mixture was quenched with water and diluted with DCM. Phases partioned and the aqueous phase extracted with DCM. Organic phases combined and washed with brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (119 mg, 0.41 mmol, 31% yield) as a colorless oil which crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.09 (d, J=6.50 Hz, 3H) 3.44 (s, 3H) 4.09 (qd, J=6.46, 4.16 Hz, 1H) 4.38-4.49 (m, 1H) 4.60 (dd, J=9.49, 2.84 Hz, 1H) 4.99 (ddd, J=8.50, 3.95, 2.96 Hz, 1H) 8.23 (s, 1H). LCMS m/z 292.0 (M+H)⁺, Rt 0.86 min.

Intermediate 11: (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one

Step 1

To a round bottom flask containing a stir bar and (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid (2.5 g, 10.7 mmol) in THF (80 mL) under nitrogen was cooled to −30° C. in a dry ice/acetone bath. To this cold solution was added isobutyl chloroformate (1.7 mL, 12.9 mmol) followed by the addition of N-methylmorpholine (1.4 mL, 12.9 mmol). Mixture was stirred for 15 min at −30° C. N-Methylmorpholine salt develops and was filtered from mixture.

Mother liquor was cooled to −30° C. where upon sodium borohydride (0.61 g, 16.1 mmol) was added followed by the addition of water (10 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. Reaction mixture was stirred for 30 min at room temperature. Reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to afford tert-butyl ((2R,3R)-1-hydroxy-3-methoxybutan-2-yl)carbamate (2.0 g, 9.1 mmol, 85% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 1.18 (d, J=6.26 Hz, 3H) 1.45 (s, 9H) 3.33 (s, 3H) 3.55-3.84 (m, 4H). LCMS m/z 220.2 (M+H)⁺, Rt 0.57 min.

Step 2

To a round bottom flask containing tert-butyl ((2R,3R)-1-hydroxy-3-methoxybutan-2-yl) (2 g, 9.1 mmol) and stir bar was added DCM (5.0 mL) followed by the addition of TFA (5.0 mL). Resulting reaction mixture allowed to stir 30 min at room temperature. Volatiles were removed to afford (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol, 99% yield) as a TFA salt. Material was used in next step without further purification. LCMS m/z 120.0 (M+H)⁺, Rt 0.15 min.

Step 3

To a round bottom flask containing (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol) and a stir bar was added acetonitrile (100 mL) followed by the addition of 2,4-dichloropyrimidine (1.34 g, 9.0 mmol) and DIEA (4.7 mL, 27.0 mmol). Resulting reaction mixture allowed to stir 18 hr at room temperature. Volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to afford (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol, 40% yield) which contains some unreacted 2,4-dichloropyrimidine. LCMS m/z 232.0 (M+H)⁺, Rt 0.38 min.

Step 4

To a round bottom flask containing (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol) and a stir bar under nitrogen was added DCM (18 mL). The resulting reaction mixture cooled to 0° C. in a brine/ice bath. To this cold solution was then added triphosgene (0.59 g, 1.99 mmol) followed by the addition of 2,6-dimethylpyridine (2 mL, 17.0 mmol). Resulting reaction mixture allowed to stir 30 min at 0° C. The reaction mixture was diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases partitioned and the aqueous phase extracted with DCM. Organic phases were combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol, 15% yield) as a white crystalline. ¹H NMR (400 MHz, CDCl₃) δ 1.09 (d, J=6.26 Hz, 3H) 3.45 (s, 3H) 4.15 (qd, J=6.39, 4.30 Hz, 1H) 4.39-4.47 (m, 1H) 4.60 (dd, J=9.39, 2.74 Hz, 1H) 5.02 (dt, J=8.61, 3.52 Hz, 1H) 8.17 (d, J=5.87 Hz, 1H) 8.48 (d, J=5.87 Hz, 1H). LCMS m/z 258.1 (M+H)⁺, Rt 0.69 min.

Step 5

To a microwave vial with stir bar was added (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol), potassium fluoride (327 mg, 5.63 mmol) and DMSO (4 mL). Vial capped and heated to 120° C. in a sand bath for 3 hr. Reaction mixture was then cooled to room temperature, diluted with water and aqueous mixture extracted with EtOAc. The Organic phases were combined and washed with water, brine, dried (Na₂SO₄), filtered and concentrated to afford a white crystalline of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (117 mg, 0.49 mmol, 86% yield). LCMS m/z 242.1 (M+H)⁺, Rt 0.63 min.

Intermediate 12: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one

Step 1

To a round bottom flask containing a stir bar and (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid (8.55 g, 21.5 mmol) in THF (72 mL) under nitrogen was cooled to −30° C. in a dry ice/acetonitrile bath. To this cold solution was added isobutyl chloroformate (3.4 mL, 25.8 mmol) followed by the addition of N-methylmorpholine (2.8 mL, 25.8 mmol). Mixture was stirred for 15 min at −30° C. N-Methylmorpholine salt develops and was filtered from mixture. Mother liquor was cooled to −30° C. where upon sodium borohydride (1.22 g, 32.3 mmol) was added followed by the addition of water (25 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. Reaction mixture was stirred for 30 min at room temperature. Reaction mixture was diluted with water, extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to afford (9H-fluoren-9-yl)methyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (8.11 g, 21.15 mmol, 98% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H) 1.24 (d, J=5.87 Hz, 3H) 4.11-4.26 (m, 2H) 4.42 (d, J=7.04 Hz, 2H) 5.73 (d, J=7.43 Hz, 1H) 7.29-7.35 (m, 2H) 7.38-7.45 (m, 2H) 7.61 (t, J=6.06 Hz, 2H) 7.78 (d, J=7.43 Hz, 2H).). LCMS m/z 384.3 (M+H)⁺, Rt 0.96 min.

Step 2

To a round bottom flask with stir bar was added (9H-fluoren-9-yl)methyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (4.7 g, 12.3 mmol) and acetonitrile (100 mL) followed by the addition of piperidine (1.8 mL, 18.4 mmol). The flask was capped and stirred for 18 hr at room temperature. The volatiles were then removed. A white solid develops which contains the amino alcohol product and the fmoc deprotection by products. Solids were redissolved in acetonitrile (50 ml) (some of the fmoc polymer is insoluble) and 2,4-dichloropyrimidine (5.48 g, 36.8 mmol) and DIEA (2.141 mL, 12.26 mmol) were added. Resulting reaction mixture allowed to stir 18 hr at room temperature. The volatiles were again removed. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.80 g, 6.58 mmol, 54% yield) as a colorless oil which crystallizes upon standing. LCMS m/z 274.1 (M+H)⁺, Rt 0.56 min.

Step 3

To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.8 g, 6.58 mmol) and a stir bar under nitrogen was added DCM (66 ml). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (1.07 g, 3.62 mmol) followed by the addition of 2,6-dimethylpyridine (3.6 mL, 30.9 mmol). Resulting reaction mixture allowed to gradually warm to room temperature and stirred for 30 min at room temperature. Reaction mixture diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous extracted with DCM. Organics phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (1.44 g, 4.80 mmol, 73% yield) as a white crystalline. LCMS m/z 300.1 (M+H)⁺, Rt 0.91 min.

Intermediate 13: (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.830 g, 4.43 mmol) and 2,4,6-trichloropyrimidine (0.894 g, 4.88 mmol, 1.10 equiv) in DMF (15 mL) was treated with NaH (60%, 0.248 g, 6.21 mmol, 1.40 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and quenched with saturated aqueous NaCl (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1.0 g, white solid) in 69% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 4.70-4.66 (m, 2H), 4.45-4.40 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.6 Hz, 3H); MS m/z 334.0 (M+H)⁺; Rt-1.10 min.

Intermediate 14: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.100 g, 0.534 mmol) and 4-chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine (0.124 g, 0.587 mmol, 1.10 equiv) in DMF (2.7 mL) was treated with NaH (60%, 0.026 g, 0.64 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, white solid) in 85% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 6.45 (t, J=54 Hz, 1H), 4.80-4.72 (m, 1H), 4.66 (dd, J=9.4, 3.0 Hz, 1H), 4.49-4.34 (m, 2H), 2.58 (s, 3H), 1.25 (s, 9H), 1.02 (d, J=6.5 Hz, 3H); MS m/z 362.3 (M+H)⁺; Rt-1.09 min.

Intermediate 15: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, 0.454 mmol) in DCM (4.5 mL) was treated with m-CPBA (0.244 g, 1.09 mmol, 2.4 equiv) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was carefully quenched with a 1:1 mixture of 1 M aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with DCM (3×20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (20 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20% to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one as a white solid in 82% yield. MS m/z 338.1 (M+H-tert-butyl)⁺; Rt-0.87 min.

Intermediate 16: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.070 g, 0.374 mmol) and 2,4-dichloro-6-(trifluoromethyl)pyrimidine (0.089 g, 0.411 mmol, 1.10 equiv) in DMF (1.3 mL) was treated with NaH (60%, 0.018 g, 0.45 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 60 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 15%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one (0.116 g, white solid) in 84% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 4.76 (ddd, J=8.5, 4.2, 2.9 Hz, 1H), 4.70 (dd, J=9.5, 2.9 Hz, 1H), 4.50-4.42 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.5 Hz, 3H). MS m/z 368.1 (M+H)⁺; Rt-1.10 min.

Intermediate 17: (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol

A solution of (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (267 mg, 1.35 mmol, 1.1 equiv), 2,4-dichloro-6-methylpyrimidine (200 mg, 1.23 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.54 mL, 3.1 mmol, 2.5 equiv) in 1,4-dioxane (6 mL) was heated at 75° C. for 4 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, white solid) in 24% yield. ¹H NMR (400 MHz, CDCl₃) δ 6.17 (s, 1H), 4.02 (m, 2H), 3.79-3.64 (m, 2H), 2.30 (s, 3H), 1.22 (s, 9H), 1.18 (d, J=6.2 Hz, 3H); MS m/z 288.1 (M+H)⁺; Rt-0.59 min.

Intermediate 18: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one

Triphosgene (35 mg, 0.12 mmol, 0.4 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, 0.30 mmol) in DCM (3 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 5 hours. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (0.057 g, white solid) in 61% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 4.73 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.65 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.26 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 314.1 (M+H)⁺; Rt-1.02 min.

Intermediate 19: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one

Potassium fluoride (0.063 g, 1.08 mmol, 10 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.108 mmol) in DMSO (1.1 mL). The suspension was heated at 120° C. for 3 hours and then cooled to room temperature. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=3.8 Hz, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.46 (m, 1H), 4.41 (m, 1H), 2.53 (s, 3H), 1.25 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 298.2 (M+H)⁺; Rt-0.96 min.

Intermediate 20: methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate

Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.58 mmol, 1.2 equiv) was added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (90 mg, 0.483 mmol, 1 equiv) in DMF (2.4 mL) at 0° C. The suspension was stirred at 0° C. for 1 hour, by which time it turned yellow. The reaction was quenched with dilute aqueous sodium chloride (20 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) separated the regioisomers and provided methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate (0.111 g, white solid) in 64% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 4.76 (m, 1H), 4.69 (dd, J=9.4, 2.7 Hz, 1H), 4.52-4.41 (m, 2H), 4.02 (s, 3H), 1.26 (s, 9H), 1.05 (d, J=6.6 Hz, 3H). MS m/z 358.2 (M+H)⁺; Rt-1.00 min.

Intermediate 21: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one

Sodium borohydride (60 mg, 1.59 mmol, 1.4 equiv) was added to a suspension of methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate (400 mg, 1.12 mmol) in methanol (11.2 mL) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (0.220 g, white solid) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 4.77-4.72 (m, 3H), 4.66 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.83 (m, 1H), 1.26 (s, 9H), 1.03 (d, J=6.6 Hz, 3H). MS m/z 330.1 (M+H)⁺; Rt-0.86 min.

Intermediate 22: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one

N,N-Diethylaminosulfur trifluoride (0.13 mL, 0.98 mmol, 1.5 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (215 mg, 0.652 mmol) in DCM at −78° C. The reaction was stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for another hour. Additional N,N-Diethylaminosulfur trifluoride (0.26 mL, 2.0 mmol, 3 equiv) was added and the reaction stirred for another 1 hour. The reaction was quenched with water (50 mL) and extracted with DCM (3×25 mL). The combined extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (0.165 g, white solid) in 76% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 5.40 (d, J=44 Hz, 1H), 4.75 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.67 (dd, J=9.4, 2.9 Hz, 1H), 4.49 (m, 1H), 4.43 (m, 1H), 1.27 (s, 9H), 1.04 (d, J=6.5 Hz, 3H). MS m/z 332.1 (M+H)⁺; Rt-1.02 min.

Intermediate 23: (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine

(S)-1-(1-(4-Fluorophenyl)-1H-pyrazol-4-yl)ethanamine (175 mg, 0.724 mmol) was added to a solution of 2,4,6-trifluoropyrimidine (146 mg, 1.09 mmol, 1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.8 mmol, 2.5 equiv) in 1,4-dioxane at room temperature. The mixture was stirred at room temperature for 1 hour and then the reaction was concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (0.085 g) in 37% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.68 (s, 1H), 7.62 (dd, J=8.9, 4.6 Hz, 1H), 7.18-7.11, (m, 2H), 5.80 (t, J=1.2 Hz, 1H), 5.49 (m, 1H), 5.25 (m, 1H), 1.62 (d, J=6.8 Hz, 3H). MS m/z 320.1 (M+H)⁺; Rt-0.95 min.

The Intermediates in Table 1a were prepared by a method similar to the one described for the preparation of Intermediate 23.

TABLE 1a
Intermediate 24
Intermediate 25

TABLE 1b
Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed
in Table 1a.
	1H NMR (400 MHz, CDCl3) δ
Intermediate: Name	ppm	LCMS
24: (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-	7.82 (s, 1H), 7.68 (s, 1H),	MS m/z
1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine	7.62 (dd, J = 8.9, 4.6 Hz, 1H),	320.1 (M + H)+;
	7.18-7.11, (m, 2H), 5.80 (t, J = 1.2 Hz,	Rt-0.95 min
	1H), 5.49 (m, 1H), 5.25 (m,
	1H), 1.62 (d, J = 6.8 Hz, 3H).
25: (S)—N-(1-(1-(4-chlorophenyl)-1H-pyrazol-		MS m/z
4-yl)ethyl)-4,6-difluoropyrimidin-2-amine		336.0 (M + H)+;
		Rt-1.04 min

Intermediate 26: (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one

Imidazole (1.74 g, 25.6 mmol, 2.0 equiv) was added to a solution of (S)-4-(hydroxymethyl)oxazolidin-2-one (1.5 g, 12.8 mmol) and tert-butylchlorodiphenylsilane (3.95 mL, 15.4 mmol, 1.2 equiv) in DCM (43 mL) at room temperature. A white precipitate formed. The solution was stirred at room temperature for 16 hours and then diluted with water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 65%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (3.55 g, sticky colorless oil) in 78% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (m, 4H), 7.50-7.38 (m, 6H), 5.31 (m, 1H), 4.44 (t, J=8.7 Hz, 1H), 4.15 (m, 1H), 4.00 (m, 1H), 3.65 (d, J=5.5 Hz, 2H), 1.07 (s, 9H). MS m/z 356.1 (M+H)⁺; Rt-1.00 min.

Intermediate 27: (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Sodium hydride (34 mg, 0.84 mmol, 1.5 equiv) was carefully added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (200 mg, 0.563 mmol) in DMF (2.8 mL). The mixture was stirred at room temperature for 20 minutes and then 2,4-difluoropyrimidine (0.072 mL, 0.84 mmol, 1.5 equiv) was added (bubbling). The yellow suspension was stirred for 10 minutes and the reaction was then carefully quenched with saturated aqueous ammonium chloride (5 mL). Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (20 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 30%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.185 g, sticky colorless oil) in 73% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (dd, J=5.8, 2.2 Hz, 1H), 8.12 (dd, J=5.8, 3.4 Hz, 1H), 7.58 (m, 2H), 7.48-7.32 (m, 6H), 7.23 (m, 2H), 4.80 (m, 1H), 4.65 (dd, J=8.6, 3.0 Hz, 1H), 4.55 (m, 1H), 4.18 (dd, J=11.1, 3.5 Hz, 1H), 3.83 (dd, J=11.1, 2.1 Hz, 1H), 1.04 (s, 9H). MS m/z 452.3 (M+H)⁺; Rt-1.15 min.

Intermediate 28: (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one

A solution of tetrabutylammonium fluoride (1.0 M in THF, 0.44 mL, 0.44 mmol, 1.1 equiv) was added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (180 mg, 0.40 mmol) in THF (4 mL) at room temperature. The solution was stirred for 1 hour and then diluted with saturated aqueous sodium chloride (30 mL). The mixture was extracted with ethyl acetate (2×30 mL) and the combined extracts were dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (0.051 g, white solid) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (dd, J=5.8, 2.1 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.86 (dq, J=8.1, 4.0 Hz, 1H), 4.55 (m, 2H), 4.09 (m, 1H), 3.96 (m, 1H), 2.18 (t, J=5.4 Hz, 1H). MS m/z 214.0 (M+H)⁺; Rt-0.37 min.

Intermediate 29: (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Perfluorobutanesulfonyl fluoride (0.18 mL, 0.98 mmol, 4 equiv) was added to a solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (52 mg, 0.24 mmol) in THF (1.2 mL) at room temperature. Triethylamine trihydrofluoride (0.16 mL, 0.98 mmol, 4 equiv) and triethylamine (0.41 mL, 3.0 mmol, 12 equiv) were then added and the solution was stirred at 40° C. for 18 hours. The reaction was then cooled to room temperature and diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.021 g, colorless oil) in 40% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (dd, J=5.7, 2.1 Hz, 1H), 8.18 (dd, J=5.7, 3.7 Hz, 1H), 5.08-4.93 (m, 2H), 4.91-4.72 (m, 1H), 4.66-4.55 (m, 2H). MS m/z 215.9 (M+H)⁺; Rt-0.57 min.

Intermediate 30: (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Step 1

To a round bottom flask containing a stir bar and (2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid DCHA (10 g, 20.4 mmol) in THF (160 mL) under nitrogen was cooled to −30° C. in a dry ice/acetone bath. To this cold white suspension was added isobutyl chloroformate (3.2 mL, 24.5 mmol) followed by the addition of N-methylmorpholine (2.7 mL, 24.5 mmol). Mixture was stirred for 20 min at −30° C. A N-Methylmorpholine salt develops and was filtered from mixture. Mother liquor was cooled to −30° C. where upon sodium borohydride (1.16 g, 30.6 mmol) was added followed by the addition of water (20 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to afford benzyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol, 88% yield) as a colorless oil. LCMS m/z 296.1 (M+H)⁺, Rt 0.84 min.

Step 2

To a round bottom flask containing benzyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for 15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5 mL) was added. A hydrogen atmosphere was then inserted. Resulting reaction mixture allowed to stir 40 min at room temperature at atmospheric pressure when water (2 mL) was added and once again a hydrogen atmosphere was inserted at atmospheric pressure and the subsequent reaction mixture allowed to stir 18 hr at room temperature. The reaction mixture was filtered through a pad of celite and concentrated to a brown oil. Oil redissolved in toluene and concentrated to afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol, 87% yield) as a brown oil. LCMS m/z 162.1 (M+H)⁺, Rt 0.41 min (Mass ion only, no UV peak).

Step 3

To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4-difluoropyrimidine (0.99 g, 8.53 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2-fluoropyrimidin-4-yl)amino)butan-1-ol (1.5 g, 5.83 mmol, 75% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.14 (s, 9H) 1.31 (d, J=6.26 Hz, 3H) 3.64 (d, J=12.91 Hz, 2H) 3.86 (br. s., 1H) 4.26 (d, J=10.17 Hz, 1H) 6.09 (br. s., 1H) 6.25 (br. s., 1H) 7.99 (br. s., 1H). LCMS m/z 258.2 (M+H)⁺, Rt 0.62 min

Step 4

To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2-fluoropyrimidin-4-yl)amino)butan-1-ol (1.5 g, 5.83 mmol) and a stir bar under nitrogen was added DCM (58 mL). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (0.95 g, 3.21 mmol) followed by the addition of 2,6-dimethylpyridine (2.7 ml, 23.3 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred for 1 hr.

The reaction mixture was then diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (502 mg, 1.77 mmol, 30% yield) as a white crystalline. LCMS m/z 284.1 (M+H)⁺, Rt 0.89 min.

Step 5

To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (502 mg, 1.77 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO₃. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (382 mg, 1.68 mmol, 95% yield). LCMS m/z 228.1 (M+H)⁺, Rt 0.44 min.

Step 6

To a round bottom flask containing a solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (348 mg, 1.53 mmol) in THF (5.1 mL) was added perfluorobutanesulfonyl fluoride (0.83 mL, 4.60 mmol) followed by the addition of triethylamine trihydrofluoride (0.75 mL, 4.60 mmol) and triethylamine (1.9 mL, 13.8 mmol). The resulting reaction mixture allowed to stir at room temperature for 6 hr. The reaction mixture was diluted with water and the aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a viscous oil of (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (125 mg, 0.44 mmol, 28% yield) which crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.34 (dd, J=24.26, 6.65 Hz, 3H) 4.45-4.55 (m, 1H) 4.61-4.68 (m, 1H) 5.11 (dt, J=7.63, 4.01 Hz, 1H) 5.30-5.52 (m, 1H) 8.13-8.17 (m, 1H) 8.52 (d, J=5.87 Hz, 1H). LCMS m/z 230.0 (M+H)⁺, Rt 0.66 min.

Intermediate 31: (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one

Step 1

To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4,5-trifluoropyrimidine (1.04 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Reaction mixture was then partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol, 73% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.15 (s, 9H) 1.32 (d, J=6.26 Hz, 3H) 3.45 (br. s., 1H) 3.67 (d, J=11.35 Hz, 1H) 3.85-3.92 (m, 1H) 4.27 (d, J=11.74 Hz, 1H) 6.29 (d, J=5.48 Hz, 1H) 7.87 (d, J=2.35 Hz, 1H). LCMS m/z 276.4 (M+H)⁺, Rt 0.71 min.

Step 2

To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol) and a stir bar under nitrogen was added DCM (57 mL). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (0.93 g, 3.12 mmol) followed by the addition of 2,6-dimethylpyridine (2.64 ml, 22.7 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred 90 hr at room temperature. The reaction mixture was then diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (0.59 g, 1.96 mmol, 35% yield) as a white crystalline. ¹H NMR (400 MHz, CDCl₃) δ 1.03 (s, 9H) 1.16 (d, J=6.65 Hz, 3H) 4.15 (qd, J=6.39, 1.96 Hz, 1H) 4.43-4.52 (m, 1H) 4.59-4.72 (m, 2H) 8.43 (d, J=1.57 Hz, 1H). LCMS m/z 246.0 (-t-butyl fragment) (M+H)⁺, Rt 0.88 min.

Step 3

To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (590 mg, 1.96 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed. Residue neutralized with a saturated solution of NaHCO₃ and aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a colorless residue of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (470 mg, 1.917 mmol, 98% yield). LCMS m/z 246.0 (M+H)⁺, Rt 0.41 min.

Step 4

To a round bottom flask containing a solution of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (0.47 g, 1.917 mmol) in THF (6.4 mL) was added perfluorobutanesulfonyl fluoride (1.03 mL, 5.75 mmol) followed by the addition of triethylamine trihydrofluoride (0.94 mL, 5.75 mmol) and triethylamine (2.40 mL, 17.3 mmol) resulting reaction mixture allowed to stir at room temperature for 6 hr. The reaction mixture was diluted with water and the aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a white crystalline of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one (150 mg, 0.61 mmol, 32% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.37 (dd, J=24.26, 6.26 Hz, 3H) 4.48 (dd, J=9.39, 4.70 Hz, 1H) 4.63 (t, J=8.80 Hz, 1H) 4.90-5.02 (m, 1H) 5.02-5.25 (m, 1H) 8.50 (s, 1H). LCMS m/z 248.0 (M+H)⁺, Rt 0.59 min.

Intermediate 32

Step 1

To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 7.41 mmol) was added DCM (18.5 mL) and TFA (18.5 mL). The resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO₃. The aqueous mixture was then extracted with EtOAc. The organic phases were combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (1.52 g, 6.69 mmol, 90% yield) which crystallizes upon standing. LCMS m/z 228.0 (M+H)⁺, Rt 0.44 min.

Step 2

To a round bottom flask containing a solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (1.52 g, 6.69 mmol) in THF (22 mL) was added perfluorobutanesulfonyl fluoride (3.6 mL, 20.1 mmol) followed by the addition of triethylamine trihydrofluoride (3.3 mL, 20.1 mmol) and triethylamine (8.4 mL, 60.2 mmol). The resulting reaction mixture allowed to stir at room temperature for 2 hr. The reaction mixture was then diluted with water and the aqueous mixture was extracted with EtOAc. The organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a white crystalline of (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg, 0.90 mmol, 14% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.44 (dd, J=23.48, 6.26 Hz, 3H) 4.47-4.57 (m, 1H) 4.66 (dd, J=8.80, 3.33 Hz, 1H) 4.71-4.86 (m, 1H) 5.22-5.45 (m, 1H) 8.21 (dd, J=5.48, 3.91 Hz, 1H) 8.52 (dd, J=5.48, 1.96 Hz, 1H). LCMS m/z 230.1 (M+H)⁺, Rt 0.63 min.

Intermediate 33: 4-(2-fluoropropan-2-yl)oxazolidin-2-one

Step 1: Preparation of 2-amino-3-fluoro-3-methylbutan-1-ol

To the solution of LiBH₄ (2M in THF, 7.40 mL, 14.8 mmol) and trimethylchlorosilane (3.78 mL, 29.6 mmol) in THF (7 mL) was added 3-fluoro-D,L-valine (1 g, 7.40 mmol). The resulting mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with methanol and then concentrated under reduced pressure to give an oily product. The oily product was diluted with DCM and 10% aqueous sodium bicarbonate solution and then stirred at room temperature for ˜16 hr. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing 2-amino-3-fluoro-3-methylbutan-1-ol (350 mg) as a solid, which was used without further purification. MS m/z 121.9 (M+H)⁺; Rt-0.16 min.

Step 2: Preparation of 4-(2-fluoropropan-2-yl)oxazolidin-2-one

To a solution of N,N′-carbonyldiimidazole (530 mg, 3.27 mmol in THF (5 mL) was added slowly a solution of 2-amino-3-fluoro-3-methylbutan-1-ol (360 mg, 2.97 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 18 hr, was diluted with DCM and stirred for additional 30 min. The separated organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 12 g, EtOAc/heptane=0/100 to 80/20] to provide 4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 148.0 (M+H)⁺; Rt-0.32 min. ¹H NMR (400 Mhz, CDCl₃) δ ppm 6.30 (br. s., 1H), 4.39-4.54 (m, 1H), 4.26 (dd, J=8.9, 5.1 Hz, 1H), 3.84-3.99 (m, 1H), 1.29-1.45 (m, 6H).

Intermediate 34: 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one

To the solution of 2,4-dichloropyrimidine (150 mg, 1.006 mmol) and 4-(2-fluoropropan-2-yl)oxazolidin-2-one (148 mg, 1.01 mmol) in DMF (4.5 mL), sodium hydride (60% wt. 89 mg, 2.21 mmol) was added to give a pale yellow mixture. The mixture was stirred at room temperature for 2 hr, diluted with EtOAc and stirred for additional 30 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 12 g, EtOAc/heptane=0/100 to 80/20] providing 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 260.1 (M+H)⁺; Rt-0.72 min. ¹H NMR (400 Mhz, CDCl₃) δ ppm 8.51 (d, J=5.9 Hz, 1H), 8.17 (d, J=5.9 Hz, 1H), 5.14 (dd, J=17.4, 8.0 Hz, 1H), 4.66 (d, J=9.4 Hz, 1H), 4.43-4.52 (m, 1H), 1.42-1.52 (m, 3H), 1.30-1.40 (m, 3H).

Intermediate 35: (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

Step 1: Preparation of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate

Reference: V. L. Truong, et al.; Synlett 2005, 8, 1279-1280.

To a solution of Boc-Asp(OBnzl)-OH (20 g, 61.9 mmol) in DME (60 mL) at −40° C. (dry ice/acetonitrile bath) was added N-methylmorpholine (7.07 mL, 64.3 mmol) over 5 min followed by isobutyl chloroformate (8.53 ml, 64.9 mmol) dropwise over 15 min, keeping the temperature below −10° C. The mixture was stirred for 30 min (−30° C. to −40° C.). The solids were quickly filtered off and rinsed with DME (60 mL). The clear filtrate was cooled to −35° C. and a solution of NaBH₄ (2.93 g, 78 mmol) in 30 mL water was added dropwise maintaining a temperature between −30° C. and −15° C. [Caution: gas development]. Water (332 mL) was added dropwise over 30 min to the white suspension maintaining a temperature below −15° C. The thick white slurry was filtered, rinsed with water (300 mL). The filtered solid was dissolved in DCM (250 mL). The solution was dried over sodium sulfate, filtered off and concentrated under reduced pressure to provide (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.35 g) as a white solid. MS m/z 254.2 (M-tert-butyl)⁺; Rt-0.78 min. ¹H NMR (400 Mhz, D₃C(CO)CD₃) δ ppm 7.45-7.28 (m, 4H), 5.92-5.80 (m, 1H), 5.11 (s, 2H), 4.07-3.91 (m, 1H), 3.67-3.48 (m, 2H), 2.82-2.77 (m, 1H), 2.74-2.68 (m, 1H), 2.61-2.52 (m, 1H), 1.39 (s, 9H).

Step 2: Preparation of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate

Reference: V. L. Truong, et al.; Synlett 2005, 8, 1279-1280.

To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol) and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was added p-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5 min. The mixture was stirred for a few minutes, then allowed to warm to room temperature and stirred for 1 hr. The mixture was heated for 6 hr at 92° C. and then allowed to cool to room temperature. The mixture was diluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 220 g, EtOAc/heptane=5/95 to 75/25] to provide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a white solid. MS m/z 236.2 (M+H)⁺; Rt-0.59 min.

Step 3: Preparation of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate

To a solution of sodium bis(trimethylsilyl)amide (1 M in THF; 68.0 mL) under argon atmosphere was added THF (40.4 mL). The mixture was cooled to −78° C. and a solution of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (7.80 g, 33.2 mmol) in THF (85 mL) was added slowly over ˜15 min. The mixture was stirred for 1 hr at −78° C. and a solution of iodomethane (4.25 mL, 68.0 mmol) in THF (40.4 mL) was added slowly over ˜10 min. The reaction mixture was stirred for 1 hr at −78° C. and ˜1 hr at −40° C. The mixture was quenched with saturated aqueous ammonium chloride solution (˜100 mL) and allowed to warm to room temperature. The mixture was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 220 g, EtOAc/heptane] to provide (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (7.47 g) as a colorless oil. MS m/z 250.1 (M+H)⁺; Rt-0.65 min. ¹H NMR (400 Mhz, DMSO-d6) δ ppm 7.85 (s, 1H), 7.44-7.28 (m, 5H), 5.10 (s, 2H), 4.36 (t, J=1.0 Hz, 1H), 4.11 (dd, J=5.4, 8.9 Hz, 1H), 4.06-3.98 (m, 1H), 2.69 (quin, J=6.9 Hz, 1H), 1.08 (d, J=7.1 Hz, 3H).

Step 4: Preparation of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid

To a solution of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (1.99 g, 7.98 mmol) in THF (18.7 mL) was added Pd/C (10% wt., Degussa; 0.425 g). The mixture was stirred under hydrogen atmosphere (balloon) at room temperature for 4 hr. The mixture was filtered through a plug of celite and rinsed several times with THF. The filtrate was concentrated under reduced pressure providing (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.17 g) as a white solid, which was directly used without further purification. MS m/z 160.0 (M+H)⁺; Rt-0.26 min. ¹H NMR (400 Mhz, CD₃OD) δ ppm 4.53-4.47 (m, 1H), 4.26 (dd, J=5.7, 9.1 Hz, 1H), 4.13 (td, J=6.0, 8.8 Hz, 1H), 2.69-2.61 (m, 1H), 1.18 (d, J=7.2 Hz, 3H).

Step 5: Preparation of (R)-N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide

To a mixture of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.1 g, 6.91 mmol) in DCM (20 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.385 g, 10.37 mmol) at 0° C. The ice bath was removed and the mixture was stirred for 30 min at ambient temperature. A mixture of N,O-dimethylhydroxylamine (1.011 g, 10.37 mmol) and pyridine (1.677 mL, 20.74 mmol) in DCM (20 mL) was added and stirring was continued for ˜1 hr. The mixture was diluted with water (˜2 mL) and saturated sodium bicarbonate solution (˜2 mL) and stirred for ˜15 min. The mixture was diluted with dichloromethane (˜30 mL). The separated aqueous layer was extracted with DCM (1×), the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure providing crude (R)-N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (2.73 g) as an orange oil which was directly used without further purification. MS m/z 203.1 (M+H)⁺; Rt-0.36 min.

Step 6: Preparation of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide

To a mixture of crude (R)-N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (1.3 g, 6.43 mmol) and (bromomethyl)benzene (1.30 mL, 11.4 mmol) in THF (25 mL) was added slowly sodium hydride (60% wt.; 0.643 g) at 0° C. [Caution: gas development!]. The ice bath was removed and the mixture was stirred for ˜2 hr. The mixture were diluted carefully with water and ethyl acetate. The reaction was repeated on the same scale and the mixtures were combined. The aqueous layer was separated and extracted with ethyl acetate (1×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 80 g, EtOAc/heptane=5/95 to 75/25] to provide (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide (1.83 g) as a slightly yellow oil, which contained also N-methoxy-N-methylisobutyramide. MS m/z 293.7 (M+H)⁺; Rt-0.64 min.

Step 7: Preparation of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal

To a solution of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide from Step 6 (1.5 g, 5.13 mmol) in THF (30 mL) was added dropwise DIBAL-H (1M solution in hexane; 11.29 mL) at −78° C. The mixture was stirred for 90 min at −78° C., diluted slowly with Rochelle's salt solution (1 M solution in water; ˜20 mL) and stirred vigorously for ˜15 min. The aqueous layer was separated and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated sodium bicarbonate solution and brine, filtered through a mixture of celite/silica gel. The filtrate was concentrated under reduced pressure providing crude (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26 g) as a colorless oil, which was directly used without further purification. MS m/z 234.2 (M+H)⁺; Rt-0.60 min.

Step 8: Preparation of (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

To a solution of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26 g, 5.40 mmol) in DCM (13 mL) was added slowly DAST (2.85 mL, 21.6 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was carefully diluted with ice-water. The separated aqueous layer was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂; 80 g, ethylacetate/heptane] providing (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (627 mg) as a slightly yellowish oil. MS m/z 255.7/257.3 (M+H)⁺; Rt-0.80 min. ¹H NMR (400 Mhz, CD₃OD) δ ppm 7.31-7.43 (m, 5H), 5.86 (dt, J=1.0 Hz, 1H), 4.70 (d, J=15.3 Hz, 1H), 4.32 (d, J=7.4 Hz, 2H), 4.23 (d, J=15.7 Hz, 1H), 4.06 (td, J=7.4, 2.7 Hz, 1H), 2.40-2.59 (m, 1H), 0.98 (d, J=7.0 Hz, 3H).

Step 9: Preparation of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

To liquid ammonia at −50° C. under argon was slowly added a solution of (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (627 mg) (200 mg, 0.784 mmol) in diethylether (10 mL). Lithium (pellets; 54.4 mg, 7.84 mmol) were added in three portions. The reaction mixture became green then dark greenish blue over ˜10 min. The mixture was stirred for additional 15 min and then quenched slowly by the addition of saturated aqueous ammonium chloride solution (3 mL). The mixture was allowed to warm slowly to room temperature. The residue was diluted with diethylether (20 mL) and water (10 mL). The separated aqueous layer was extract with ether (2×25 mL) and DCM (3×20 mL). The DCM and ether layers were separately concentrated under reduced pressure. The residues were dissolved in DCM and combined. The organic layer was dried over magnesium sulfate, filtered off and concentrated under reduced pressure providing crude (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114 mg) as a colorless solid, which was directly used without further purification. MS m/z 166.1 (M+H)⁺; Rt-0.37 min.

Intermediate 36: (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (223 mg, 1.35 mmol) and 2,4-difluoropyrimidine (157 mg, 1.35 mmol) in DMF (4.09 mL) was added sodium hydride (60% wt.; 70.2 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 20 mL) and ethylacetate (20 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 12 g, EtOAc/heptane] to provide (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg) as a white solid.

MS m/z 262.1 (M+H)⁺; Rt-0.72 min. ¹H NMR (400 Mhz, CD₃OD) δ ppm 8.55 (dd, J=2.3, 5.8 Hz, 1H), 8.17 (dd, J=3.8, 5.8 Hz, 1H), 6.02 (q, J=1.0 Hz, 1H), 5.17 (td, J=3.1, 8.3 Hz, 1H), 4.62-4.52 (m, 2H), 3.11-2.88 (m, 1H), 1.05 (dd, J=0.7, 7.2 Hz, 3H).

Intermediate 37: (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114 mg, 069 mmol) and 2,4-dichloro-5-fluoropyrimidine (115 mg, 0.690 mmol) in DMF (2.26 mL) was added sodium hydride (60% wt.; 35.9 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 10 mL) and ethylacetate (10 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 12 g, EtOAc/heptane] to provide (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (134 mg) as a white solid. MS m/z 296.1 (M+H)⁺; Rt-0.75 min. ¹H NMR (400 Mhz, CD₃OD) δ ppm 8.69 (d, J=2.6 Hz, 1H), 5.99 (q, J=1.0 Hz, 1H), 5.17 (ddd, J=3.5, 7.4, 8.6 Hz, 1H), 4.69-4.50 (m, 2H), 2.88-2.70 (m, 1H), 1.04 (d, J=7.1 Hz, 3H).

Intermediate 38: 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole

Sodium azide (635 mg, 9.760 mmol) and a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane was added to a solution of 2-(1-chloroethyl)-5-(4-chlorophenyl)-4-methyloxazole (250 mg, 0.976 mmol) in acetonitrile (10 ml) and refluxed at 80° C. for 3 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 0-5% EtOAc/DCM provided the title compound (254 mg, clear oil). HRMS (C) tR=1.52 min; MS m/z 262.0621

Intermediate 39: 1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethanamine

SiliaBond®Diphenylphosphine (1500 mg, 1.19 mmol/g) was added to a solution of 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole (366 mg, 1.393 mmol) in anhydrous methanol (15 ml) and shaken for 3 hours. The reaction was filtered and concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded 160 mg (white solid). HRMS (B) tR=1.73 min; MS m/z 236.0716

Intermediate 40: (2S)-N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide

A solution of 2-amino-1-(4-chlorophenyl)ethanol (1000 mg, 5.83 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (1280 mg, 5.83 mmol) in THF (20 ml) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 1322 mg, 6.41 mmol) and allowed to stir at ambient temperature for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Used crude directly in the next step. 2 g of white solid. HRMS (B) tR=1.04 min; MS m/z 373.1

Intermediate 41: (S)-N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide

1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.091 g, 7.29 mmol) was added to a solution of (2S)-N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.173 g, 5.83 mmol) in dichloromethane (20 ml) and allowed to stir for 2 hours. Dilute w/dichloromethane (50 ml), wash w/a sol'n of sat. sodium bicarbonate and 10% Na₂S₂O₃ solution, dry, concentrate in vacuo. 2.162 g (Used directly in the next step without further purification. HRMS (B) tR=1.24 min; MS m/z 371.2

Intermediate 42: (S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione

Phosphoryl trichloride (1.m7 ml, 10.8 mmol) was added to a solution of (S)-N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.162 g, 5.83 mmol) in toluene and heated at 110° C. for 15 hours. Dilute with dichloromethane (50 ml), wash with saturated sodium bicarbonate solution, water, brine, dried and concentrated in vacuo. Flash column chromatography (silica, 80 g) eluting with 0-50% EtOAc/DCM afforded the pure product 430 mg (yellow foam). HRMS (B) tR=1.42 min; MS m/z 353.1

Intermediate 43: (S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione

To a stirred solution of (Z)-3-chloro-N′-hydroxybenzimidamide (500 mg, 2.93 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (642 mg, 2.93 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 665 mg, 3.22 mmol) and allowed to reflux at 100° C. for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 300 mg. HRMS m/z 353.0567

Intermediate 44: (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine

Hydrazine (0.55 ml, 6.09 mmol) was added to a solution of (S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione (430 mg, 1.219 mmol) in ethanol (15 ml) and heated at 80° C. for 13 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded the desired product (200 mg, yellow oil). ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.51 (m, 9H), 7.47-7.35 (m, 8H), 7.31-7.21 (m, 1H), 4.25 (q, J=6.8 Hz, 4H), 1.97-1.66 (m, 15H), 1.63-1.48 (m, 2H). HRMS (B) tR=1.49 min; MS m/z 222.0560

Intermediate 45: (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide

To a solution of 3-chloror-4-(trifluoromethoxy)benzonitrile (1.0 g, 4.51 mmol) and hydroxylamine hydrochloride (1.5 eq, 0.47 g, 6.77 mmol) in ethanol (10 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.6 eq, 1.26 ml, 7.22 mmol) and refluxed at 80° C. for 12 hours under N₂. Allow to cool to rt. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), dry, concentrate in vacuo afforded (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (0.71 g, 62.1%, white solid). Used crude in the next step. HRMS (B) m/z 254.0070

The intermediates in Table 2a were prepared using a method similar to that described for the preparation of Intermediate 45

TABLE 2a
Intermediate 46
Intermediate 47
Intermediate 48
Intermediate 49
Intermediate 50
Intermediate 51
Intermediate 52
Intermediate 53
Intermediate 54
Intermediate 55
Intermediate 56
Intermediate 57
Intermediate 58
Intermediate 59
Intermediate 60
Intermediate 61
Intermediate 62
Intermediate 63
Intermediate 64

TABLE 2b
Chemical name and analytical data for each intermediate listed in Table 2a.
Intermediate: Name               Analytical data
46: (Z)-4-bromo-N′-hydroxy-3-    HRMS (B) tR = 1.24 min; MS m/z
methoxybenzimidamide             243.9847.
47: (Z)-4-chloro-N′-hydroxy-3-   HRMS (B) tR = 1.35 min; MS m/z
methylbenzimidamide              184.0403
48: (Z)-N′-hydroxy-1,2-dimethyl-1H-indole-4- HRMS (B) tR = 1.13 min; MS m/z
carboximidamide                  203.1059
49: (Z)-N′-hydroxy-2-            HRMS (B) tR = 1.20 min; MS m/z
(trifluoromethoxy)benzimidamide  220.0460
50: (Z)-2,2-difluoro-N′-hydroxybenzo[d][1,3]dioxole- HRMS (B) tR = 1.33 min; MS m/z
5-carboximidamide                216.0347
51: (Z)-N′-hydroxy-3-(2,2,2-     HRMS (B) tR = 1.46 min; MS m/z
trifluoroethoxy)benzimidamide    234.061
52: (Z)-4-chloro-N′-hydroxy-3-(trifluoromethoxy) HRMS (B) tR = 1.44 min; MS m/z
benzimidamide                    254.0070
53: (Z)-N′-hydroxyisoquinoline-8-carboximidamide Anal. RP-HPLC tR = 0.93 min (Gradient:
                                 1 to 30% B in 3.2 min to 98% in 1.95 min.-
                                 flow 1 mL/min. Eluent A: Water + 3.75 mM
                                 H4Ac + 0.001% formic acid.
                                 Eluent B: ACN. Column: Acquity CSH
                                 1.7 μm 2.1 × 50 mm-50° C.) MS m/z
                                 187.0746
54: (Z)-4-chloro-N′-hydroxy-2-(trifluoromethyl) HRMS (B) tR = 1.35 min; MS m/z
benzimidamide                    238.0121
55: (Z)-N′-hydroxy-3-            HRMS (B) tR = 1.36 min; MS m/z
(trifluoromethyl)benzimidamide   204.0510
56: (Z)-N′-hydroxy-4-            HRMS (B) tR = 1.69 min; MS m/z
(trifluoromethoxy)benzimidamide  220.0460
57: (Z)-4-fluoro-N′-hydroxy-3-(trifluoromethoxy) HRMS (B) tR = 1.55 min; MS m/z
benzimidamide                    238.0365
58: (Z)-3-(difluoromethoxy)-N′-  HRMS (B) tR = 1.05 min; MS m/z
hydroxybenzimidamide             202.0554
59: (Z)-4-chloro-N′-hydroxy-3-   HRMS (B) tR = 1.14 min; MS m/z
methoxybenzimidamide             200.0352
60: (Z)-4-chloro-N′-hydroxy-3-(trifluoromethyl) HRMS (B) tR = 1.19 min; MS m/z
benzimidamide                    239.3000 (M + H)
61: (Z)-3-(tert-butyl)-N′-hydroxybenzimidamide HRMS (B) tR = 1.51 min; MS m/z
                                 193.1342 (M + H)
62: (Z)-N′-hydroxy-1-methyl-1H-indole-6- HRMS (B) tR = 1.03 min; MS m/z
carboximidamide                  190.0883 (M + H)
63: (Z)-N′-hydroxy-2,3-dihydro-1H-indene-5- HRMS (B) tR = 1.30 min; MS m/z
carboximidamide                  176.0950
64: 4-chloro-N′-hydroxybenzimidamide MS m/z 171.0 (M + H)+; Rt-0.35 min.

Intermediate 65: (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate

A solution of 4-chloro-N′-hydroxybenzimidamide (1.24 g, 7.27 mmol), (S)-2-(tert-butoxycarbonylamino)propanoic acid (1.38 g, 7.27 mmol, 1.0 equiv), and DCC (1.65 g, 8.00 mmol, 1.1 equiv) in 1,4-dioxane (73 mL) was heated at 100° C. for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 35%) provided (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (1.13 g, white solid) in 48% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 5.18 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).

Intermediate 66: (S)-tert-butyl (1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate

To a stirred solution of (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (500 mg, 1.964 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (372 mg, 1.964 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 446 mg, 2.160 mmol) and allowed to reflux at 100° C. for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica, 80 g) eluting w/0-5% EtOAc/DCM afforded 230 mg. HRMS m/z 407.0860

The intermediates in Table 3a were prepared using a method similar to that described for the preparation of Intermediate 66

TABLE 3a
Inter- me- diate 67
Inter- me- diate 68
Inter- me- diate 69
Inter- me- diate 70
Inter- me- diate 71
Inter- me- diate 72
Inter- me- diate 73
Inter- me- diate 74
Inter- me- diate 75
Inter- me- diate 76
Inter- me- diate 77
Inter- me- diate 78
Inter- me- diate 79
Inter- me- diate 80
Inter- me- diate 81
Inter- me- diate 82
Inter- me- diate 83
Inter- me- diate 84
Inter- me- diate 85

TABLE 3b
Chemical name and analytical data for each intermediate listed in Table 3a.
Intermediate: Name               Analytical data
67: (S)-tert-butyl (1-(3-(4-bromo-3-methoxyphenyl)-1,2,4- HRMS (C) tR = 1.20 min;
oxadiazol-5-yl)ethyl)carbamate   MS m/z 397.0637
68: (S)-tert-butyl (1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5- HRMS (C) tR = 1.42 min;
yl)ethyl)carbamate               MS m/z 337.1193
69: (S)-tert-butyl (1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol- HRMS (C) tR = 1.12 min;
5-yl)ethyl)carbamate             MS m/z 356.1848
70: (S)-tert-butyl (1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.12 min;
5-yl)ethyl)carbamate             MS m/z 373.1249
71: (S)-tert-butyl(1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4- HRMS (C) tR = 1.41 min;
oxadiazol-5-yl)ethyl)carbamate   MS m/z 369.1136
72: (S)-tert-butyl(1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4- HRMS (C) tR = 1.33 min;
oxadiazol-5-yl)ethyl)carbamate   MS m/z 387.1406
73: (S)-tert-butyl (1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5- HRMS (C) tR = 0.71 min;
yl)ethyl)carbamate               MS m/z 340.1535
74: (S)-tert-butyl(1-(3-(4-chloro-2-(trifluoromethyl)phenyl)-1,2,4- HRMS (C) tR = 1.35 min;
oxadiazol-5-yl)ethyl)carbamate   MS m/z 392.1055
75: (S)-tert-butyl (1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.41 min;
5-yl)ethyl)carbamate             MS m/z 357.1300
76: (S)-tert-butyl(1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4- HRMS (C) tR = 1.42 min;
oxadiazol-5-yl)ethyl)carbamate   MS m/z 392.1302
77: (S)-tert-butyl (1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.59 min;
5-yl)ethyl)carbamate             MS m/z 357.1300
78: (S)-tert-butyl (1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.38 min;
5-yl)ethyl)carbamate             MS m/z 374.1378 (M + H)
79: (S)-tert-butyl (1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.69 min;
5-yl)ethyl)carbamate             MS m/z 373.1249
80: (S)-tert-butyl (1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.12 min;
5-yl)ethyl)carbamate             MS m/z 355.1344
81: (S)-tert-butyl (1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.14 min;
5-yl)ethyl)carbamate             MS m/z 353.1142
82: (S)-tert-butyl(1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4- HRMS (C) tR = 1.52 min;
oxadiazol-5-yl)ethyl)carbamate   MS m/z 391.0911
83: (S)-tert-butyl (1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS (C) tR = 1.03 min;
yl)ethyl)carbamate               MS m/z 342.1692
84: (S)-tert-butyl (1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5- HRMS (C) tR = 1.62 min;
yl)ethyl)carbamate               MS m/z 345.2052
85: (S)-tert-butyl (1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol- HRMS (C) tR = 1.50 min;
5-yl)ethyl)carbamate             MS m/z 329.1740

Intermediate 86: (S)-tert-butyl (1-(5-bromopyridin-2-yl)ethyl)carbamate

To a solution of (S)-1-(5-bromopyridin-2-yl)ethanamine (300 mg, 1.49 mmol) in DCM (7.5 mL) was added di-tert-butyl dicarbonate (358 mg, 1.64 mmol) and triethylamine (0.31 mL, 2.24 mmol). The solution was stirred for 16 h at room temperature then washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided a white solid (308 mg, 68.5% yield).

¹H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.2 Hz, 1H), 7.76 (dd, J=8.3, 2.4 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 5.57-5.42 (m, 1H), 4.86-4.73 (m, 1H), 1.43 (t, J=3.4 Hz, 12H); MS m/z 303.4 (M+H).

The intermediates in Table 4a were prepared using a method similar to that described for the preparation of Intermediate 86

TABLE 4a
Intermediate 87
Intermediate 88
Intermediate 89
Intermediate 90
Intermediate 91

TABLE 4b
Chemical name and analytical data for each intermediate listed in Table 4a.
Intermediate: Name               Analytical data
87: (S)-tert-butyl (1-(6-bromopyridin-3- 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.6 Hz,
yl)ethyl)carbamate               1H), 7.49 (dd, J = 8.2, 2.5 Hz,
                                 1H), 7.44 (d, J = 8.3 Hz, 1H),
                                 4.88-4.69 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H), 1.41 (s,
                                 9H); MS m/z 303.4 (M + H).
88: (S)-tert-butyl (1-(5-bromo-4-methylpyridin-2- LCMS tR = 1.31 min; MS m/z 317.0
yl)ethyl)carbamate               (M + H)
89: (S)-tert-butyl (1-(5-bromo-6-methylpyridin-2- LCMS tR = 1.35 min; MS m/z 317.1
yl)ethyl)carbamate               (M + H)
90: (S)-tert-butyl (1-(5-bromo-3-fluoropyridin-2- LCMS tR = 1.31 min; MS m/z 319.0
yl)ethyl)carbamate               (M + H)
91: (S)-tert-butyl (1-(5-bromo-3-methylpyridin-2- LCMS tR = 1.37 min; MS m/z 317.0
yl)ethyl)carbamate               (M + H)

Intermediate 92: (S)-tert-butyl (1-(5-(4-fluoro-3-methyl phenyl)pyridin-2-yl)ethyl)carbamate

In a 5 mL microwave vial a solution of (S)-tert-butyl (1-(5-bromopyridin-2-yl)ethyl)carbamate (60 mg, 0.2 mmol), (4-fluoro-3-methylphenyl)boronic acid (37 mg, 0.24 mmol), Sodium bicarbonate (0.2 mL, 0.4 mmol, 2 M aqueous solution) in Dioxane (2 mL) was bubbled N2 for 3 min then Cl₂Pd(dppf)CH₂Cl₂ (16 mg, 0.02 mmol) was added. The capped tube was heated to 100° C. for 16 h. After cooling the reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude material was purified through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (66 mg, 80% yield). LCMS tR=1.43 min; MS m/z 331.1 (M+H).

The intermediates in Table 5a were prepared using a method similar to that described for the preparation of Intermediate 92

TABLE 5a
Intermediate 93
Intermediate 94
Intermediate 95
Intermediate 96
Intermediate 97
Intermediate 98
Intermediate 99
Intermediate 100
Intermediate 101
Intermediate 102
Intermediate 103
Intermediate 104
Intermediate 105

TABLE 5b
Chemical name and analytical data for each intermediate listed in Table 5a.
Intermediate: Name               Analytical data
93: (S)-tert-butyl (1-(5-(3-     LCMS tR = 1.69 min; MS m/z 365.5 (M − H).
(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)carbamate
94: (S)-tert-butyl (1-(6-(4-fluoro-3- LCMS tR = 1.62 min; MS m/z 329.5 (M − H).
methylphenyl)pyridin-3-yl)ethyl)carbamate
95: (S)-tert-butyl (1-(6-(3-     LCMS tR = 1.68 min; MS m/z 365.4 (M − H).
(trifluoromethyl)phenyl)pyridin-3-yl)ethyl)carbamate
96: (S)-tert-butyl (1-(2′-(trifluoromethyl)-[3,4′- 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J = 3.9 Hz,
bipyridin]-6-yl)ethyl)carbamate  2H), 7.92 (dd, J = 8.3, 2.5 Hz,
                                 1H), 7.87 (d, J = 1.7 Hz, 1H),
                                 7.73-7.66 (m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.59 (d,
                                 J = 7.6 Hz, 1H), 4.93 (p, J = 6.9 Hz, 1H),
                                 1.50 (d, J = 7.0 Hz, 3H), 1.45 (s, 9H); MS
                                 m/z 368.2 (M + H).
97: (S)-tert-butyl (1-(6′-(trifluoromethyl)-[2,3′- 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 2.1 Hz,
bipyridin]-5-yl)ethyl)carbamate  1H), 8.71 (s, 1H), 8.49 (dd, J = 8.3,
                                 2.1 Hz, 1H), 7.80-7.75 (m, 3H),
                                 4.90 (br s, 1H), 1.52 (d, J = 6.3 Hz, 3H),
                                 1.43 (s, 9H); MS m/z 368.2 (M + H).
98: (S)-tert-butyl (1-(6′-(trifluoromethyl)-[3,3′- 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.1 Hz,
bipyridin]-6-yl)ethyl)carbamate  1H), 8.79 (d, J = 2.3 Hz, 1H),
                                 8.04 (dd, J = 8.2, 2.3 Hz, 1H), 7.88 (dd, J = 8.1,
                                 2.4 Hz, 1H), 7.80 (d, J = 8.2 Hz,
                                 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.60 (d, J = 7.8 Hz,
                                 1H), 4.93 (p, J = 6.9 Hz, 1H),
                                 1.50 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H); MS
                                 m/z 368.2 (M + H).
99: (S)-tert-butyl (1-(6-(trifluoromethyl)-[2,3′- 1H NMR (400 MHz, CDCl3) δ 9.15 (d, J = 2.3 Hz,
bipyridin]-6′-yl)ethyl)carbamate 1H), 8.36 (dd, J = 7.8, 2.4 Hz,
                                 1H), 8.01-7.89 (m, 2H), 7.66 (dd, J = 7.5,
                                 1.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H),
                                 5.69 (d, J = 7.9 Hz, 1H), 4.92 (p, J = 6.9 Hz,
                                 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.45 (s,
                                 9H); MS m/z 368.2 (M + H).
100: (S)-tert-butyl (1-(4-methyl-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz,
[3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 8.36 (s, 1H), 7.66 (s, 1H),
                                 7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d,
                                 J = 7.7 Hz, 1H), 4.87 (p, J = 6.9 Hz, 1H),
                                 2.30 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H),
                                 1.45 (s, 9H); MS m/z 326.4 (M + H − 56).
101: (S)-tert-butyl (1-(2-methyl-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 5.0 Hz,
[3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 7.66 (s, 1H), 7.50 (d, J = 7.9 Hz,
                                 1H), 7.47 (dd, J = 4.9, 1.6 Hz, 1H),
                                 7.20 (d, J = 7.8 Hz, 1H), 5.75 (d, J = 7.5 Hz,
                                 1H), 4.86 (p, J = 6.9 Hz, 1H), 2.51 (s,
                                 3H), 1.48 (d, J = 6.9 Hz, 3H), 1.46 (s,
                                 9H); MS m/z 326.4 (M + H − 56).
102: (S)-tert-butyl (1-(5-fluoro-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 5.1 Hz,
[3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 8.66 (s, 1H), 7.87-7.84 (m,
                                 1H), 7.70-7.67 (m, 1H), 7.65 (dd, J = 9.8,
                                 1.9 Hz, 1H), 5.76 (d, J = 7.7 Hz, 1H),
                                 5.31-5.23 (m, 1H), 1.47 (d, J = 6.8 Hz,
                                 3H), 1.45 (s, 9H); MS m/z 386.1 (M + H).
103: (S)-tert-butyl (1-(5-methyl-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 5.1 Hz,
[3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 8.68 (d, J = 2.2 Hz, 1H),
                                 7.88-7.85 (m, 1H), 7.71 (d, J = 1.7 Hz,
                                 1H), 7.68 (dd, J = 5.0, 1.7 Hz, 1H),
                                 5.99 (d, J = 8.2 Hz, 1H), 5.13 (p, J = 6.7 Hz,
                                 1H), 2.48 (s, 3H), 1.45 (s, 9H), 1.42 (d, J = 6.6 Hz,
                                 3H); MS m/z 382.2 (M + H).
104: 1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2- 1H NMR (400 MHz, CDCl3) δ 9.30 (d, J = 1.5 Hz,
yl)ethanone                      1H), 9.11 (d, J = 1.5 Hz, 1H),
                                 8.39 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H),
                                 7.78 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H),
                                 2.76 (s, 3H).); MS m/z 266.9 (M + H).
105: 1-(5-(4-fluoro-3-methylphenyl)pyrazin-2- 1H NMR (400 MHz, CDCl3) δ 9.24 (d, J = 1.5 Hz,
yl)ethanone                      1H), 9.01 (d, J = 1.5 Hz, 1H),
                                 7.97 (dd, J = 7.3, 1.9 Hz, 1H), 7.89 (ddd,
                                 J = 7.6, 4.8, 2.3 Hz, 1H), 7.17 (t, J = 8.9 Hz,
                                 1H), 2.74 (s, 3H), 2.39 (d, J = 2.0 Hz,
                                 3H); MS m/z 230.9 (M + H).

The following intermediates were prepared using a method similar to that described for the preparation of Intermediate 92

Intermediate 106: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-MS)-1-(2′-(tert-butyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.67 min; MS m/z 519.3 (M+H).

Intermediate 107: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(1,1,1-trifluoro-2-methylpropan-2-yl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.2 Hz, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.90 (dd, J=8.1, 2.3 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=5.8 Hz, 1H), 7.47-7.41 (m, 2H), 5.34 (p, J=6.9 Hz, 1H), 4.81-4.72 (m, 1H), 4.64 (dd, J=9.3, 2.9 Hz, 1H), 4.45 (p, J=6.3 Hz, 1H), 4.36 (t, J=9.0 Hz, 1H), 1.69 (s, 6H), 1.63 (d, J=6.9 Hz, 3H), 1.26 (s, 9H), 1.04 (d, J=6.4 Hz, 3H); MS m/z 573.3 (M+H).

Intermediate 108: (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid

To a solution of (S)-4-(1-aminoethyl)-2-fluorobenzoic acid (5 g, 22.76 mmol) in water (66 mL) and THF (66 mL) was added di-tert-butyl dicarbonate (6.95 g, 31.9 mmol) and sodium carbonate (5.74 g, 68.3 mmol). The solution was stirred for 16 h at room temperature then THF was removed under reduced pressure. The aqueous solution was acidified with 1N HCl to pH 3-4 and extracted with EtOAc (3×60 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give a white solid (1.94 g, 30.1% yield). The crude product was used to next step without further purification.

¹H NMR (400 MHz, MeOD) δ 7.89 (t, J=7.8 Hz, 1H), 7.20 (dd, J=8.2, 1.7 Hz, 1H), 7.13 (dd, J=12.0, 1.6 Hz, 1H), 4.70 (d, J=7.1 Hz, 1H), 1.47-1.35 (m, 12H); MS m/z 282.0 (M−H).

Intermediate 109: (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate

A solution of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (1.416 g, 5 mmol), N,O-dimethylhydroxylamine hydrochloride (732 mg, 7.5 mmol), HATU (2.85 g, 7.5 mmol) and DIPEA (3.49 mL, 20 mmol) in DMF (25 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water. After separation, the aqueous phase was washed with EtOAc (2×75 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate as a white solid (1.5 g, 92% yield).

¹H NMR (400 MHz, CDCl3) δ 7.40 (t, J=7.4 Hz, 1H), 7.13 (dd, J=7.8, 1.6 Hz, 1H), 7.04 (dd, J=10.7, 1.6 Hz, 1H), 4.80 (br s, 1H), 3.56 (s, 3H), 3.34 (s, 3H), 1.50-1.29 (m, 12H); MS m/z 327.1 (M+H).

Intermediate 110: (S)-tert-butyl 1-(3-fluoro-4-formyl phenyl)ethylcarbamate

To a cooled (0° C.) Solution of (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g, 3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18 mL, 18 mmol) and the resulting mixture was stirred at 0° C. for 20 min. The reaction mixture was quenched by addition of a saturated Na2SO4 solution until gas evolution ceased. The reaction mixture was extracted with EtOAc (2×100 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (760 mg, 79% yield).

¹H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.87-7.80 (m, 1H), 7.20 (dd, J=8.2, 1.3 Hz, 1H), 7.11 (dd, J=11.5, 1.4 Hz, 1H), 4.80 (br s, 1H), 1.45 (br s, 12H); MS m/z 212.1 (M-56+H).

Intermediate 111: (S)-tert-butyl 1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate

A solution of (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate (267 mg, 1 mmol) and 1,2,2-trimethylpiperazine dihydrochloride (402 mg, 2 mmol) in THF (5 mL) was stirred at room temperature for 1 h and treated with sodium triacetoxyborohydride (848 mg, 4 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 (15 mL) and extracted with EtOAc (3×25 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH/CH₂Cl₂ 0 to 10%) provided (S)-tert-butyl 1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate as a white solid (186 mg, 49% yield).

¹H NMR (400 MHz, CDCl3) δ 7.35 (t, J=7.7 Hz, 1H), 7.03 (dd, J=7.9, 1.9 Hz, 1H), 6.95 (dd, J=11.1, 1.8 Hz, 1H), 4.77 (s, 1H), 3.49 (s, 2H), 2.56 (br s, 4H), 2.24 (br s, 5H), 1.42 (br s, 12H), 1.04 (s, 6H); MS m/z 380.4 (M+H).

Intermediate 112: (S)-tert-butyl 1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)ethylcarbamate

Following the procedure for intermediate 111: Title compound was prepared from (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate and 4,4-difluoropiperidine hydrochloride as a white solid. LCMS tR=1.63 min; MS m/z 371.5 (M−H).

Intermediate 113: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone

A cloudy solution of 1-(5-bromopyrimidin-2-yl)ethanone (300 mg, 1.49 mmol), 3-(trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K₃PO₄ (950 mg, 4.48 mmol), DavePhos ligand [2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl] (59 mg, 0.15 mmol), and Pd(OAc)₂ (17 mg, 0.075 mmol) in 6 mL toluene was heated at 100° C. for 1 h. The mixture was cooled to room temperature, and filtered through Celite. Filter cake was rinsed with 30 mL EtOAc. The filtrate was poured into 20 mL water. Layers were separated, and the aqueous was further extracted with EtOAc (20 mL). Combined organics were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentrated directly onto silica gel. Column chromatography (10-100% EtOAc/heptane) gave 0.26 g 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone as tan solid. MS m/z 267.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 2H), 7.93-7.69 (m, 4H), 2.87 (s, 3H).

The intermediates in Table 6a were prepared using a method similar to that described for the preparation of Intermediate 113

TABLE 6a
Intermediate 114
Intermediate 115
Intermediate 116
Intermediate 117
Intermediate 118
Intermediate 119
Intermediate 120
Intermediate 121
Intermediate 122
Intermediate 123
Intermediate 124

TABLE 6b
Chemical name and analytical data for each intermediate listed in Table 6a, using
Anal. RP-HPLC Column = Inertsil C8 Column, 3.0 μm, 3.0 × 30 mm.
Column Temperature = 50° C. Eluents = A: Water (5 mM Ammonium formate,
2% ACN); B: ACN. Flow Rate = 2 mL/min. Gradient = 0 min 5% B; 5% to 95% B in
1.70 min; 0.3 min 95% B; 2.1 min 1% B.)
Intermediate: Name               Analytical data
114: 1-(5-(3,4-dichlorophenyl) pyrimidin-2- Anal. RP-HPLC tR = 1.17 min. MS m/z 266.9
yl)ethanone.                     (M + H)+.
115: 1-(5-(4-fluoro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.26 min. MS m/z 285.2
pyrimidin-2-yl)ethanone.         (M + H)+.
116: 1-(5-(4-chloro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.33 min. MS m/z 301.3
pyrimidin-2-yl)ethanone.         (M + H)+.
117:: 1-(5-(5-fluoro-2-methylphenyl) Anal. RP-HPLC tR = 1.16 min. MS m/z 231.2
pyrimidin-2-yl)ethanone          (M + H)+.
118: 1-(5-(4-fluoro-3-methylphenyl) pyrimidin- 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 2H),
2-yl)ethanone.                   7.52-7.41 (m, 2H), 7.24-7.16 (m, 1H),
                                 2.85 (s, 3H), 2.41 (d, J = 2.0 Hz, 3H). Anal. RP-
                                 HPLC tR = 1.20 min. MS m/z 231.0 (M + H)+.
119: 1-(5-(2,3-dichlorophenyl) pyrimidin-2- Anal. RP-HPLC tR = 1.15 min. MS m/z 267.9
yl)ethanone                      (M + H)+.
120: 1-(5-(4-fluoro-3-methylphenyl) pyridin-2- 1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J = 2.3,
yl)ethanone.                     0.8 Hz, 1H), 8.13 (dd, J = 8.1, 0.8 Hz, 1H),
                                 7.98 (dd, J = 8.1, 2.3 Hz, 1H), 7.50-7.39 (m,
                                 2H), 7.21-7.12 (m, 1H), 2.78 (s, 3H),
                                 2.42-2.36 (m, 3H). Anal. RP-HPLC tR = 1.40 min.
                                 MS m/z 230.8 (M + H)+.
121: 1-(5-(2-fluoro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.19 min. MS m/z 285.0
pyrimidin-2-yl)ethanone.         (M + H)+.
122: 1-(5-(4-chloro-3-methylphenyl) Anal. RP-HPLC tR = 1.30 min. MS m/z 247.2
pyrimidin-2-yl)ethanone.         (M + H)+.
123: 1-(5-(3-chloro-5-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.27 min. MS m/z 301.0
pyrimidin-2-yl)ethanone.         (M + H)+.
124: 1-(5-(4-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.22 min. MS m/z 266.8
pyrimidin-2-yl)ethanone.         (M + H)+.

Intermediate 125: (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine

2,2,2-Trifluoroacetic acid (4 mL, 52 mmol) was added to a solution of (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (0.613 g, 1.89 mmol) in DCM (10 mL) at room temperature. The solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (500 mg, yellow oil). The material was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 4.37 (q, J=6.9 Hz, 1H), 1.62 (d, J=6.9 Hz, 3H). MS m/z 224.0 (M+H)⁺; Rt-0.56 min.

Intermediate 126: (S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine

(S)-tert-butyl (1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (2.0 g, 4.90 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 1.4 g waxy off-white solid. HRMS m/z 307.0335

Intermediate 127: (S)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine

To a stirred solution of (S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione (100 mg, 0.283 mmol) in ethanol (5 ml) was added methylhydrazine (16 μL, 0.311 mmol). Stir for 13 hours at 80° C. Concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting with dichloromethane afforded 50 mg of desired product. HRMS m/z 224.4 (M+H)

The intermediates in Table 7a were prepared using a method similar to that described for the preparation of Intermediate 126 or Intermediate 127

TABLE 7a
Intermediate 128
Intermediate 129
Intermediate 130
Intermediate 131
Intermediate 132
Intermediate 133
Intermediate 134
Intermediate 135
Intermediate 136
Intermediate 137
Intermediate 138
Intermediate 139
Intermediate 140
Intermediate 141
Intermediate 142
Intermediate 143
Intermediate 144
Intermediate 145
Intermediate 146
Intermediate 147
Intermediate 148

TABLE 7b
Chemical name and analytical data for each intermediate listed in Table 7a.
Intermediate: Name               Analytical data
128: (S)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.88 min;
yl)ethanamine                    m/z 297.0113
129: (S)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.05 min;
yl)ethanamine                    m/z 237.0669
130: (S)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.38 min;
yl)ethanamine                    m/z 256.1324
131: (S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.92 min;
yl)ethanamine                    m/z 273.0725
132: (S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol- HRMS (B) tR = 2.04 min;
5-yl)ethanamine                  m/z 269.0612
133: (S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.02 min;
yl)ethanamine                    m/z 287.0882
134: (S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS (B) tR = 0.68 min;
                                 m/z 240.1011
135: (S)-1-(3-(4-chloro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (B) tR = 2.08 min;
5-yl)ethanamine                  m/z 291.0386
136: (S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.02 min;
yl)ethanamine                    m/z 257.0776
137: (S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.01 min;
yl)ethanamine                    m/z 257.0776
138: (S)-1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.20 min;
yl)ethanamine                    m/z 274.0 (M + H)
139: (S)-1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.09 min;
yl)ethanamine                    m/z 273.0725
140: (S)-1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (B) tR = 2.16 min;
5-yl)ethanamine                  m/z 291.0631
141: (S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS (B) tR = 0.71 min;
                                 m/z 240.1011
142: (S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.67 min;
yl)ethanamine                    m/z 242.1168
143: (S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.74 min;
yl)ethanamine                    m/z 255.0819
144: (S)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.82 min;
yl)ethanamine                    m/z 253.0618
145: (S)-1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (B) tR = 2.26 min;
5-yl)ethanamine                  m/z 291.0386
146: (S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.67 min;
yl)ethanamine                    m/z 242.1168
147: (S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS (B) tR = 2.33 min;
                                 m/z 246.1552
148: (S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.02 min;
yl)ethanamine                    m/z 229.1215

Intermediate 149: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine

1-(5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (260 mg, 0.977 mmol), NH4OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) were taken up in 8 mL 200 proof EtOH, and heated at 120° C. for 5 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na₂SO₄. Filtered and concentrated with reduced pressure to give 262 mg crude yellow oil, which was carried forward without further purification. Anal. RP-HPLC tR=0.90 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient ═O min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.1 (M+H)⁺.

The intermediates in Table 8a were prepared using a method similar to that described for the preparation of Intermediate 149

TABLE 8a
Intermediate 150
Intermediate 151
Intermediate 152
Intermediate 153
Intermediate 154
Intermediate 155
Intermediate 156
Intermediate 157
Intermediate 158
Intermediate 159
Intermediate 160
Intermediate 161
Intermediate 162

TABLE 8b
Chemical name and analytical data for each intermediate listed in Table 8a.
Intermediate: Name               Analytical data
150: 1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethanamine. Anal. RP-HPLC tR = 1.09 min; MS
                                 m/z 268.4 (M + H)+.
151: 1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.04 min. MS
yl)ethanamine.                   m/z 286.3 (M + H)+.
152: 1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.06 min. MS
yl)ethanamine.                   m/z 302.3 (M + H)+.
153: 1-(5-(5-fluoro-2-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.79 min. MS
yl)ethanamine                    m/z 232.0 (M + H)+.
154: 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.81 min. MS
yl)ethanamine                    m/z 231.9 (M + H)+.
155: 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine Anal. RP-HPLC tR = 1.01 min. MS
                                 m/z 269.0 (M + H)+.
156: 1-(5-(4-fluoro-3-methylphenyl)pyridin-2- Anal. RP-HPLC tR = 0.92 min. MS
yl)ethanamine                    m/z 230.9 (M + H)+.
157: 1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.96 min. MS
yl)ethanamine.                   m/z 286.0 (M + H)+.
158: 1-(5-(4-chloro-3-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.97 min. MS
yl)ethanamine.                   m/z 247.9 (M + H)+.
159: 1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.06 min. MS
yl)ethanamine.                   m/z 301.9 (M + H)+.
160: 1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.02 min. MS
yl)ethanamine.                   m/z 268.2 (M + H)+.
161: 1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2- LCMS tR = 1.04 min; MS m/z
yl)ethanamine                    267.9 (M + H)+.
162: 1-(5-(4-fluoro-3-methylphenyl)pyrazin-2- LCMS tR = 0.91 min; MS m/z
yl)ethanamine                    231.9 (M + H)+.

Intermediate 163: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine

Step 1: A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, and dried over Na₂SO₄. Mixture was filtered and concentrated on silica gel. Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%) 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid used directly in the following step. MS m/z 233.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).

Step 2: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH₃CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na₂SO₄. Filtered and concentrated with reduced pressure to give 275 mg crude tan oil, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.26 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.1 (M+H)⁺

Intermediate 164: 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine

Step 1: In a well vented vial, 90% t-butyl nitrite (4.74 mL, 35.8 mmol) and CuCl (2.96 g, 29.9 mmol) were taken up in 30 mL ACN. Over 15 mins, 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine (6.0 g, 19.9 mmol) was added in portions. Gas evolved. The mixture was stirred 30 min at r.t., then warmed to 65 C for another 30 min. The reaction mixture was filtered through Celite. 200 mL Water was added to the filtrate. This was extracted with (2×150 mL) EtOAc. Organics were washed with 200 mL brine, and dried over Na2SO4. Filtered and concentrated on silica gel. Flash column chromatography (10-50% EA/hept) gave 3.35 g (52%) 2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole as a green oil. MS m/z 321.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=5.1, 0.8 Hz, 1H), 7.52 (dq, J=1.7, 0.8 Hz, 1H), 7.31-7.22 (m, 1H), 2.55 (s, 3H), 1.67 (s, 6H).

Step 2: To a solution of 2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole (3.3 g, 10.3 mmol) and Pd(PPh3)2Cl2 (0.72 g, 1.03 mmol) in 50 mL dioxane under nitrogen, tributyl(1-ethoxyvinyl)stannane (3.82 ml, 11.32 mmol) was added. The mixture was heated to 100 C for 16 h. The reaction was cooled to r.t. and diluted with 25 mL EtOAc. 2M KF (15.4 ml) solution was added and stirred for 1 h. Copious precipitate formed. The reaction was filtered through Celite and chased with EtOAc. The organic layer was rinsed with 60 mL water, and concentrated to give grey solid. Crude solid was dissolved in THF (50 mL) and 1N HCl (20.58 mL) was added. The reaction was stirred at r.t. for 2 h. The mixture was neutralized by addition of 1 N NaOH. THF was removed in vacuo. Extracted aqueous with 2×50 mL EtOAc. The organic layers were washed with 50 mL brine, and dried over Na2SO4. Filtered and concentrated on silica gel. Flash chromatography using 10-50% EtOAc in heptane gave 1.65 g (49%) 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone as a yellow oil. MS m/z 329.0 (M+H)+. ¹H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=5.2, 0.9 Hz, 1H), 7.60 (dq, J=1.8, 0.9 Hz, 1H), 7.34 (dd, J=5.1, 1.6 Hz, 1H), 2.74 (s, 3H), 2.63 (s, 3H), 1.69 (s, 6H).

Step 3: 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone ethanone (1.6 g, 4.87 mmol), NH4OAc (5.6 g, 73.1 mmol), and NaBH3CN (1.2 g, 19.5 mmol) were taken up in 40 mL 200 proof EtOH, and heated at 130 C for 10 minutes in a sealed tube. The mixture was concentrated to remove the EtOH. Crude was taken up in 50 ml water+50 mL EtOAc. 6N NaOH was added until aqueous pH was −9. Separated layers, and extracted aqueous with EtOAc (50 ml). The combined organic layer was washed with 60 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 1.58 g crude tan oil. This material was taken up in 20 mL dioxane. 2.2 eq HCl (4N in dioxane) was added, and stirred 1 h. Yellow ppt was formed. The suspension was concentrated in vacuo to give 1.97 g 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine dihydrochloride salt as a yellow-green solid, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.23 min. MS m/z 330.1 (M+H)⁺.

Intermediate 165: 4-((S)-1-Amino-ethyl)piperidine-1-carboxylic acid benzyl ester

Benzyl 4-((1S)-1-(1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate (1.825 g, 4.98 mmole) was dissolved in dioxane (10 mL) and 4N HCl in dioxane (5 mL, 1.3 eq.) was added. The mixture was stirred for 3 hours at room temperature. The solvents were removed by rotary evaporation to give the title compound as a hydrochloride salt (1.3 g). ¹H NMR (400 MHz, CD2Cl2) δ 8.46 (s, 2H), 7.44-7.27 (m, 5H), 5.11 (s, 2H), 4.26 (d, J=13.57 Hz, 2H), 3.24-3.12 (m, 1H), 2.86-2.61 (m, 2H), 1.99-1.86 (m, 3H), 1.38 (d, J=6.33 Hz, 3H), 1.34-1.23 (m, 2H). HRMS (C) tR=1.87 min; MS m/z 263.1760 (M+H)+

Intermediate 166: (S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethanamine

To a solution of (S)-tert-butyl (1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)carbamate (66 mg, 0.47 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 hr at room temperature. The resin was removed by filtration and washed (2×5 mL) with DCM. The filtrate was concentrated and the crude residue was used to next step without further purification. LCMS tR=0.97 min; MS m/z 231.1 (M+H).

The intermediates in Table 9a were prepared using a method similar to that described for the preparation of Intermediate 166

TABLE 9a
Intermediate 167
Intermediate 168
Intermediate 169
Intermediate 170
Intermediate 171
Intermediate 172
Intermediate 173
Intermediate 174
Intermediate 175
Intermediate 176
Intermediate 177
Intermediate 178
Intermediate 179

TABLE 9b
Chemical name and analytical data for each intermediate listed in Table 9a.
Intermediate: Name               Analytical data
167: (S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethanamine LCMS tR = 1.12 min; MS
                                 m/z 267.7 (M + H).
168: (S)-1-(6-(4-fluoro-3-methylphenyl)pyridin-3-yl)ethanamine LCMS tR = 1.05 min; MS
                                 m/z 231.4 (M + H).
169: (S)-1-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)ethanamine LCMS tR = 1.14 min; MS
                                 m/z 267.4 (M + H).
170: (S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine LCMS tR = 0.79 min; MS
                                 m/z 268.1 (M + H).
171: (S)-1-(6′-(trifluoromethyl)-[2,3′-bipyridin]-5-yl)ethanamine LCMS tR = 0.81 min; MS
                                 m/z 268.1 (M + H).
172: (S)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)ethanamine LCMS tR = 0.81 min; MS
                                 m/z 268.1 (M + H).
173: (S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethanamine LCMS tR = 0.89 min; MS
                                 m/z 268.1 (M + H).
174: (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.85 min; MS
yl)ethanamine                    m/z 282.1 (M + H).
175: (S)-1-(2-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.86 min; MS
yl)ethanamine                    m/z 282.1 (M + H).
176: (S)-1-(5-fluoro-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.88 min; MS
yl)ethanamine                    m/z 286.1 (M + H).
177: (S)-1-(5-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.89 min; MS
yl)ethanamine                    m/z 282.1 (M + H).
178: (S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1- LCMS tR = 0.29 min; MS
yl)methyl)phenyl)ethanamine      m/z 280.2 (M + H).
179: (S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3- LCMS tR = 0.29 min; MS
fluorophenyl)ethanamine          m/z 273.2 (M + H).

Intermediate 180: (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate

A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 4.92 mmol) and hydrazine (0.23 mL, 1.5 equiv) in THF (8 mL) was heated in a sealed tube at 72° C. for 15 hours. Additional hydrazine (0.23 mL, 1.5 equiv) was added and heating was continued for another 21 hours. The reaction was then cooled to room temperature and concentrated in vacuo to give crude (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (1 g, white solid), which was used without purification. ¹H NMR (400 MHz, CDCl₃) δ 4.20 (m, 1H), 1.44 (s, 9H), 1.36 (d, J=7.1 Hz, 3H).

Intermediate 181: (S)-tert-butyl (1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate

4-Chlorobenzoyl chloride (0.63 mL, 4.92 mmol, 1.0 equiv) was added to a solution of (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (1.0 g, 4.92 mmol) in DCM (25 mL) at 0° C. A white precipitate formed. The mixture was stirred at 0° C. for 1 hour and the reaction mixture was then concentrated in vacuo to give crude (S)-tert-butyl (1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.55 g), which was used without purification. ¹H NMR (400 MHz, CD₃OD) δ 7.85 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 4.21 (q, J=7.0 Hz, 1H), 1.45 (s, 9H), 1.41 (d, J=7.2 Hz, 3H). MS m/z 342.1 (M+H)⁺; Rt-0.69 min.

Intermediate 182

(S)-tert-butyl (1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate

A solution of (S)-tert-butyl (1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.0 g, 2.93 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (1.18 g, 2.93 mmol, 1.0 equiv) in THF (29 mL) was heated at reflux for 2 hours. The reaction wash then cooled to room temperature and filtered through a pad of celite, using THF to wash through. The filtrate was concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 30%) provided (S)-tert-butyl (1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (0.600 g, light green solid) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 5.23 (m, 1H), 1.72 (d, J=6.5 Hz, 3H), 1.48 (s, 9H). MS m/z 340.1 (M+H)⁺; Rt-0.99 min.

Intermediate 183

(S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine

A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 4 mL, 16 mmol, 9 equiv) was added to a solution of (S)-tert-butyl (1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (600 mg, 1.77 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution was stirred for 3 hours, by which time a white precipitate had formed. The reaction was concentrated in vacuo to give the hydrochloride salt of (S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine (480 mg, white solid) in 97% yield. The material was used without purification. ¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 5.10 (q, J=6.9 Hz, 1H), 1.82 (d, J=6.9 Hz, 3H). MS m/z 240.0 (M+H)⁺; Rt-0.54 min.

Intermediate 184: (S)-tert-butyl but-3-yn-2-ylcarbamate

A solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (500 mg, 2.89 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (610 mg, 3.18 mmol, 1.1 equiv), and potassium carbonate (638 mg, 4.62 mmol, 1.6 equiv) in methanol (14.4 mL) was stirred at room temperature for 18 hours. The reaction was then diluted with ethyl acetate (30 mL) and saturated aqueous sodium chloride (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic extracts were dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (20% EtOAc in Heptane) provided (S)-tert-butyl but-3-yn-2-ylcarbamate (0.258 g, white solid) in 53% yield. ¹H NMR (400 MHz, CDCl₃) δ 4.49 (m, 1H), 2.26 (d, J=2.2 Hz, 1H), 1.46 (s, 9H), 1.41 (d, J=6.8 Hz, 3H).

Intermediate 185: (S)-tert-butyl (1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate

A solution of (S)-tert-butyl but-3-yn-2-ylcarbamate (250 mg, 1.48 mmol), 1-azido-4-chlorobenzene (227 mg, 1.48 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.77 mL, 4.43 mmol, 3.0 equiv) in anhydrous acetonitrile (14.8 mL) was stirred at room temperature for 10 min. Copper(I) iodide (563 mg, 2.95 mmol, 2.0 equiv) was then added in portions. The mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-tert-butyl (1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (0.428 g, white solid) in 90% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.02 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.46 (s, 9H). MS m/z 323.1 (M+H)⁺; Rt-0.92 min.

Intermediate 186: (S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine

A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 3.3 mL, 13.2 mmol, 10 equiv) was added to a solution of (S)-tert-butyl (1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (425 mg, 1.32 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution was stirred for 1 hour, by which time a white precipitate had formed. The reaction was concentrated in vacuo to give the hydrochloride salt of (S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine (338 mg, white solid) in 99% yield. The material was used without purification. ¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 4.77 (q, J=6.9 Hz, 1H), 1.78 (d, J=6.9 Hz, 3H). MS m/z 223.1 (M+H)⁺; Rt-0.50 min.

Intermediate 187: 2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde

A mixture of 2-bromothiazole-5-carbaldehyde (400 mg, 2.08 mmol), (6-methylpyridin-3-yl)boronic acid (428 mg, 3.12 mmol, 1.5 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (170 mg, 0.21 mmol, 0.1 equiv) and 2.0 M aqueous sodium carbonate (5.2 mL, 10.4 mmol, 5 equiv) in 1,2-dimethoxyethane (6.9 mL) was heated in a microwave reactor at 110° C. for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc) provided 2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde (0.176 g, brown solid) in 41% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.19 (dd, J=8.1, 2.4 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 2.66 (s, 3H). MS m/z 205.0 (M+H)⁺; Rt-0.36 min.

The intermediates in Table 10a were prepared using a method similar to that described for the preparation of Intermediate 187

TABLE 10a
Intermediate 188
Intermediate 189
Intermediate 190

TABLE 10b
Chemical name, NMR chemical shifts and LCMS signal for each intermediate
listed in Table 10a.
	1H NMR (400 MHz, CDCl3) δ
Intermediate: Name	ppm	LCMS
188: 2-(6-methylpyridin-3-yl)thiazole-5-	10.08 (s, 1H), 9.15 (d, J = 2.0 Hz,	MS m/z
carbaldehyde	1H), 8.47 (s, 1H), 8.19 (dd,	205.0 (M + H)+;
	J = 8.1, 2.4 Hz, 1H), 7.31 (d, J = 8.3 Hz,	Rt-0.36 min
	1H), 2.66 (s, 3H).
189: 2-(6-(trifluoromethyl)pyridin-3-	10.13 (s, 1H), 9.37 (d, J = 1.6 Hz,	MS m/z
yl)thiazole-5-carbaldehyde	1H), 8.55 (s, 1H), 8.50 (dd,	259.0 (M + H)+;
	J = 8.2, 2.0 Hz, 1H), 7.85 (d, J = 8.2 Hz,	Rt-0.74 min
	1H)
190: 2-(2-(trifluoromethyl)pyridin-4-	10.14 (s, 1H), 8.91 (d, J = 5.0 Hz,	MS m/z
yl)thiazole-5-carbaldehyde	1H), 8.57 (d, J = 0.6 Hz,	259.0 (M + H)+;
	1H), 8.30 (s, 1H), 8.06 (d, J = 5.1 Hz,	Rt-0.76 min
	1H)

Intermediate 191: 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole

A solution of ethane-1,2-diol (0.081 mL, 1.45 mmol, 1.5 equiv), 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (200 mg, 0.968 mmol), and camphorsulfonic acid (45 mg, 0.19 mmol, 0.2 equiv) in toluene (10 mL) was heated at reflux with a Dean-Stark apparatus for 1 hour. The reaction was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (0.100 g, tan solid) in 41% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.96 (s, 1H), 4.20 (m, 2H), 4.05 (m, 2H). MS m/z 251.0 (M+H)⁺; Rt-0.53 min.

Intermediate 192: 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole

A solution of n-butyllithium (1.6 M in hexane, 0.37 mL, 0.60 mmol, 1.5 equiv) was added to a solution of N,N-diisopropylamine (0.085 mL, 0.60 mmol, 1.5 equiv) in THF (1.5 mL) at −78° C. The solution was stirred at −78° C. for 10 min and then a solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (100 mg, 0.40 mmol) in THF (1 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min, and then iodomethane (0.042 mL, 0.68 mmol, 1.7 equiv) was added. The solution was allowed to warm to room temperature and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic extract was washed with saturated aqueous sodium chloride (15 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo to give crude 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole. The material was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.09 (s, 1H), 5.88 (s, 1H), 4.20 (m, 2H), 4.03 (m, 2H), 2.35 (s, 3H). MS m/z 265.0 (M+H)⁺; Rt-0.57 min.

Intermediate 193: 1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde

A solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole (1.05 g, 3.97 mmol) and camphorsulfonic acid (92 mg, 0.40 mmol, 0.1 equiv) in THF (26.5 mL) and water (13.3 mL) was heated at 60° C. for 1 hour. The reaction was then cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated aqueous sodium chloride (50 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde (0.600 g, tan solid) in 69% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.89 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 2.40 (s, 3H). MS m/z 221.0 (M+H)⁺; Rt-0.47 min.

Intermediate 194: 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde

A mixture of 1H-pyrazole-3-carbaldehyde (0.700 g, 7.29 mmol), 5-bromo-2-(trifluoromethyl)pyridine (2.31 g, 10.2 mmol, 1.4 equiv), cesium carbonate (4.75 g, 14.6 mmol, 2.0 equiv), copper(I) iodide (0.069 g, 0.36 mmol, 0.05 equiv), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.23 mL, 1.46 mmol, 0.2 equiv) in DMF (9.5 mL) was heated in a sealed reaction vessel at 110° C. for 16 hours. The reaction was then cooled to room temperature and saturated aqueous ammonium chloride (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc/heptane) provided 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (0.470 g, brown solid) in 27% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 9.18 (d, J=2.1 Hz, 1H), 8.34 (dd, J=8.7, 2.0 Hz, 1H), 8.12 (m, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H). MS m/z 241.9 (M+H)⁺; Rt-0.78 min.

Intermediate 195: (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

A suspension of 5-(4-chlorophenyl)isoxazole-3-carbaldehyde (2.00 g, 9.63 mmol), (R)-2-methylpropane-2-sulfinamide (1.28 g, 10.6 mmol, 1.1 equiv) and anhydrous copper(II) sulfate (2.31 g, 14.5 mmol, 1.5 equiv) in 1,2-dichloroethane (19 mL) was heated at 55° C. for 2-18 hours. The reaction was then cooled to room temperature and filtered through a pad of celite, using 1,2-dichloroethane to wash through. The filtrate was concentrated in vacuo to give crude (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide as a green solid, which was used without further purification. MS m/z 311.0 (M+H)⁺; Rt-1.11 min.

The intermediates in Table 11a were prepared using a method similar to that described for the preparation of Intermediate 195

TABLE 11a
Intermediate 196
Intermediate 197
Intermediate 198
Intermediate 199
Intermediate 200
Intermediate 201
Intermediate 202
Intermediate 203
Intermediate 204
Intermediate 205
Intermediate 206
Intermediate 207
Intermediate 208
Intermediate 209
Intermediate 210
Intermediate 211
Intermediate 212
Intermediate 213
Intermediate 214

TABLE 11b
Chemical name and analytical data for each intermediate listed in Table 11a.
Intermediate: Name               Analytical data
196: (R,E)-N-((5-(4-chlorophenyl)isoxazol-3- MS m/z 311.0 (M + H)+; Rt-1.11 min
yl)methylene)-2-methylpropane-2-sulfinamide
197: (R,E)-N-((2-(4-chlorophenyl)thiazol-5- MS m/z 327.1 (M + H)+; Rt-1.13 min
yl)methylene)-2-methylpropane-2-sulfinamide
198: (R,E)-2-methyl-N-((5-phenylthiophen-2- MS m/z 292.0 (M + H)+; Rt-1.05 min
yl)methylene)propane-2-sulfinamide
199: (R,E)-2-methyl-N-((5-phenylisoxazol-3- MS m/z 277.1 (M + H)+; Rt-1.02 min
yl)methylene)propane-2-sulfinamide
200: (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-4- MS m/z 310.1 (M + H)+; Rt-1.00 min
yl)methylene)-2-methylpropane-2-sulfinamide
201: (R,E)-N-((5-(4-fluorophenyl)isoxazol-3- MS m/z 295.1 (M + H)+; Rt-1.00 min
yl)methylene)-2-methylpropane-2-sulfinamide
202: (R,E)-N-((1-(4-fluorophenyl)-1H-pyrazol-4- MS m/z 294.1 (M + H)+; Rt-0.90 min
yl)methylene)-2-methylpropane-2-sulfinamide
203: (R,E)-2-methyl-N-((5-(pyridin-2-yl)thiophen-2- MS m/z 293.1 (M + H)+; Rt-0.85 min
yl)methylene)propane-2-sulfinamide
204: (R,E)-2-methyl-N-((5-       MS m/z 300.1 (M + H)+; Rt-0.43 min
(morpholinomethyl)isoxazol-3-
yl)methylene)propane-2-sulfinamide
205: (R,E)-2-methyl-N-((2-morpholinothiazol-5- MS m/z 302.1 (M + H)+; Rt-0.69 min
yl)methylene)propane-2-sulfinamide
206: (R,E)-2-methyl-N-((2-(pyridin-2-yl)thiazol-5- MS m/z 294.2 (M + H)+; Rt-0.92 min
yl)methylene)propane-2-sulfinamide
207: (R,E)-2-methyl-N-((2-(pyridin-3-yl)thiazol-5- MS m/z 294.1 (M + H)+; Rt-0.63 min
yl)methylene)propane-2-sulfinamide
208: (R,E)-2-methyl-N-((2-(pyridin-4-yl)thiazol-5- MS m/z 294.1 (M + H)+; Rt-0.55 min
yl)methylene)propane-2-sulfinamide
209: (R,E)-N-((2-(4-(difluoromethyl)phenyl)thiazol- MS m/z 342.9 (M + H)+; Rt-0.86 min
5-yl)methylene)-2-methylpropane-2-sulfinamide
210: (R,E)-2-methyl-N-((2-(6-methylpyridin-3- MS m/z 308.1 (M + H)+; Rt-0.58 min
yl)thiazol-5-yl)methylene)propane-2-sulfinamide
211: (R,E)-2-methyl-N-((2-(6-    MS m/z 362.1 (M + H)+; Rt-0.96 min
(trifluoromethyl)pyridin-3-yl)thiazol-5-
yl)methylene)propane-2-sulfinamide
212: (R,E)-2-methyl-N-((2-(2-    MS m/z 362.1 (M + H)+; Rt-0.97 min
(trifluoromethyl)pyridin-4-yl)thiazol-5-
yl)methylene)propane-2-sulfinamide
213: (R,E)-2-methyl-N-((1-(6-    MS m/z 345.0 (M + H)+; Rt-0.95 min
(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-
yl)methylene)propane-2-sulfinamide
214: (R,E)-N-((1-(4-chlorophenyl)-2-methyl-1H- MS m/z 324.0 (M + H)+; Rt-0.62 min
imidazol-4-yl)methylene)-2-methylpropane-2-
sulfinamide

Intermediate 215: (R)-N-((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A solution of methylmagnesium bromide (3.0 M in diethyl ether, 12.8 mL, 38.4 mmol, 4 equiv) was added to a solution of (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.98 g, 9.6 mmol) in DCM (96 mL) at 0° C. The solution became orange, then faded to yellow. The reaction was stirred at 0° C. for 30 min and then carefully quenched with saturated aqueous ammonium chloride (100 mL). The layers were separated and the aqueous layer was extracted with DCM (40 mL). The combined organic layers were washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-N-((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, white solid) in 32% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 6.50 (s, 1H), 4.75 (m, 1H), 3.47 (m, 1H), 1.70 (d, J=6.8 Hz, 3H), 1.25 (s, 9H). MS m/z 327.0 (M+H)⁺; Rt-0.94 min.

The intermediates in Table 12a were prepared using a method similar to that described for the preparation of Intermediate 215.

TABLE 12a
Intermediate 216
Intermediate 217
Intermediate 218
Intermediate 219
Intermediate 220
Intermediate 221
Intermediate 222
Intermediate 223
Intermediate 224
Intermediate 225
Intermediate 226
Intermediate 227
Intermediate 228
Intermediate 229
Intermediate 230
Intermediate 231
Intermediate 232
Intermediate 233
Intermediate 234
Intermediate 235

TABLE 12b
Chemical name, NMR chemical shifts and LCMS signal for each intermediate
listed in Table 12a.
	1H NMR (400 MHz, CDCl3) δ
Intermediate: Name	ppm	LCMS
216: (R)-N-((S)-1-(5-(4-	7.71 (d, J = 8.6 Hz, 2H),	MS m/z
chlorophenyl)isoxazol-3-yl)ethyl)-2-	7.45 (d, J = 8.6 Hz, 2H), 6.50 (s, 1H),	327.0 (M + H)+;
methylpropane-2-sulfinamide	4.75 (m, 1H), 3.47 (m, 1H),	Rt-0.94 min
	1.70 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H).
217: (R)-N-((S)-1-(2-(4-chlorophenyl)thiazol-	CD3OD: 7.88 (d, J = 8.7 Hz,	MS m/z
5-yl)ethyl)-2-methylpropane-2-sulfinamide	2H), 7.73 (d, J = 1.0 Hz, 1H),	343.1 (M + H)+;
	7.47 (d, J = 8.7 Hz, 2H),	Rt-0.97 min
	4.83 (m, 1H), 1.71 (d, J = 6.7 Hz,
	3H), 1.25 (s, 9H)
218: (R)-2-methyl-N-((S)-1-(5-	7.58 (d, J = 7.4 Hz, 2H),	MS m/z
phenylthiophen-2-yl)ethyl)propane-2-	7.37 (m, 2H), 7.27 (m, 1H), 7.16 (d, J = 3.7 Hz,	308.1 (M + H)+;
sulfinamide	1H), 6.95 (d, J = 3.7 Hz,	Rt-0.95 min
	1H), 4.84 (m, 1H), 3.42 (m,
	1H), 1.70 (d, J = 6.6 Hz, 3H),
	1.26 (s, 9H)
219: (R)-2-methyl-N-((S)-1-(5-		MS m/z
phenylisoxazol-3-yl)ethyl)propane-2-		293.2 (M + H)+;
sulfinamide		Rt-0.85 min
220: (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-	7.84 (s, 1H), 7.63 (s, 1H),	MS m/z
pyrazol-4-yl)ethyl)-2-methylpropane-2-	7.61 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz,	326.1 (M + H)+;
sulfinamide	2H), 4.64 (m, 1H),	Rt-0.89 min
	3.31 (m, 1H), 1.62 (d, J = 6.7 Hz,
	3H), 1.24 (s, 9H)
221: (R)-N-((S)-1-(5-(4-	7.77 (dd, J = 8.9, 5.2 Hz, 2H),	MS m/z
fluorophenyl)isoxazol-3-yl)ethyl)-2-	7.16 (t, J = 8.7 Hz, 2H), 6.46 (s,	311.1 (M + H)+;
methylpropane-2-sulfinamide	1H), 4.77 (m, 1H), 3.47 (d, J = 5.7 Hz,	Rt-0.85 min
	1H), 1.70 (d, J = 6.8 Hz,
	3H), 1.25 (s, 9H)
222: (R)-N-((S)-1-(1-(4-fluorophenyl)-1H-	7.80 (s, 1H), 7.63 (m, 3H),	MS m/z
pyrazol-4-yl)ethyl)-2-methylpropane-2-	7.14 (t, J = 8.5 Hz, 2H), 4.63 (m, 1H),	310.1 (M + H)+;
sulfinamide	3.31 (d, J = 5.0 Hz, 1H),	Rt-0.79 min
	1.62 (d, J = 6.7 Hz, 3H), 1.24 (s, 9H)
223: (R)-2-methyl-N-((S)-1-(5-(pyridin-2-	8.53-8.59 (m, 1 H),	MS m/z
yl)thiophen-2-yl)ethyl)propane-2-sulfinamide	7.60-7.73 (m, 2 H), 7.43 (d, J = 3.7 Hz, 1	309.1 (M + H)+;
	H), 7.15 (ddd, J = 7.1, 5.0, 1.2 Hz,	Rt-0.58 min
	1 H),
	6.99 (d, J = 3.8 Hz, 1 H), 4.84 (quin,
	J = 6.3 Hz, 1 H), 3.43 (d, J = 5.5 Hz,
	1 H), 1.70 (d, J = 6.6 Hz, 3
	H), 1.26 (s, 9 H)
224: (R)-2-methyl-N-((S)-1-(5-		MS m/z
(morpholinomethyl)isoxazol-3-		316.1 (M + H)+;
yl)ethyl)propane-2-sulfinamide		Rt-0.38 min
225: (R)-2-methyl-N-((S)-1-(2-	7.06 (s, 1H), 4.69 (quin, J = 6.1 Hz,
morpholinothiazol-5-yl)ethyl)propane-2-	1H), 3.81 (m, 4H), 3.44 (m,
sulfinamide	4H), 3.32 (d, J = 4.9 Hz, 1H),
	1.60 (d, J = 6.6 Hz, 3H),
	1.22 (s, 9H)
226: (R)-2-methyl-N-((S)-1-(2-(pyridin-2-	8.60 (m, 1H), 8.15 (m, 1H),	MS m/z
yl)thiazol-5-yl)ethyl)propane-2-sulfinamide	7.80 (m, 2H), 7.33 (m, 1H), 4.93 (m,	310.0 (M + H)+;
	1H), 1.71 (d, J = 6.6 Hz, 3H),	Rt-0.69 min
	1.25 (s, 9H)
227: (R)-2-methyl-N-((S)-1-(2-(pyridin-3-	9.11 (m, 1H), 8.65 (m, 1H),	MS m/z
yl)thiazol-5-yl)ethyl)propane-2-sulfinamide	8.23 (m, 1H), 7.75 (m, 1H), 7.38 (m,	310.0 (M + H)+;
	1H), 4.90 (m, 1H), 3.50 (m, 1H),	Rt-0.50 min
	1.71 (d, J = 6.6 Hz, 3H),
	1.24 (s, 9H)
228: (R)-2-methyl-N-((S)-1-(2-(pyridin-4-	8.70 (m, 2H), 7.79 (m, 3H),	MS m/z
yl)thiazol-5-yl)ethyl)propane-2-sulfinamide	4.94 (m, 1H), 1.72 (d, J = 6.6 Hz, 3H)	310.2 (M + H)+;
		Rt-0.46 min
229: (R)-N-((S)-1-(2-(4-	8.01 (d, J = 8.0 Hz, 2H),	MS m/z
(difluoromethyl)phenyl)thiazol-5-yl)ethyl)-2-	7.74 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H),	359.1 (M + H)+;
methylpropane-2-sulfinamide	6.69 (t, J = 56 Hz, 1H), 4.91 (m,	Rt-0.89 min
	1H), 3.45 (d, J = 4.7 Hz, 1H),
	1.72 (d, J = 6.6 Hz, 3H),
	1.25 (s, 9H)
230: (R)-2-methyl-N-((S)-1-(2-(6-	9.01 (d, J = 2.2 Hz, 1H),	MS m/z
methylpyridin-3-yl)thiazol-5-	8.10 (dd, J = 8.1, 2.3 Hz, 1H),	324.1 (M + H)+;
yl)ethyl)propane-2-sulfinamide	7.73 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H),	Rt-0.49 min
	4.91 (m, 1H), 3.46 (d, J = 4.8 Hz,
	1H), 2.62 (s, 3H), 1.72 (d, J = 6.6 Hz,
	3H), 1.25 (s, 9H)
231: (R)-2-methyl-N-((S)-1-(2-(6-	9.23 (s, 1H), 8.40 (d, J = 8.3 Hz,	MS m/z
(trifluoromethyl)pyridin-3-yl)thiazol-5-	1H), 7.82 (s, 1H), 7.78 (d, J = 8.3 Hz,	378.1 (M + H)+;
yl)ethyl)propane-2-sulfinamide	1H), 4.95 (m, 1H),	Rt-0.84 min
	3.49 (d, J = 4.1 Hz, 1H),
	1.74 (d, J = 6.6 Hz, 3H), 1.26 (s, 9H)
232: (R)-2-methyl-N-((S)-1-(2-(2-	8.82 (d, J = 5.0 Hz, 1H),	MS m/z
(trifluoromethyl)pyridin-4-yl)thiazol-5-	8.19 (s, 1H), 7.97 (dd, J = 5.0, 1.6 Hz,	378.1 (M + H)+;
yl)ethyl)propane-2-sulfinamide	1H), 7.85 (s, 1H), 4.95 (m,	Rt-0.85 min
	1H), 3.49 (d, J = 4.5 Hz, 1H),
	1.74 (d, J = 6.6 Hz, 3H),
	1.26 (s, 9H)
233: (R)-2-methyl-N-((R)-1-(5-		MS m/z
(morpholinomethyl)isoxazol-3-		316.2 (M + H)+;
yl)ethyl)propane-2-sulfinamide		Rt-0.43 min
234: (R)-2-methyl-N-((S)-1-(1-(6-	9.06 (d, J = 2.3 Hz, 1H),	MS m/z
(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-	8.22 (dd, J = 8.6, 1.9 Hz, 1H),	361.1 (M + H)+;
yl)ethyl)propane-2-sulfinamide	7.98 (dd, J = 2.6, 0.9 Hz, 1H),	Rt-0.85 min
	7.78 (d, J = 8.6 Hz, 1H), 6.51 (dd, J = 2.5,
	0.9 Hz, 1H), 4.76 (m,
	1H), 3.48 (d, J = 4.1 Hz, 1H),
	1.68 (d, J = 6.8 Hz, 3H),
	1.24 (s, 9H)
235: (R)-N-((S)-1-(1-(4-chlorophenyl)-2-	7.45 (d, J = 8.6 Hz, 2H),	MS m/z
methyl-1H-imidazol-4-yl)ethyl)-2-	7.24 (d, J = 8.6 Hz, 2H), 6.87 (s, 1H),	340.1 (M + H)+;
methylpropane-2-sulfinamide	4.54 (m, 1H), 3.48 (d, J = 5.8 Hz,	Rt-0.64 min
	1H), 2.33 (s, 3H), 1.65 (d, J = 6.8 Hz,
	3H), 1.22 (s, 9H)

Intermediate 236: (R)-N-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To an oven dried round bottom flask with stir bar was added 4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), (R)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) and DCE (49 mL). To this mixture was then added copper (II) sulfate (5.90 g, 36.9 mmol). Reaction mixture was heated in a preheated oil bath to 55° C. for 18 hours. Reaction mixture was filtered through a pad celite, washing the solids with CH₂Cl₂. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol, 103% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.27 (s, 9H) 7.31-7.42 (m, 2H) 7.87 (t, J=7.87 Hz, 1H) 8.83 (s, 1H). LCMS m/z 307.9 (M+H)⁺, Rt 1.01 min.

Step 2

To a solution of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol) in CH₂Cl₂ (252 mL), cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33.7 mL, 101 mmol) in Et₂O. Reaction mixture allowed to stir for 30 min at 0° C., then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH₄Cl. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4.93 g, 15.3 mmol, 60% yield) as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.56 (d, J=6.70 Hz, 3H) 3.34 (br. s., 1H) 4.77-4.87 (m, 1H) 7.19-7.31 (m, 3H). LCMS m/z 324.0 (M+H)⁺, Rt 0.90 min.

Step 3

To a microwave vial with stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-(1 g, 3.10 mmol), isopropenyl boronic acid pinacol ester (1.51 ml, 8.07 mmol), DME (8 ml), sodium carbonate (7.76 ml, 15.5 mmol) (2.0 M aq) and PdCl₂(dppf). CH₂Cl₂ adduct (0.127 g, 0.155 mmol). Vessel was capped and heated by microwave irradiation for 20 min at 100° C. Reaction mixture was diluted with a saturated solution of NH₄Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 50 to 100%) provided (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (830 mg, 2.93 mmol, 94% yield) as a pale brown crystalline. ¹H NMR (400 MHz, DMSO) δ 1.08-1.11 (m, 9H) 1.47 (d, J=6.80 Hz, 3H) 2.09 (d, J=0.54 Hz, 3H) 4.61-4.71 (m, 1H) 5.14 (t, J=1.32 Hz, 1H) 5.43 (d, J=5.58 Hz, 1H) 5.49 (s, 1H) 7.24-7.30 (m, 1H) 7.31-7.36 (m, 1H) 7.41-7.47 (m, 1H). LCMS m/z 284.0 (M+H)⁺, Rt 0.93 min.

Step 4

To a round bottom flask containing (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-(0.37 g, 1.31 mmol) in DCE (13 mL) at 0° C. was added under argon diethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) followed by the dropwise addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. Reaction mixture was cooled to 0° C. whereupon a second addition of diethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) took place followed by the addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reaction mixture allowed to warm to room temperature and stirred 18 hours under argon. Reaction mixture was cooled to 0° C. in a ice bath and to the cold reaction mixture was slowly added a saturated solution of NH₄Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 20 to 100%) provided a white crystalline of (R)-N-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (89 mg, 0.299 mmol, 22.92% yield). ¹H NMR (400 MHz, CDCl₃) δ 0.75-0.79 (m, 2H) 0.85-0.90 (m, 2H) 1.20 (s, 9H) 1.55 (s, 3H) 1.57 (d, J=6.80 Hz, 1H) 3.34 (d, J=5.23 Hz, 1H) 4.75-4.85 (m, 1H) 6.90 (dd, J=12.30, 1.74 Hz, 1H) 6.97 (dd, J=8.05, 1.78 Hz, 1H) 7.22 (t, J=7.97 Hz, 1H). LCMS m/z 298.1 (M+H)⁺, Rt 1.01 min.

Intermediate 237: (R)-N-((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a microwave vial with stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.55 mmol) followed by the addition of tributyl(1-ethoxyvinyl)stannane (1.12 g, 3.10 mmol), triethylamine (0.65 ml, 4.65 mmol) and PdCl₂(dppf). CH₂Cl₂ adduct (63 mg, 0.078 mmol). To the solids was added toluene (10 ml). Vial capped and heated in a preheated sand bath at 100° C. for 1 hour. Reaction mixture was loaded onto silica gel column. Silica gel column chromatography (MeOH/CH₂Cl₂ 0 to 10% with 1% NH₄OH buffer) provided (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (498 mg, 1.59 mmol, 102% yield) as a brown viscous oil which crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.43 (t, J=6.97 Hz, 3H) 1.58 (d, J=6.75 Hz, 3H) 3.35 (d, J=4.74 Hz, 1H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (d, J=2.79 Hz, 1H) 4.65 (d, J=2.79 Hz, 1H) 4.79-4.89 (m, 1H) 7.16-7.20 (m, 1H) 7.29-7.34 (m, 1H) 7.39 (dd, J=8.07, 1.66 Hz, 1H).

Step 2

To a round bottom flask containing (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, 15.6 mmol) in toluene (15 mL) at 0° C. under argon was added diethylzinc (1.0M in hexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. Reaction mixture was cooled to 0° C. in an ice bath and to the cold reaction mixture was slowly added a saturated solution of NH₄Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (MeOH/CH₂Cl₂ 0 to 10%) provided (R)-N-((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (145 mg, 0.44 mmol, 28% yield) as a viscous brown oil. ¹H NMR (300 MHz, CDCl₃) δ 0.93-0.99 (m, 2H) 1.14-1.20 (m, 3H) 1.21 (s, 9H) 1.22-1.27 (m, 2H) 1.57-1.61 (m, 4H) 3.35 (d, J=4.98 Hz, 1H) 3.45 (q, J=7.07 Hz, 2H) 4.77-4.87 (m, 1H) 6.98 (dd, J=7.58, 1.43 Hz, 3H) 7.00-7.03 (m, 4H) 7.28-7.32 (m, 1H). LCMS m/z 328.1 (M+H)⁺, Rt 0.95 min.

Intermediate 238: (R)-N-((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a microwave vial with a stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 0.93 mmol), 4-isoxazoleboronic acid pinacol ester (218 mg, 1.12 mmol), PdCl₂(dppf).CH₂Cl₂ adduct (76 mg, 0.09 mmol), potassium fluoride (2.7 mL, 1.0 M in water, 2.79 mmol) and finally DMSO (9 mL). The reaction mixture was degassed with bubbling nitrogen (3 min) and the vial capped and heated in a preheated oil bath at 130° C. for 18 hours. The reaction mixture was diluted with a saturated solution of NH₄Cl and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptanes 40 to 100%) provided (R)-N-((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (136 mg, 0.48 mmol, 52% yield) as a viscous brown oil. ¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H) 1.57 (d, J=6.80 Hz, 3H) 3.39 (d, J=4.35 Hz, 1H) 3.74 (s, 2H) 4.81-4.88 (m, 1H) 7.04 (d, J=10.66 Hz, 1H) 7.11 (d, J=7.97 Hz, 1H) 7.38 (t, J=7.73 Hz, 1H). LCMS m/z 283.0 (M+H)⁺, Rt 0.72 min.

Step 2

To a scintillation vial containing (R)-N-((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-(86 mg, 0.31 mmol) and a stir bar was added toluene (2 mL). To this mixture was then added tetrabutylammonium bromide (19 mg, 0.06 mmol) followed by the addition of NaOH (1.52 ml, 1.0 M (aq), 1.52 mmol) and 1,2-dibromoethane (0.11 ml, 1.22 mmol). Vial capped and reaction mixture was stirred vigorously at room temperature for 18 hours. Whereupon, 1,2-dibromoethane (0.11 ml, 1.22 mmol) and tetrabutylammonium bromide (19 mg, 0.06 mmol) were added and reaction mixture allowed to stir an additional 18 hours. A third addition of 1,2-dibromoethane (0.11 ml, 1.22 mmol) was added and the reaction mixture heated to 50° C. for an additional 18 hours in a preheated aluminum tray. The reaction mixture was quenched with a saturated solution of NH₄Cl and the aqueous mixture extracted with EtOAc. Organics combined and washed twice with water, brine, dried (Na₂SO₄), filtered and concentrated. Crude material was passed through a small plug of silica gel using 10% MeOH:90% DCM to elute product. The solution was concentrated to afford a viscous orange oil of (R)-N-((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (23 mg, 0.08 mmol, 24% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.38-1.44 (m, 2H) 1.56 (d, J=6.75 Hz, 3H) 1.73-1.79 (m, 2H) 3.37 (d, J=4.45 Hz, 1H) 4.78-4.88 (m, 1H) 6.94 (dd, J=11.35, 1.91 Hz, 1H) 7.09 (dd, J=8.07, 1.91 Hz, 1H) 7.34 (t, J=7.90 Hz, 1H). LCMS m/z 309.2 (M+H)⁺, Rt 0.83 min.

Intermediate 239: (R)-N-((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide

To a round bottom flask containing (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To this solution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH (1 mL). A hydrogen atmosphere was inserted and the resulting reaction mixture stirred at room temperature for 18 hours, at which time more palladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogen atmosphere was inserted again and the reaction mixture allowed to stir an additional 18 hours at room temperature. The reaction mixture was filtered through a syringe filter and concentrated to afford a light brown viscous oil of (R)-N-((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (149 mg, 0.52 mmol, 73% yield) which crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.24 (d, J=5.87 Hz, 6H) 1.58 (d, J=6.70 Hz, 3H) 2.89 (dt, J=13.79, 6.90 Hz, 1H) 3.35 (d, J=5.04 Hz, 1H) 4.76-4.85 (m, 1H) 6.90 (dd, J=12.03, 1.52 Hz, 1H) 6.98 (dd, J=7.90, 1.54 Hz, 1H) 7.24 (t, J=7.97 Hz, 1H). LCMS m/z 286.3 (M+H)⁺, Rt 1.01 min.

Intermediate 240: (R)-N-((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a two microwave vials with stir bars were added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.65 mmol), 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (2.91 g, 13.9 mmol), DME (20 mL), sodium carbonate (11.6 mL, 23.3 mmol, 2.0 M aq) and PdCl₂(dppf).CH₂Cl₂ adduct (190 mg, 0.23 mmol) divided between the two vials. The vials were capped and heated by microwave irradiation for 20 min at 100° C. respectively. The reaction mixtures combined, diluted with a saturated solution of NH₄Cl and EtOAc. The phases were partitioned and the aqueous phase extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided a orange crystalline of (R)-N-((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.07 g, 3.31 mmol, 71% yield. ¹H NMR (400 MHz, CDCL₃) δ ppm 1.21 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.36 (d, J=4.25 Hz, 1H) 3.96 (s, 3H) 4.79-4.91 (m, 1H) 7.13 (dd, J=11.69, 1.61 Hz, 1H) 7.23 (dd, J=8.00, 1.64 Hz, 1H) 7.30-7.37 (m, 1H) 7.60 (s, 1H) 7.74 (s, 1H). LCMS m/z 324.0 (M+H)⁺, Rt 0.74 min.

The Intermediates in Table 13a were prepared by a method similar to the one described for the preparation of Intermediate 240.

TABLE 13a
Intermediate 241
Intermediate 242

TABLE 13b
Chemical name, NMR chemical shifts and LCMS signal for each intermediate
listed in Table 13.
Intermediate: Name	1H NMR (400 MHz) δ ppm	LCMS
241: (R)-2-methyl-N-((S)-1-(4-(1-		MS m/z 306.0
methyl-1H-pyrazol-4-		(M + H)+, Rt
yl)phenyl)ethyl)propane-2-		0.71 min.
sulfinamide
242: (R)-N-((S)-1-(2-fluoro-4-	(DMSO) 1.10 (s, 9 H) 1.47 (d, J = 6.75 Hz, 3	MS m/z 310.0
(1H-pyrazol-4-yl)phenyl)ethyl)-2-	H) 4.60-4.70 (m, 1 H) 5.41 (d, J = 5.48 Hz,	(M + H)+, Rt
methylpropane-2-sulfinamide	1 H) 7.38-7.44 (m, 3 H) 7.96 (br. s., 1 H)	0.67 min.
	8.23 (br. s., 1 H) 12.97 (br. s., 1 H)

Intermediate 243: (R)-N-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a oven dried round bottom flask with stir bar was added 2-fluoro-4-(trifluoromethyl)benzaldehyde (5 g, 26.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL). To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol). The reaction mixture was heated in a preheated oil bath at 55° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methyl propane-2-sulfinamide (7.3 g, 24.7 mmol, 95% yield). Material was taken onto next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.29 (s, 9H) 7.44 (d, J=10.08 Hz, 1H) 7.51 (d, J=8.27 Hz, 1H) 8.13 (t, J=7.46 Hz, 1H) 8.92 (s, 1H). LCMS m/z 296.0 (M+H)⁺, Rt 1.02 min.

Step 2

To a solution of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (7.3 g, 24.7 mmol) in CH₂Cl₂ (247 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33 mL, 99 mmol) in Et₂O. Reaction mixture allowed to stir for 30 min at 0° C., then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH₄Cl. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (4.68 g, 15.0 mmol, 61% yield) as a white crystalline solid. ¹H NMR (400 MHz, CDCL₃) δ 1.22 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.38 (d, J=4.01 Hz, 1H) 4.87-4.97 (m, 1H) 7.33 (d, J=10.32 Hz, 1H) 7.39-7.45 (m, 1H) 7.49-7.55 (m, 1H). LCMS m/z 312.0 (M+H)⁺, Rt 0.92 min.

Intermediate 244: (S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethyl carbamate

Step 1

To a round bottom flask with stir bar was added 4-((S)-1-aminoethyl-2-chlorobenzoic acid HCl salt (1.05 g, 4.45 mmol) followed by the addition of THF (40 mL). To this solution was added DIEA (1.86 ml, 10.7 mmol). The reaction mixture becomes cloudy white followed by the addition of di-tert-butyl dicarbonate (1.07 g, 4.89 mmol). Resulting reaction mixture allowed to stir for 18 hours at room temperature. At which time the reaction mixture was then heated to 60° C. for 2 hours in a oil bath. Di-tert-butyl dicarbonate (1.07 g, 4.89 mmol) and NMP (20 ml) were then added and the resulting reaction mixture allowed to stir for 2 hours at 60° C. Volatiles were removed. The resulting oil was diluted with a saturated solution of NH₄Cl and the aqueous mixture extracted with EtOAc. The organic phases combined, washed twice with water, brine, dried (Na₂SO₄), filtered and concentrated to a viscous yellow oil of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (2.32 g, 6.19 mmol, 139% yield) which contains some excess di-tert-butyl dicarbonate and NMP. LCMS m/z 284.9 (M+H)⁺ (carboxylic acid fragment+CH₃CN adduct), Rt 0.75 min.

Step 2

To a round bottom flask with stir bar was added (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg, 1.20 mmol), cyclopentylamine (355 μL, 3.60 mmol), EDC HCl (460 mg, 2.40 mmol), 1-hydroxy-7-aza-benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL). To this mixture was then added DIEA (629 μL, 3.60 mmol). Reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with twice with water, brine, dried (Na₂SO₄), filtered and concentrated to a brown crystalline of (S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethylcarbamate (476 mg, 1.17 mmol, 97% yield). LCMS m/z 367.0 (M+H)⁺, Rt 0.90 min.

Intermediate 245: (R)-N-((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a round bottom flask with stir bar was added 4-bromo-2,5-difluorobenzaldehyde (5.3 g, 24.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DCE (80 mL). To this mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). The reaction mixture was heated in a preheated oil bath at 60° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol, 93% yield). Material was taken onto next step without further purification. LCMS m/z 326.0 (M+H)⁺, Rt 1.04 min.

Step 2

To a solution of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol in CH₂Cl₂ (200 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (29.6 mL, 89 mmol) in Et₂O. Reaction mixture allowed to stir for 5 hours at 0° C. then quenched with the slow addition of a saturated solution of NH₄Cl. Aqueous mixture adjusted to pH 8 with HCl (1 N) and extracted with DCM. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 30 to 100%) provided (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (6.86 g, 20.2 mmol, 91% yield) LCMS m/z 342.1 (M+H)⁺, Rt 0.96 min.

Step 3

To two microwave vials with stir bars were added (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.47 mmol), 1-Methyl-4-1H-pyrazoleboronic acid, pinacol ester (917 mg, 4.41 mmol), DME (6 ml), Na₂CO₃ (3.67 ml, 7.35 mmol) (2.0 M aq) and PdCl₂(dppf).CH₂Cl₂ adduct (60.0 mg, 0.07 mmol) divided evenly between the two vessels. Vessels were capped and heated by microwave irradiation for 20 min at 100° C. Reaction mixtures were combined, diluted with a saturated solution of NH₄Cl and EtOAc. Phases partitioned. Aqueous phase extracted with EtOAc and organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 60 to 100%) provided (R)-N-((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (370 mg, 1.08 mmol, 73.7% yield). ¹H NMR (400 MHz, CDCL₃) δ ppm 1.23 (s, 9H) 1.57-1.60 (m, 3H) 3.33 (d, J=4.06 Hz, 1H) 3.97 (s, 3H) 4.79-4.88 (m, 1H) 7.10 (dd, J=11.20, 6.06 Hz, 1H) 7.20 (dd, J=10.78, 6.19 Hz, 1H) 7.76 (d, J=2.20 Hz, 1H) 7.82 (s, 1H). LCMS m/z 342.1 (M+H)⁺, Rt 0.77 min.

Intermediate 246: (S)-N-((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a mixture of 1H-imidazole-4-carbaldehyde (3.71 g, 38.6 mmol), 1-chloro-4-iodobenzene (13.81 g, 57.9 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.10 g, 7.72 mmol), copper(I) iodide (0.368 g, 1.93 mmol) and cesium carbonate (25.2 g, 77 mmol) was added DMF (50 mL). The reaction was sealed and heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with a saturated solution of NH₄Cl. A brown solid develops. Solid was collected, washed with water and air dried. Solid material was then dissolved in 10% MeOH:90% DCM solution and dried (Na₂SO₄), filtered and concentrated to afford a dark brown solid 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (8.55 g, 41.4 mmol, 107% yield). Material as used without further purification. LCMS m/z 207.1 (M+H)⁺, Rt 0.58 min.

Step 2

To a suspension of (S)-(−)tert-Butanesulfinamide (2.35 g, 19.4 mmol) and 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (4 g, 19.4 mmol) in DCE (39 mL) was added CuSO₄ (4.63 g, 29.0 mmol). The reaction mixture was heated at 60° C. for 18 hours in a oil bath. A dark brown suspension resulted. The reaction mixture was then cooled to room temperature, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol, 28.2% yield) as a light brown solid. LCMS m/z 310.0 (M+H)⁺, Rt 0.75 min.

Step 3

To a solution of (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol) in DCM (27 mL), cooled to −40° C. (acetone/dry ice) under N₂, was added 3M MeMgBr (7.27 ml, 21.8 mmol) in diethyl ether. Reaction mixture allowed to stir for 1 hr at −40° C. Reaction mixture was quenched with the slow addition of a saturated solution of NH₄Cl and diluted with EtOAc. Phases partitioned, aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/MeOH:EtOAc 0 to 5%) provided (S)-N-((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g, 3.41 mmol, 62% yield). ¹H NMR (400 MHz, CDCL₃) δ 1.25 (s, 9H) 1.58 (d, J=6.65 Hz, 3H) 3.80 (d, J=5.48 Hz, 1H) 4.59 (quin, J=6.36 Hz, 1H) 7.26 (s, 1H) 7.33 (d, J=8.61 Hz, 2H) 7.41-7.47 (m, 2H) 7.76 (d, J=1.17 Hz, 1H). LCMS m/z 326.1 (M+H)⁺, Rt 0.59 min.

Intermediate 247: (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine

A solution of hydrochloric acid (4.0 M in 1,4-dioxane, 2.1 mL, 8.2 mmol, 2 equiv) was added to a solution of (R)-N-((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.34 g, 4.1 mmol) in 1,4-dioxane at room temperature. A precipitate formed. The suspension was stirred for 1 hour and then concentrated in vacuo to give the hydrochloride salt of (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (1.1 g, light yellow solid), which was used without purification. ¹H NMR (400 MHz, CD₃OD) δ 7.87 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 4.72 (q, J=6.9 Hz, 1H), 1.72 (d, J=7.0 Hz, 3H). MS m/z 223.1 (M+H)⁺; Rt-0.59 min.

The intermediates in Table 14a were prepared using a method similar to that described for the preparation of Intermediate 247.

TABLE 14a
Intermediate 248
Intermediate 249
Intermediate 250
Intermediate 251
Intermediate 252
Intermediate 253
Intermediate 254
Intermediate 255
Intermediate 256
Intermediate 257
Intermediate 258
Intermediate 259
Intermediate 260
Intermediate 261
Intermediate 262
Intermediate 263
Intermediate 264
Intermediate 265
Intermediate 266
Intermediate 267
Intermediate 268
Intermediate 269
Intermediate 270
Intermediate 271
Intermediate 272
Intermediate 273
Intermediate 274
Intermediate 275
Intermediate 276
Intermediate 277

TABLE 14b
Chemical name, NMR chemical shifts and LCMS signal for each intermediate
listed in Table 14a.
	1H NMR (400 MHz, CD3OD) δ
Intermediate: Name	ppm	LCMS
248: (S)-1-(2-(4-chlorophenyl)thiazol-5-	7.97 (d, J = 8.7 Hz, 2H),	MS m/z
yl)ethanamine	7.94 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H),	239.9 (M + H)+;
	4.95 (m, 1H), 1.78 (d, J = 6.8 Hz,	Rt-0.59 min
	3H)
249: (S)-1-(5-phenylthiophen-2-	7.29 (dd, J = 8.3, 1.2 Hz, 2H),	MS m/z
yl)ethanamine	7.05 (m, 2H), 6.99 (m, 2H),	187.1 (M − NH2)+;
	6.89 (dd, J = 3.8, 0.6 Hz, 1H),	Rt-
	4.45 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H)	0.59 min
250: (S)-1-(5-phenylisoxazol-3-	7.87 (m, 2H), 7.55 (m, 3H),	MS m/z
yl)ethanamine	6.95 (s, 1H), 4.72 (q, J = 6.9 Hz, 1H),	189.2 (M + H)+;
	1.73 (d, J = 6.9 Hz, 3H)	Rt-0.50 min
251: (S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-	8.43 (s, 1H), 7.87 (s, 1H),	MS m/z
yl)ethanamine	7.78 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz,	223.1 (M + H)+;
	2H), 4.61 (q, J = 6.9 Hz,	Rt-0.54 min
	1H), 1.72 (d, J = 6.9 Hz, 3H)
252: (S)-1-(5-(4-fluorophenyl)isoxazol-3-	7.92 (dd, J = 9.0, 5.2 Hz, 2H),	MS m/z
yl)ethanamine	7.30 (t, J = 8.8 Hz, 2H), 6.92 (s,	207.1 (M + H)+;
	1H), 4.71 (q, 7.0 Hz, 1H),	Rt-0.51 min
	1.72 (d, J = 7.0 Hz, 3H)
253: (S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-	8.39 (s, 1H), 7.86 (s, 1H),	MS m/z
yl)ethanamine	7.78 (dd, J = 9.2, 4.6 Hz, 2H),	207.1 (M + H)+;
	7.25 (dd, J = 9.1, 8.4 Hz, 2H),	Rt-0.46 min
	4.60 (q, J = 6.9 Hz, 1H), 1.71 (d, J = 6.9 Hz,
	3H)
254: (S)-1-(5-(pyridin-2-yl)thiophen-2-	8.73-8.78 (m, 1 H), 8.57 (td,	MS m/z
yl)ethanamine	J = 8.0, 1.6 Hz, 1 H), 8.31 (d,	206.0 (M + H)+;
	J = 8.3 Hz, 1 H), 8.03 (d, J = 4.0 Hz,	Rt-0.35 min
	1 H), 7.92 (ddd, J = 7.5, 6.0,
	1.1 Hz, 1 H), 7.50 (dd, J = 4.0,
	0.6 Hz, 1 H), 4.91-4.98 (m, 1
	H) 1.80 (d, J = 6.8 Hz, 3 H)
255: (S)-1-(5-(morpholinomethyl)isoxazol-3-	6.97 (s, 1H), 4.72 (m, 3H),	MS m/z
yl)ethanamine	3.96 (m, 4H), 3.38 (m, 4H), 1.70 (d, J = 7.0 Hz,	212.1 (M + H)+;
	3H)	Rt-0.14 min
256: (S)-1-(2-morpholinothiazol-5-	7.56 (s, 1H), 4.78 (quin, J = 6.8 Hz,	MS m/z
yl)ethanamine	1H), 3.88 (m, 4H), 3.68 (m,	197.0 (M − NH2)+;
	4H), 1.71 (d, J = 6.9 Hz, 3H)	Rt-
		0.26 min
257: (S)-1-(2-(pyridin-2-yl)thiazol-5-	8.68 (m, 1H), 8.30 (m, 1H),	MS m/z
yl)ethanamine	8.17 (m, 1H), 8.09 (m, 1H), 7.66 (m,	189.0 (M − NH2)+;
	1H), 4.99 (q, J = 7.1 Hz, 1H),	Rt-
	1.80 (d, J = 6.9 Hz, 3H)	0.39 min
258: (S)-1-(2-(pyridin-3-yl)thiazol-5-	9.49 (d, J = 2.0 Hz, 1H),	MS m/z
yl)ethanamine	9.14 (m, 1H), 8.96 (m, 1H),	189.0 (M − NH2)+;
	8.23 (ddd, J = 8.3, 5.8, 0.7 Hz, 1H),	Rt-
	8.17 (d, J = 0.7 Hz, 1H),	0.25 min
	5.04 (q, J = 6.9 Hz, 1H), 1.82 (d, J = 6.9 Hz,
	3H)
259: (S)-1-(2-(pyridin-4-yl)thiazol-5-	8.97 (d, J = 6.9 Hz, 2H),	MS m/z
yl)ethanamine	8.62 (d, J = 6.9 Hz, 2H), 8.29 (d, J = 0.6 Hz,	189.0 (M − NH2)+;
	1H), 5.08 (q, J = 6.8 Hz,	Rt-
	1H), 1.84 (d, J = 6.9 Hz, 3H)	0.24 min
260: (S)-1-(2-(4-	8.09 (d, J = 7.7 Hz, 2H),	MS m/z
(difluoromethyl)phenyl)thiazol-5-	7.99 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H),	256.0 (M + H)+;
yl)ethanamine	6.84 (t, J = 56 Hz, 1H), 4.96 (m,	Rt-0.56 min
	1H), 1.78 (d, J = 6.9 Hz, 3H)
261: (S)-1-(2-(6-methylpyridin-3-yl)thiazol-5-	9.30 (d, J = 2.0 Hz, 1H),	MS m/z
yl)ethanamine	8.98 (dd, J = 8.5, 2.0 Hz, 1H),	220.1 (M + H)+;
	8.14 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H),	Rt-0.27 min
	5.03 (q, J = 6.9 Hz, 1H),
	2.87 (s, 3H), 1.82 (d, J = 6.9 Hz, 3H)
262: (S)-1-(2-(6-(trifluoromethyl)pyridin-3-	9.31 (d, J = 2.1 Hz, 1H),	MS m/z
yl)thiazol-5-yl)ethanamine	8.59 (dd, J = 8.2, 1.7 Hz, 1H),	274.0 (M + H)+;
	8.10 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H),	Rt-0.51 min
	5.01 (q, J = 6.8 Hz, 1H),
	1.81 (d, J = 6.8 Hz, 3H)
263: (S)-1-(2-(2-(trifluoromethyl)pyridin-4-	8.87 (d, J = 5.1 Hz, 1H),	MS m/z
yl)thiazol-5-yl)ethanamine	8.34 (dd, J = 1.5, 0.7 Hz, 1H),	274.0 (M + H)+;
	8.17 (m, 1H), 5.02 (q, J = 6.9 Hz,	Rt-0.51 min
	1H), 1.82 (d, J = 6.9 Hz, 3H)
264: (R)-1-(5-(morpholinomethyl)isoxazol-3-	7.01 (s, 1H), 4.74 (m, 3H),	MS m/z
yl)ethanamine	4.00-3.86 (br m, 4H),	212.2 (M + H)+;
	3.45-3.37 (br m, 4H), 1.70 (d, J = 6.9 Hz,	Rt-0.14 min
	3H)
265: (S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-	9.29 (d, J = 2.4 Hz, 1H),	MS m/z
1H-pyrazol-3-yl)ethanamine	8.56 (d, J = 2.6 Hz, 1H), 8.47 (dd, J = 8.6,	257.0 (M + H)+;
	2.5 Hz, 1H), 7.98 (d, J = 8.6 Hz,	Rt-0.12 min
	1H), 6.73 (d, J = 2.6 Hz,
	1H), 4.68 (q, J = 7.0 Hz, 1H),
	1.72 (d, J = 6.9 Hz, 3H)
266: (S)-1-(1-(4-chlorophenyl)-2-methyl-1H-	7.83 (d, J = 0.7 Hz, 1H),	MS m/z
imidazol-4-yl)ethanamine	7.72 (m, 2H), 7.63 (m, 2H), 4.75 (q, J = 7.0 Hz,	236.1 (M + H)+;
	1H), 2.63 (s, 3H),	Rt-0.45 min
	1.79 (d, J = 7.0 Hz, 3H)
267: (S)-1-(2-fluoro-4-(1-		MS m/z
methylcyclopropyl)phenyl)ethanamine		194.1 (M + H)+,
		Rt
		0.60 min.
268: (S)-1-(4-(1-ethoxycyclopropyl)-2-	(D2O) 0.98 (s, 1 H)	MS m/z
fluorophenyl)ethanamine	1.03-1.08 (m, 2 H) 1.14 (t, J = 7.09 Hz, 1 H)	224.1 (M + H)+,
	1.25-1.30 (m, 2 H) 1.64 (d,	Rt
	J = 6.99 Hz, 3 H) 3.45-3.59 (m,	0.56 min.
	2 H) 7.16 (dd, J = 5.58, 1.47 Hz,
	1 H) 7.17-7.21 (m, 1 H)
	7.40-7.48 (m, 1 H)
269: (S)-1-(4-(1-aminoethyl)-3-		MS m/z
fluorophenyl)cyclopropanecarbonitrile		205.1 (M + H)+,
		Rt
		0.44 min.
270: (S)-1-(2-fluoro-4-		MS m/z
isopropylphenyl)ethanamine		182.1 (M + H)+,
		Rt
		0.59 min.
271: (S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-		MS m/z
4-yl)phenyl)ethanamine		220.1 (M + H)+,
		Rt
		0.43 min.
272: (S)-1-(4-(1-methyl-1H-pyrazol-4-		MS m/z
yl)phenyl)ethanamine		185.1 (M + H)+,
		Rt
		0.41 min.
273: (S)-1-(2-fluoro-4-(1H-pyrazol-4-	(D2O) 1.66 (d, J = 6.99 Hz, 3 H)	MS m/z
yl)phenyl)ethanamine	4.76-4.82 (m, 1 H)	206.1 (M + H)+,
	7.39-7.52 (m, 3 H) 8.16 (s, 2 H)	Rt
		0.37 min.
274: (S)-1-(2-fluoro-4-	(D2O) 1.67 (d, J = 6.94 Hz, 3 H)	MS m/z
(trifluoromethyl)phenyl)ethanamine	4.84 (q, J = 6.94 Hz, 1 H)	208.0 (M + H)+,
	7.54-7.70 (m, 3 H)	Rt
		0.51 min.
275: (S)-4-(1-aminoethyl)-2-chloro-N-		MS m/z
cyclopentylbenzamide		267.0 (M + H)+,
		Rt
		0.50 min.
276: (S)-1-(2,5-difluoro-4-(1-methyl-1H-	(D2O) 1.65 (d, J = 6.94 Hz, 3 H)	MS m/z
pyrazol-4-yl)phenyl)ethanamine	3.53 (q, J = 7.11 Hz, 1 H)	239.1 (M + H)+,
	3.91 (s, 3 H) 7.28 (dd, J = 11.10, 6.26 Hz,	Rt
	1 H) 7.44 (dd, J = 11.18,	0.45 min.
	6.24 Hz, 1 H) 7.94 (s, 1 H)
	8.06 (d, J = 1.86 Hz, 1 H)
277: (S)-1-(1-(4-chlorophenyl)-1H-imidazol-	(D2O) 1.74 (d, J = 6.65 Hz, 3 H)	MS m/z
4-yl)ethanamine	4.76-4.85 (m, 1 H) 7.61 (q,	222.1 (M + H)+,
	J = 9.00 Hz, 4 H) 8.00 (s, 1 H)	Rt
	9.04 (s, 1 H)	0.44 min.

Intermediate 278: (S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine

Step 1

To a round bottom flask containing (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.02 g, 3.60 mmol) was added dioxane (7 mL). To this homogenous solution was then added HCl in Dioxane (1.80 mL, 7.20 mmol, 4 M). Resulting reaction mixture allowed to stir 10 min at room temperature. Volatiles removed. Et₂O was added and mixture sonnicated briefly. Volatiles removed again. Et₂O was added and the solid collected and washed with Et₂O to afford a white HCl salt of (S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine (742 mg, 3.44 mmol, 96% yield). ¹H NMR (400 MHz, D₂O) δ 1.65 (d, J=6.94 Hz, 3H) 2.12 (s, 3H) 5.23 (s, 1H) 5.50 (s, 1H) 7.37 (d, J=13.06 Hz, 1H) 7.43 (m, 2H). LCMS m/z 163.2 (deamino fragment) (M+H)⁺, Rt 0.56 min.

Step 2

To a RBF containing (S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine (742 mg, 3.44 mmol) was added NMP (7 mL). To this solution was then added TEA (959 μl, 6.88 mmol) followed by the addition of Di-tert-butyl dicarbonate (976 mg, 4.47 mmol). Resulting reaction mixture allowed to stir 2 hr at room temperature. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptanes 0 to 100%) provided (S)-tert-butyl (1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)carbamate (1.28 g, 4.58 mmol, 133% yield) as a white crystalline. ¹H NMR (400 MHz, CDCl₃) δ 1.40-1.48 (m, 12H) 2.12 (d, J=0.44 Hz, 3H) 4.98 (br. s., 2H) 5.10-5.12 (m, 1H) 5.37 (s, 1H) 7.11-7.16 (m, 1H) 7.19-7.24 (m, 2H). LCMS m/z 163.0 (deamino fragment) (M+H)⁺, Rt 1.13 min.

Step 3

To a round bottom flask containing (S)-tert-butyl (1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)carbamate (1.28 g, 4.58 mmol) was added DCM (23 mL). The homogenous solution was cooled to −70° C. in a acetone/dry ice bath. Ozone (g) was then gently bubbled through the solution for 25 min at which time the solution becomes pale blue in color. Dimethyl sulfide (1.02 mL, 13.8 mmol) was then added to the cold solution and mixture gradually allowed to warm to room temperature and stirred for 30 min. Reaction mixture was diluted with a water. Phases partitioned. Aqueous phase extracted with DCM. Organic phases combined, washed with brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided (S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol, 23% yield) as a colorless oil that crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H) 7.40 (t, J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd, J=7.95, 1.54 Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH₃CN) (M+H)⁺, Rt 0.89 min.

Step 4

To a solution of (S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol) in DCM (5.2 mL), cooled to 0° C. (water/ice bath) under N₂, was added 3M MeMgBr (1.4 mL, 4.21 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH₄Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na₂SO₄), filtered and concentrated to (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg, 0.97 mmol, 92% yield) afford as a colorless oil which slowly crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).

Step 5

To a RBF containing (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg, 0.97 mmol) was added DCM (5 mL) the resulting colorless solution was cooled to −70° C. in a dry ice/acetone bath. To this cold solution under N₂ was then added DAST (0.26 mL, 1.94 mmol) resulting reaction mixture allowed to stir 1 hr at −70° C. To the cold solution was added ice and resulting mixture allowed to warm to room temperature. Mixture diluted with DCM, phases partioned and the aqueous phase extracted with DCM. Organic layers combined, washed with brine, dried (Na₂SO₄), filtered and concentrated to onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 50%) provided (S)-tert-butyl (1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42 mmol, 44% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.39-1.49 (m, 12H) 1.66 (d, J=21.52 Hz, 6H) 4.97 (br. s., 1H) 7.04-7.12 (m, 2H) 7.22-7.26 (m, 1H). LCMS m/z 285.1 (carboxylic acid fragment+CH₃CN) (M+H)⁺, Rt 1.06 min.

Step 6

To a round bottom flask containing (S)-tert-butyl (1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42 mmol) was added HCl in dioxane (2.1 mL, 8.42 mmol). Resulting reaction mixture allowed to stir 1 hr at room temperature. Volatiles were removed. Et₂O was then added and the mixture sonnicated briefly. Volatiles were once again removed to a afford an HCl salt of (S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine (104 mg, 0.44 mmol, 105% yield) as a white solid. ¹H NMR (400 MHz, D₂O) δ 1.59-1.80 (m, 9H) 7.24-7.37 (m, 2H) 7.43-7.56 (m, 1H). LCMS m/z 200.1 (M+H)⁺, Rt 0.54 min.

Intermediate 279: (S)-2-(4-(1-aminoethyl)-3-fluorophenyl)propan-2-ol

Step 1

To a microwave vial with stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 3.10 mmol) followed by the addition of tributyl(1-ethoxyvinyl)stannane (2.24 g, 6.21 mmol), TEA (1.3 mL, 9.31 mmol) and PdCl₂(dppf).CH₂Cl₂ adduct (0.127 g, 0.155 mmol). To the solids was then added toluene (10 mL). Vial capped and heated by microwave irradiation at 100° C. for 30 min. To this reaction mixture was added 1 ml of TFA to try to convert vinyl ether to the ketone which was unsuccessful. Resulting reaction mixture allowed to stir 5 min at room temperature. Reaction mixture was then quenched with a saturated solution of NaHCO₃ to pH 8. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.60 g, 1.91 mmol, 62% yield) as a yellow viscous residue. ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.43 (t, J=6.94 Hz, 3H) 1.56-1.63 (m, 5H) 3.36 (d, J=3.13 Hz, 1H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (br. s., 1H) 4.65 (s, 1H) 4.79-4.91 (m, 1H) 7.30 (s, 2H) 7.40 (d, J=8.02 Hz, 1H).

Step 2

To a round bottom flask containing (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.91 mmol) was added MeOH (19 mL). To this homogenous solution was then added HCl (aq) (3.2 mL, 19.1 mmol, 3 M). Resulting reaction mixture was stirred at room temperature for 30 min. Volatiles were then removed. Residue triturated with Et₂O to provide (S)-1-(4-(1-aminoethyl)-3-fluorophenyl)ethanone (0.43 g, 1.98 mmol, 103% yield) as a HCl salt. ¹H NMR (400 MHz, D₂O) δ 1.67 (d, J=6.99 Hz, 3H) 2.64 (s, 3H) 4.80-4.87 (m, 1H) 7.61 (t, J=7.73 Hz, 1H) 7.77 (dd, J=11.30, 1.66 Hz, 1H) 7.87 (dd, J=8.09, 1.64 Hz, 1H). LCMS m/z 182.0 (M+H)⁺, Rt 0.36 min.

Step 3

To a round bottom flask with stir bar was added (S)-1-(4-(1-aminoethyl)-3-fluorophenyl)ethanone (0.43 g, 1.98 mmol) followed by the addition of NMP (9.9 mL). To this solution was then added DIEA (0.83 mL, 4.74 mmol) and Di-tert-butyl dicarbonate (0.95 g, 4.35 mmol). The resulting reaction mixture allowed to stir 2 hr at room temperature. Reaction mixture was diluted with water, extracted with EtOAc. Organic phase washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (S)-tert-butyl 1-(4-acetyl-2-fluorophenyl)ethylcarbamate (369 mg, 1.31 mmol, 66.4% yield) as a colorless oil which crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H) 7.40 (t, J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd, J=7.95, 1.54 Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH₃CN) (M+H)⁺, Rt 0.89 min.

Step 4

To a solution of (S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (200 mg, 0.71 mmol) in DCM (7.1 mL), cooled to 0° C. (water/ice bath) under N₂, was added 3M MeMgBr (10.95 mL, 2.84 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH₄Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na₂SO₄), filtered and concentrated to (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg, 0.62 mmol, 87% yield) afford as a colorless oil which slowly crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).

Step 5

To a round bottom flask containing (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg, 0.62 mmol) and a stir bar was added dioxane (2 mL). To this reaction mixture was then added HCl in dioxane (0.93 ml, 3.71 mmol, 4.0M). Resulting reaction mixture allowed to stir at room temperature for 18 hr. Volatiles were then removed. Residue triturated with Et₂O to afford (S)-2-(4-(1-aminoethyl)-3-fluorophenyl)propan-2-ol (142 mg, 0.61 mmol, 98% yield) as a HCl salt. ¹H NMR (400 MHz, D₂O) δ 1.53 (s, 6H) 1.64 (d, J=7.04 Hz, 3H) 3.73 (s, 1H) 7.28-7.37 (m, 2H) 7.42-7.48 (m, 1H). LCMS m/z 198.1 (M+H)⁺, Rt 0.37 min.

Intermediate 280: (R)-N-((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a mixture of ethyl 2-oxocyclohexanecarboxylate (58.0 mg, 0.341 mmol), (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (580 mg, 1.705 mmol), Cs₂CO₃ (1555 mg, 4.77 mmol), copper(I) iodide (32.5 mg, 0.170 mmol) was added 2,2,2-trifluoroethanol (871 μl, 11.93 mmol). The reaction was sealed and heated at 78° C. for 24 hours. LCMS indicated complete conversion to product. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL). The mixture was filtered through a pad of celite and the pad was rinsed with EtOAc (20 mL). The organic was washed with water (2×15 mL), dried (Na₂SO₄) and concentrated. The residue was then filtered through a pad of silica gel (30 g) with EtOAc/heptane (1:3) to give crude (R)-N-((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.601 g). LCMS (B) m/z 360.1 (M+H)⁺

Intermediate 281: (S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine

To a solution of (R)-N-((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.601 g, 1.672 mmol) in dioxane (10 ml) was added dropwise HCl (0.836 ml, 3.34 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na₂SO₄) and concentrated to give crude product. LCMS (B) m/z 256.2 (M+H)⁺

The intermediates in Table 15a were prepared using a method similar to that described for the preparation of Intermediate 281.

TABLE 15a
Intermediate 282
Intermediate 283
Intermediate 284

TABLE 15b
Chemical name and analytical data for each intermediate
listed in Table 15a.
Intermediate: Name               Analytical data
282: (S)-1-(4-bromo-2,5-         LCMS m/z (M + H)+ 239.2,
difluorophenyl)ethanamine        RT 0.52 min.
283: (S)-1-(2-fluoro-4-(2,2,2-   LCMS m/z (M + H)+ 238.3,
trifluoroethoxy)phenyl)ethanamine RT 0.57 min.
284: (S)-1-(3-fluoro-4-(2,2,2-   LCMS m/z (M + H)+ 238.3,
trifluoroethoxy)phenyl)ethanamine RT 0.58 min.

Intermediate 285: (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 1H-pyrazole-3-carbaldehyde (1.52 g, 15.82 mmol), 1-chloro-4-iodobenzene (5.66 g, 23.73 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.450 g, 3.16 mmol), copper(I) iodide (0.151 g, 0.791 mmol) and K₂CO₃ (4.37 g, 31.6 mmol) was added toluene (20 mL). The reaction was sealed and heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with water (50 mL), and extracted with EtOAc (3×30 mL). The combined organic was then dried (Na₂SO₄) and concentrated to give crude 1-(4-chlorophenyl)-1H-pyrazole-3-carbaldehyde (1.86 g, 9.0 mmol), to which was added (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.90 mmol), CuSO4 (2.155 g, 13.50 mmol) and DCE (30 ml). The reaction was sealed, heated at 60° C. for 18 hours. A dark green suspension resulted. The reaction mixture was then cooled to 20° C., filtered through a pad of celite, rinsed with DCM. The solution was then concentrated to give final crude product as a light green oil. The residue was purified via silica gel chromatography (EtOAc/Heptane). LCMS (B) m/z 310.3 (M+H)⁺

Intermediate 286: (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH₄Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na₂SO₄) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g). LCMS (B) m/z 326.3 (M+H)⁺

Intermediate 287: (R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethanamine

To a solution of (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na₂SO₄) and concentrated to give product (0.556 g). LCMS (B) m/z 222.2 (M+H)⁺

Intermediate 288: (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH₄Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na₂SO₄) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.01 g). LCMS (B) m/z 326.3 (M+H)⁺

Intermediate 289: (S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethanamine

To a solution of (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na₂SO₄) and concentrated to give crude product (0.501 g). LCMS (B) m/z 222.2 (M+H)⁺

The intermediates in Table 16a were prepared using a method similar to that described for the preparation of Intermediate 289

TABLE 16a
Intermediate 290
Intermediate 291
Intermediate 292
Intermediate 293
Intermediate 294
Intermediate 295

TABLE 16b
Chemical name and analytical data for each intermediate listed in Table 16a.
Intermediate: Name               Analytical data
290: (S)-1-(5-bromo-3-fluoropyridin-2- LCMS (B) m/z (M + H)+ 219.0, 221.0, RT
yl)ethanamine                    0.37 min.
291: (R)-1-(5-bromo-3-fluoropyridin-2- LCMS (B) m/z (M + H)+ 219.0, 221.0, RT
yl)ethanamine                    0.38 min.
292: (S)-1-(5-bromopyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 201.0, 203.0, RT
                                 0.37 min.
293: (R)-1-(5-bromopyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 201.0, 203.0, RT
                                 0.40 min.
294: (S)-1-(3,5-dichloropyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 191.1, RT 0.45 min.
295: (R)-1-(3,5-dichloropyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 191.1, RT 0.44 min.

Intermediate 296: (R)-N-((S)-1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (230 mg, 0.676 mmol) in dioxane/H₂O (5 mL/1 mL) was added sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1′-biphenyl]-3-sulfonate (34.7 mg, 0.068 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid (194 mg, 1.014 mmol), K₂CO₃ (234 mg, 1.690 mmol) followed by Pd₂ dba₃ (31.0 mg, 0.034 mmol). The reaction mixture was sealed and heated to 110° C. and stirred for 2 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL) and water (10 mL). The aqueous layer was then extracted with EtOAc (2×20 mL). The combined organic was then concentrated. The residue was purified by silica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) to give product. (0.25 g). LCMS (B) m/z 407.6 (M+H)⁺

Intermediate 297: (S)-1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethanamine

To a solution of (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na₂SO₄) and concentrated to give crude product (0.501 g). LCMS (B) m/z 303.2 (M+H)⁺

The intermediates in Table 17a were prepared using a method similar to that described for the preparation of Intermediate 297

TABLE 17a
Intermediate 298
Intermediate 299
Intermediate 300

TABLE 17b
Chemical name and analytical data for each intermediate
listed in Table 17a.
Intermediate: Name        Analytical data
298: (S)-1-(2,5-difluoro- LCMS (B) m/z (M + H)+ 249.2, RT 0.34 min.
4-(2-methylpyridin-4-
yl)phenyl)ethanamine
299: (S)-1-(2,5-difluoro- LCMS (B) m/z (M + H)+ 249.1, RT 0.32 min.
4-(6-methylpyridin-3-
yl)phenyl)ethanamine
300: (S)-1-(2,5-          LCMS (B) m/z (M + H)+ 303.2, RT 0.64 min.
difluoro-4-(6-
(trifluoromethyl)pyridin-
3-yl)phenyl)ethanamine

Intermediate 301: (R)-N-((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (80 mg, 0.166 mmol) in toluene/dioxane (8 mL/2 mL) was added Pd₂ dba₃ (60 mg, 0.066 mmol). The reaction mixture was sealed and heated to 120° C. and stirred for 5 minutes. The reaction was cooled to room temperature and 4-methyl-1H-imidazole (157 mg, 1.910 mmol), (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.470 mmol) and K₃PO₄ (624 mg, 2.94 mmol) was added to the reaction mixture. The reaction was sealed and heated to 120° C. for 2 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL) and water (10 mL). The aqueous layer was then extracted with EtOAc (2×20 mL). The combined organic was then concentrated. The residue was purified by silica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) to give (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (500 mg). LCMS (B) m/z 342.6 (M+H)⁺

Intermediate 302: (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine

To a solution of (R)-N-((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg) in MeOH (10 mL) was added dropwise HCl (732 μl, 2.93 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na₂SO₄) and concentrated to give (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (330 mg). LCMS (B) m/z 238.1 (M+H)⁺

Intermediate 303: (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride

Step 1: preparation of tert-butyl 4-formyl-1H-imidazole-1-carboxylate

To di-tert-butyl dicarbonate (23.25 g, 107 mmol) and 1H-imidazole-4-carbaldehyde (9.75 g, 101 mmol) in THF (200 mL) was added DMAP (100 mg, 0.819 mmol). The reaction was stirred for two hours. The reaction mixture was then diluted with saturated NaHCO₃ solution/EtOAc (100 mL/100 mL). The aqueous was then extracted with EtOAc (2×100 mL) and the combined organic was dried (Na₂SO₄) and concentrated to give crude product (19.9 g). LCMS (B) m/z 197.2 (M+H)+

Step 2: preparation of (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate

To CuSO₄ (24.28 g, 152 mmol) and tert-butyl 4-formyl-1H-imidazole-1-carboxylate (19.9 g, 101 mmol) in DCE (100 mL) was added (S)-2-methylpropane-2-sulfinamide (13.52 g, 112 mmol). The reaction was heated to 65° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The pad was rinsed with DCM (200 mL) and the filtrated was concentrated. The residue was then run through a pad of silica gel with heptane/EtOAc (3:1) as eluent. The filtrate was concentrated to give crude (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (22 g). LCMS (B) m/z 300.2 (M+H)⁺

Step 3: preparation of (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide

To (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (18.61 g, 62.2 mmol) in DCM (250 mL) at −70° C. was added dropwise methylmagnesium bromide (83 mL, 249 mmol) in Et₂O. The reaction was stirre at −70° C. for 4 hours. The reaction mixture was then warmed to −40° C. and stirred for one hour. The reaction was then quenched with cautious addition of HCl (1N). Cold bath was removed and while with stirring the aqueous layer was adjusted pH=8. The aqueous layer was separated and extracted with DCM (3×100 mL). The combined organic was dried (Na₂SO₄) and concentrated to give crude product as a mixture of tert-butyl 4-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1H-imidazole-1-carboxylate and (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide, to which was added DCM (300 mL) at 0° C. and formic acid (100 mL, 2651 mmol). The cold bath was then removed and he reaction was stirre for 2 hours. The reaction mixture was then concentrated under reduce pressure to remove DCM and formic acid. The residue was diluted with DCM (400 mL) and washed with saturated Na₂CO₃ aqueous solution (2×200 mL). The combined aqueous was extracted with DCM (2×200 mL). The combined organic was then dried (Na₂SO₄) and concentrated to give (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (12.5 g). LCMS (B) m/z 216.1 (M+H)⁺

Step 4: preparation of (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride

To a 200 mL RBF was added toluene/dioxane (80 ml/20 mL). The flask was cooled to 0° C. and the mixture of solvents was evacuated under high vacuum for 2 minutes and then recharged with argon. The process was repeated three more times. This solvent was then used for the reaction.

A vial containing di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (55.8 mg, 0.116 mmol) and Pd₂(dba)₃ (42 mg, 0.046 mmol) was evacuated under high vacuum for 1 minute and then recharged with argon. The process was repeated three more times and the toluene/dioxane solvent (10 mL) prepared as above was added followed by the palladium/ligand complex prepared as above was then added to the reaction vial containing the other starting materials. The reaction mixture was sealed and heated to 120° C. and stirred for 5 minutes. The reaction was cooled to room temperature.

A separate reaction vial was charged with (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 2.322 mmol), 1-bromo-4-fluorobenzene (447 mg, 2.55 mmol) and K₃PO₄ (986 mg, 4.64 mmol). The vial was evacuated under high vacuum for 1 minute and then recharged with argon. The process was repeated three more times and the palladium/ligand complex prepared as above was then added to the reaction vial containing the other starting materials. The reaction was sealed and heated to 120° C. for 18 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The solid was rinsed with EtOAc (30 mL). The filtrate was then washed with water (2×20 mL). The aqueous layer was then extracted with EtOAc (20 mL). The combined organic was then concentrated. The residue was purified via silica gel chromatography (EtOAc/Heptane 70%-100% with 5% MeOH) to give (S)-N-((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS (B) m/z 310.2 (M+H)⁺

To the above intermediate product was added MeOH (5 mL) and HCl (4M in dioxane, 1 mL). The reaction mixture was stirred for one hour and LCMS showed complete conversion, The mixture was then concentrated to give (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride (300 mg). LCMS (B) m/z 206.0 (M+H)⁺

Intermediate 304: 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde

Step 1: Preparation of ethyl 5,6-dichloronicotinate

To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH (500 mL) at 20° C. was added chlorotrimethylsilane (132 mL, 1042 mmol). The reaction was stirred for 72 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and washed with saturated NaHCO₃ (2×100 mL) and brine (100 mL). The organic was then dried (Na₂SO₄) and concentrated under reduced pressure to give final crude product (21.25 g). LCMS m/z 220.1 (M+H)⁺, Rt 0.94 min.

Step 2: Preparation of ethyl 6-acetyl-5-chloronicotinate

To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) and tetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) was added tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) and PdCl₂(PPh₃)₂ (0.671 g, 0.956 mmol). The reaction was sealed, heated at 80° C. for 5 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20° C., concentrated and diluted with EtOAc (200 mL), and washed with water (50 mL) and brine (50 mL). The organic was then dried (Na₂SO₄) and concentrated to give crude ethyl 5-chloro-6-(1-ethoxyvinyl)nicotinate. The residue was then dissolved in THF (100 mL) and HCl (20 mL, 3M in H₂O) was added. The reaction mixture was stirred at 20° C. for 5 hours, and saturated NaHCO₃ solution was added until pH=8. The mixture was then diluted with EtOAc (200 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics was washed with brine (20 mL), dried (Na₂SO₄) and concentrated to afford the desired product (3.56 g). LCMS m/z 228.5 (M+H)⁺, Rt 0.83 min.

Step 3: Preparation of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate

To a solution of ethyl 6-acetyl-5-chloronicotinate (3.01 g, 13.22 mmol) in CHCl3 (7 mL) was added DAST (5.20 mL, 39.7 mmol) and ethanol (0.061 g, 1.32 mmol). The reaction was sealed, heated at 60° C. for 24 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20° C., and added cautiously with cold concentrated NaHCO₃ aqueous solution (50 mL). The aqueous layer was extracted with DCM (2×100 mL). The combined organic was then dried (Na₂SO₄) and concentrated. The residue was purified via silica gel flash chromatography (0-20 percent EtOAc-Hexanes) to afford the desired product as yellow oil (2.88 g). LCMS m/z 250.1 (M+H)⁺, Rt 0.99 min.

Step 4: Preparation of (5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol

To a solution of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate (2.68 g, 10.74 mmol) in Et₂O (40 mL) was added LiBH₄ (0.351 g, 16.10 mmol), followed by dropwise addition of methanol (0.653 mL, 16.10 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×50 mL). The organic was then dried (Na₂SO₄) and concentrated under reduced pressure to give final crude product (2.12 g). LCMS m/z 208.0 (M+H)⁺, Rt 0.63 min.

Step 5: Preparation of 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde

To a solution of (5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol (2.12 g, 10.21 mmol) in DCM (100 ml) was added PCC (3.30 g, 15.32 mmol). The reaction was stirred at 20° C. for 3 hours. A dark color suspension resulted. LCMS showed clean conversion to the product. The reaction mixture was then filtered through a pad of celite, and washed with DCM (200 mL). The filtrate was then concentrated to give crude product (1.78 g). LCMS m/z 224.0 (M+H2O+H)⁺, Rt 0.72 min.

Intermediate 305: 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde

Step 1: Preparation of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate

To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and 2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at −73° C. was added NaHMDS (37.1 ml, 37.1 mmol). The reaction was stirred at −73° C. for 30 minutes, then at 0° C. for 5 hours. The reaction was quenched with 30 mL saturated NH₄Cl solution. The reaction mixture was then poured into 50 mL brine and phases were separated. The aqueous layer was extracted with DCM (2×100 mL). The combined organics were dried (Na₂SO₄) and concentrated. Silica gel chromatography with 100% heptane to 30% EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M+H)⁺, Rt 1.07 min.

Step 2: Preparation of (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH₄ (0.865 g, 39.7 mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×200 mL). The organic was then dried (Na₂SO₄) and concentrated under reduced pressure to give final crude product (6.31 g). LCMS m/z 242.1 (M+H)⁺, Rt 0.77 min.

Step 3: Preparation of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde

To a solution of (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (4.00 g, 16.56 mmol) in EtOAc (15 mL) was added manganese(IV) oxide (16.93 g, 166 mmol). The reaction was heated with microwave at 120° C. for 30 minutes. The mixture was then filtered through a pad of celite, and rinsed with EtOAc. The filtrated was concentrated to give crude product (3.38 g).

Intermediate 306: (S)-1-(2,3-difluorophenyl)ethanamine

Step 1

To a oven dried round bottom flask with stir bar was added 2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol), (R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04 mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28 mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24 hr. The reaction mixture was filtered through a celite pad washing solids with DCE. Combined filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007 g, 3.26 mmol, 93% yield). MS m/z 246.1 (M+H)⁺; Rt-0.91 min.

Step 2

To a solution of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.800 g, 3.26 mmol) in DCM (32.6 mL), cooled to 0° C. (water/icebath) under N2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in diethyl ether. Reaction mixture allowed to stir for 30 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with EtOAc. Phases partitioned aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried with MgSO4, filtered and concentrated to afford (R)-N-((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.7868 g, 3.01 mmol, 92% yield) as yellow solid. MS m/z 262.0 (M+H)+; Rt-0.70 min.

Step 3

To a round bottom flask containing (R)-N-((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL). To this solution was added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution was allowed to stir 15 min at room temperature. The reaction mixture was concentrated, dissolved in Et2O 10 ml, and concentrated again. Et2O was again added and resulting mixture sonnicated and a solid material was filtered and dried to afford (S)-1-(2,3-difluorophenyl)ethanamine (0.4213 g, 2.176 mmol, 72.3% yield) as a white crystalline HCl salt. ¹H NMR (400 MHz, <d2o>) d ppm 1.55 (d, J=6.99 Hz, 3H) 4.71 (q, J=6.96 Hz, 1H) 7.10-7.26 (m, 3H); MS m/z 158.0 (M+H)+; Rt-0.37 min.

The intermediates in Table A were prepared using a method similar to that described for the preparation of Intermediate 306

TABLE 18a
Intermediate 307
Intermediate 308
Intermediate 309

TABLE 18b
Chemical name, NMR chemical shifts and LCMS signal for
each compound listed in Table 18a.
Intermediate: Name        Analytical data
307: (S)-1-(3,4-          1H NMR (400 MHz, <cd3od>) δ ppm
difluorophenyl)ethanamine 1.61 (d, J = 6.90 Hz, 3 H) 4.47 (q, J = 6.90
                          Hz, 1 H) 7.25-7.30 (m, 1 H)
                          7.32-7.46 (m, 2 H)
                          LCMS m/z 158.1.1 (M + H)+; Rt-0.39 min.
308: (S)-1-(2,4-          1H NMR (400 MHz, <cd3od>) δ ppm
difluorophenyl)ethanamine 1.65 (d, J = 1.00 Hz, 3 H) 4.71 (q, J = 6.91
                          Hz, 1 H) 7.05-7.15 (m, 2 H)
                          7.51-7.61 (m, 1 H)
                          LCMS m/z 158.1.1 (M + H)+; Rt-0.37 min.

Intermediate 310: (S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine

Step 1: Preparation 1-(4-bromo-3-fluorophenyl)ethanol

Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification.

LCMS m/z 201.0 (M−H₂O)⁺, Rt 0.75 min.

Step 2: Preparation 1-(4-bromo-3-fluorophenyl)ethanone

To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (from Step 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82 mmol). The mixture was stirred overnight at room temperature. To the mixture was added celite, the reaction mixture was filtered through a celite pad and rinsed several times with DCM. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography [SiO₂, 40 g, heptane/ethyl acetate] providing 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid. ¹H NMR (400 Mhz, CDCl₃) δ ppm 7.72-7.58 (m, 3H), 2.59 (s, 3H).

Step 3: Preparation 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene

To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g, 14.19 mmol) in chloroform (15 mL) was added DAST (5.62 mL, 42.6 mmol) and ethanol (0.083 mL, 1.42 mmol). The orange solution was heated at 60° C. for 24 hr in a sealed container. The reaction mixture was allowed to cool to ˜20° C. and to the mixture was added slowly saturated aqueous sodium bicarbonate solution (75 mL). Stirring was continued until off-gassed ceased (˜15 min). The separated aqueous layer was diluted with additional saturated aqueous sodium bicarbonate solution (25 mL) and carefully mixed. The basic aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, heptane/ethyl acetate] providing 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g) as a slightly cloudy colorless oil. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.73 (dd, J=7.2, 8.1 Hz, 1H), 7.40 (dd, J=2.0, 9.4 Hz, 1H), 7.29 (m, J=1.0 Hz, 1H), 1.92 (t, J=18.4 Hz, 3H).

Step 4: Preparation 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde

To a solution of 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g, 8.79 mmol) in THF (30.3 mL) was added n-butyllithium (1.6M in hexanes, 5.60 mL) over ˜20 min at −78° C. The mixture was stirred for 30 min at −78° C. and DMF (1.02 mL, 13.18 mmol) was added dropwise over ˜4 min. Stirring was continued for 1 hr, the mixture was diluted/quenched with 1N aqueous HCl/MeOH (2/1, 15 mL) and allowed to warm to room temperature. The reaction mixture was diluted further with water (50 mL) and extracted with diethylether (2×50 mL). The combined organic layers were washed with 1N aqueous sodium hydroxide solution (50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography [SiO₂, 40 g, heptane/ethyl acetate] providing 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (699 mg) as a dark yellow, volatile oil, which was contaminated with 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene. ¹H NMR (400 Mhz, CDCl₃) δ ppm 10.40 (s, 1H), 7.95 (t, J=7.4 Hz, 1H), 7.39-7.47 (m, 2H), 7.35 (d, J=10.6 Hz, 1H), 1.94 (t, J=18.2 Hz, 4H) 7.73 (dd, J=7.2, 8.1 Hz, 1H).

Step 5: Preparation (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (693 mg, from Step 4) and (R)-2-methylpropane-2-sulfinamide (513 mg, 4.24 mmol) in DCE (12.9 mL) was added copper(II) sulfate (882 mg, 5.52 mmol). The reaction mixture was placed in a pre-heated oil bath (55° C.) and heated for ˜2 d. The mixture was allowed to cool to room temperature, filtered through a pad of celite and rinsed with DCE. The combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 24 g, heptane/ethyl acetate] providing (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg) as a yellow oil. LCMS m/z 292.1 (M+H)⁺, Rt 0.97 min.

Step 6: Preparation N-((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg, 1.706 mmol) in DCM (9.59 mL) was added methylmagnesium bromide (3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowed to stir for 1 hr at 0° C., gradually allowed to warm to room temperature and stirred for 1 hr at room temperature. The mixture was cooled to 0° C., additional methylmagnesium bromide (3M in diethylether; 0.5 mL) was added and stirring was continued for 30 min at 0° C. The reaction mixture was carefully quenched with saturated aqueous ammonium chloride solution (6 mL) and diluted with water (20 mL). The separated aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with brine (50 mL), concentrated under reduced pressure. The residue was purified by column chromatography [SiO₂, 24 g, heptane/ethyl acetate] providing N-((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg) as a white solid. LCMS m/z 308.2 (M+H)⁺, Rt 0.91 min.

Step 7: Preparation (5)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine

To N-((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg, 1.135 mmol) was added 4M HCl in dioxane (3.01 mL) to give a purple solution. To the mixture was added diethylether (20 mL) and the mixture was stirred for 15 min at ˜10° C. The mixture was concentrated under reduced pressure to ˜2 mL of volume and diethylether (20 mL) was added. The solids were filtered off, rinsed with diethylether (4×10 mL) and dried under reduced pressure providing (S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine (244 mg) as an off-white solid (HCl salt). LCMS m/z 204.1 (M+H)⁺, Rt 0.42 min.

Intermediate 311: (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate

A slurry of (S)-3-(1-aminoethyl)phenol (1.188 g, 6.84 mmol) and Boc₂O (1.747 mL, 7.53 mmol) in DCM (17.10 mL) was stirred at room temperature under N₂ while slowly adding DIEA (1.434 mL, 8.21 mmol). The initially insoluble starting materials slowly dissolve. The solution was stirred at room temperature for 16 hours and then concentrated. The oily residue was re-dissolved in EtOAc and washed with Na₂CO₃ saturated, followed by brine. The original aqueous layer was re-extracted with EtOAc, which was then washed with brine and combined with the previous EtOAc batch. The combined organics were dried over Na₂SO₄, filtered and concentrated to 2.4 g crude clear yellowish oil which was purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%), yielding (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate as a clear colourless oil, which solidifies upon sitting (1.79 g, 7.55 mmol, 110% yield). ¹H NMR (400 MHz, CDCl₃) d 1.44 (br. s., 12H) 4.08-4.18 (m, 1H) 4.76 (br. s., 1H) 6.72 (dd, J=7.46, 1.83 Hz, 1H) 6.78 (br. s., 1H) 6.88 (br. s., 1H) 7.16-7.24 (m, 1H). LCMS m/z 223.0/182.0 (the parent not observed, just the Boc fragments) (M+H)⁺, Rt 0.71 min.

Intermediate 312: (S)-tert-butyl 1-(4-hydroxy-3-methylphenyl)ethylcarbamate

Made as above Intermediate 195: (S)-tert-butyl 1-(4-hydroxy-3-methylphenyl)ethylcarbamate, clear colourless oil. (1.27 g, 5.05 mmol, 103% yield). ¹H NMR (400 MHz, CDCl₃) d 1.42 (s, 9H) 1.54 (s, 3H) 2.24 (s, 3H) 4.70 (br. s., 1H) 6.72 (d, J=8.22 Hz, 1H) 7.01 (d, J=9.00 Hz, 1H) 7.05 (s, 1H). LCMS m/z 252.2 (M+H)⁺, Rt 0.80 min.

Intermediate 313: (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine hydrochloride

Step 1

To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100 mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh₃ (221 mg, 0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol) dropwise, under N₂, at room temperature. The resulting yellow solution was stirred for 3 hours, at which point another batch of cyclohexanol (0.180 ml, 1.686 mmol), PPh₃ (221 mg, 0.843 mmol), and 10 min later DEAD (0.133 ml, 0.843 mmol), was added at room temperature. The reaction mixture was stirred for 16 hours and then concentrated. The crude clear oil was re-dissolved in DMSO and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na₂CO₃ in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to yield (S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0% yield) as a clear colourless film. LCMS m/z 305.0/264.0 (the parent not observed, just the Boc fragments) (M+H)⁺, Rt 1.12 min.

Step 2

(S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and the resulting mixture was allowed to sit for 1 hour, then concentrated to yield (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine as an HCl salt (yield assumed quantitative). LCMS m/z 220.1 (M+H)⁺, Rt 0.66 min.

The Intermediates in Table 19 were prepared using the method described for the preparation of Intermediate 313.

TABLE 19
Intermediate: Name	Structure	LCMS
314: (S)-1-(3-((S)-tetrahydrofuran-3- yloxy)phenyl)ethanamine		MS m/z 208.1 (M + H)+, Rt 0.41 min.
315: (S)-1-(3- isobutoxyphenyl)ethanamine		MS m/z 194.1 (M + H)+, Rt 0.61 min.
316: (S)-1-(4-isobutoxy-3- methylphenyl)ethanamine		MS m/z 191.1 (M + H)+, Rt 0.70 min.
317: (S)-1-(2-fluoro-4- isobutoxyphenyl)ethanamine		MS m/z 195.2 (M + H)+, Rt 0.64 min.
318: (S)-1-(4- (cyclopropylmethoxy)phenyl)ethanamine		MS m/z 175.1 (M + H)+, Rt 0.53 min.

Intermediate 319: (S)-1-(3-phenoxyphenyl)ethanamine

Into a 20 ml microwave vial was weighted 1-(pyridin-2-yl)propan-2-one ligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg, 0.332 mmol) and Cs₂CO₃ (2166 mg, 6.65 mmol). To the mixture was added DMSO (5 ml) and (S)-1-(3-bromophenyl)ethanamine (0.5 ml, 3.32 mmol). The tube was flushed with N₂, capped, and the black mixture heated in the oil bath at 90° C. for 18 hours. The heterogenous mixture was diluted with EtOAc and filtered through a glass-fritted funnel, eluting with EtOAc and another 5 mls of DMSO. The volatiles were then removed in vacuo and the crude brown liquid was filtered through 1 um PTFE filter and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na₂CO₃ in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to yield (S)-1-(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5% yield) as an amber oil. LCMS m/z 214.1 (M+H)⁺, Rt 0.61 min.

Intermediate 320: (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine

Step 1

To a cloudy solution of 4-(trifluoromethoxy)benzaldehyde (5 g, 26.3 mmol) and (R)-2-methylpropane-2-sulfinamide (3.51 g, 28.9 mmol) in DCE (52 mL), under N₂, was added copper (II) sulfate (6.30 g, 39.4 mmol), and the resulting mixture heated in a preheated oil bath at 55° C. for 22 hours. The reaction mixture was filtered through a pad of celite, eluting with DCM. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.9 g, 26.9 mmol, 102% yield). Material was taken onto next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.27 (s, 9H) 7.32 (d, J=8.07 Hz, 2H) 7.91 (d, J=8.75 Hz, 2H) 8.59 (s, 1H). LCMS m/z 294.1 (M+H)⁺, Rt 1.01 min.

Step 2

To a solution of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.7 g, 26.3 mmol) in CH₂Cl₂ (150 mL), cooled to 0° C. (water/ice bath), under nitrogen, was added 3M methyl magnesium bromide (35 mL, 105 mmol) in Et₂O. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm up to room temperature and stirred additional 4 hrs. The reaction mixture was cooled again to 0° C. and quenched with the slow addition of a saturated NH₄Cl solution. The by-phasic mixture was diluted with DCM and Water and the aqueous extracted with DCM two times. The organic phases were combined, washed with brine, dried (Na₂SO₄), filtered and concentrated to 11.5 g crude white solid. Silica gel column chromatography (EtOAc/Heptane 0 to 30%) afforded (R)-2-methyl-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.2 mmol, 62% yield) as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 1.21 (s, 9H) 1.53 (d, J=6.70 Hz, 3H) 3.31 (d, J=2.74 Hz, 1H) 4.59 (qd, J=6.67, 3.37 Hz, 1H) 7.18 (d, J=8.02 Hz, 2H) 7.36 (d, J=8.66 Hz, 2H). LCMS m/z 310.2 (M+H)⁺, Rt 0.90 min.

Step 3

(R)-2-methyl-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.4 mmol) was dissolved by swirling in 4M HCl in dioxane (16.4 ml, 65.6 mmol), at room temperature. The solution was allowed to sit for 1 hr with occasional swirling. To the clear solution was added 45 ml ether and the resulting cloudy solution sonicated for 1 min, upon which time the white solid product precipitates out. The solid was filtered through a Buchner funnel, washed 5 times with ˜20 ml ether and allowed to air dry. Obtained (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (3.2 g, 13.2 mmol, 80% yield), ¹H NMR (400 MHz, CD₃OD) δ 1.64 (d, J=6.90 Hz, 3H) 4.52 (q, J=6.88 Hz, 1H) 7.38 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.71 Hz, 2H). LCMS m/z 206.1 (M+H)⁺, Rt 0.52 min.

The Intermediates in Table 20 were prepared using the method described for the preparation of Intermediate 320.

TABLE 20
Intermediate: Name	Structure	1H NMR (400 MHz, CD3OD), LCMS
321: (S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl) ethanamine		δ ppm 1.66 (d, J = 6.94 Hz, 3 H) 4.75 (q, J = 6.94 Hz, 1 H) 7.23-7.31 (m, 2 H) 7.60- 7.68 (m, 1 H). MS m/z 224.1 (M + H)+ Rt 0.54 min.
322: (S)-1-(4- (difluoromethoxy)phenyl) ethanamine		δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.48 (q, J = 6.88 Hz, 1 H) 6.63-7.10 (m, 1 H) 7.24 (d, J = 8.71 Hz, 2 H) 7.50 (d, J = 8.66 Hz, 2 H). MS m/z 171.1 (M + H)+, Rt 0.43 min.
323: (S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl) ethanamine		δ ppm 1.64 (d, J = 6.90 Hz, 3 H) 4.54 (q, J = 6.88 Hz, 1 H) 7.39 (dt, J = 8.52, 1.56 Hz, 1 H) 7.46-7.59 (m, 2 H). MS m/z 224.1 (M + H)+, Rt 0.55 min.
324: (S)-1-(4- (difluoromethoxy)-3- fluorophenyl)ethanamine		δ ppm 1.62 (d, J = 6.90 Hz, 3 H) 4.49 (q, J = 6.83 Hz, 1 H) 6.67-7.10 (m, 1 H) 7.27- 7.33 (m, 1 H) 7.35-7.44 (m, 2 H). MS m/z 206.1 (M + H)+, Rt 0.46 min.
325: (S)-1-(4- (difluoromethoxy)-2- fluorophenyl)ethanamine		δ ppm 1.65 (d, J = 6.94 Hz, 3 H) 4.71 (q, J = 6.94 Hz, 1 H) 6.71-6.97 (m, 1 H) 7.05- 7.14 (m, 2 H) 7.55 (t, J = 8.68 Hz, 1 H). MS m/z 206.1 (M + H)+, Rt 0.46 min.
326: (S)-1-(3- (trifluoromethoxy)phenyl) ethanamine		δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.53 (q, J = 6.86 Hz, 1 H) 7.35 (ddt, J = 8.21, 2.27, 1.09, 1.09 Hz, 1 H) 7.41 (s, 1 H) 7.47 (d, J = 7.82 Hz, 1 H) 7.54-7.61 (m, 1 H). MS m/z 206.1 (M + H)+, Rt 0.51 min.
327: (S)-1-(3- (difluoromethoxy)phenyl) ethanamine		δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.49 (q, J = 6.88 Hz, 1 H) 6.64-7.08 (m, 1 H) 7.21 (dd, J = 8.19, 1.83 Hz, 1 H) 7.26 (t, J = 2.03 Hz, 1 H) 7.33 (d, J = 7.78 Hz, 1 H) 7.45-7.53 (m, 1 H). MS m/z 188.1 (M + H)+, Rt 0.43 min.

Intermediate 328: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To a Parshaker flask were added benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (850 mg, 1.56 mmole) and 20% Pd(OH)₂ in activated carbon (880 mg, 1.25 mmole), then was added MeOH (100 mL) under nitrogen gas. The reaction mixture was shaked under 50 psi hydrogen overnight. The reaction mixture was filtered through a celite. The celite cake was washed with MeOH and the filtrate was concentrate in vacuo. The resulting crude product was purified by flash column chromatography (basic alumina, 40 g) eluting w/0-20% MeOH/DCM to afford the title product as a white solid (230 mg). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.18 (d, J=2.87 Hz, 1H), 5.15 (br s, 1H), 4.71-4.63 (m, 1H), 4.56-4.47 (m, 1H), 4.47-4.34 (m, 2H), 4.25-4.14 (m, 1H), 3.96-3.82 (m, 1H), 3.16 (d, J=12.34 Hz, 2H), 2.67-2.54 (m, 2H), 1.85-1.66 (m, 2H), 1.64-1.52 (m, 1H), 1.40-1.26 (m, 2H), 1.20 (d, J=6.60 Hz, 3H), 1.18 (s, 9H), 1.10 (d, J=6.46 Hz, 3H). HRMS (C) tR=2.36 min; MS m/z 410.2571 (M+H)+

Intermediate 329: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (32 mg, 0.078 mmol), 4-bromo-1-chloro-2-(trifluoromethyoxy)benzene (26 mg, 0.094 mmol), Pd(OAc)₂ (2 mg, 8 umol), BINAP (5 mg, 8 umol), and Cs₂CO₃ (51 mg, 0.156 mmol) in 6 mL toluene was heated at 90° C. for 3 days. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (34 mg). (400 MHz, CD₂Cl₂) δ 8.19 (d, J=2.95 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.87-6.80 (m, 2H), 5.05 (br s, 1H), 4.73-4.63 (m, 1H), 4.56-4.44 (m, 2H), 4.25-4.13 (m, 1H), 4.01-3.88 (m, 1H), 3.79-3.69 (m, 2H), 2.82-2.69 (m, 2H), 2.00-1.79 (m, 2H), 1.68-1.56 (m, 1H), 1.54-1.36 (m, 2H), 1.23 (d, J=6.87 Hz, 3H), 1.15 (s, 9H), 1.09 (d, J=6.44 Hz, 3H), HRMS (C) tR=5.61 min; MS m/z 604.2328 (M+H)+

The intermediates in Table 21 were prepared with procedures similar to those used to prepare Intermediate 301

TABLE 21
Intermediate: Name	Structure	LCMS
330: (R)-N-((S)-1-(5-chloro-6- (1,1-difluoroethyl)pyridin-3- yl)ethyl)-2-methylpropane-2- sulfinamide		MS m/z 325.2 (M + H)+, Rt 0.85 min.
331: (R)-N-((S)-1-(5-chloro-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-2-methylpropane-2- sulfinamide		MS m/z 359.1 (M + H)+, Rt 0.95 min.
332: (S)-1-(5-chloro-6-(1,1- difluoroethyl)pyridin-3- yl)ethanamine		MS m/z 221.1 (M + H)+, Rt 0.50 min.
333: (S)-1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethanamine		MS m/z 255.1 (M + H)+, Rt 0.62 min.

The intermediates in Table 22 were prepared with procedures similar to those used to prepare Intermediate 302

TABLE 22
Intermediate: Name	Structure	LCMS
332: (S)-1-(5-chloro-6-(1,1- difluoroethyl)pyridin-3- yl)ethanamine		MS m/z 221.1 (M + H)+, Rt 0.50 min.
333: (S)-1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethanamine		MS m/z 255.1 (M + H)+, Rt 0.62 min.

The intermediates in Table 23a were prepared using a method similar to that described for the preparation of Intermediate 306

TABLE 23a
Intermediate 334
Intermediate 335
Intermediate 336
Intermediate 337
Intermediate 338
Intermediate 339
Intermediate 340
Intermediate 341

TABLE 23b
Chemical name and analytical data for each intermediate listed in Table 23a.
Intermediate: Name               Analytical data
334: (S)-1-(4-bromo-2,5-difluorophenyl)ethanamine LCMS m/z (M + H)+ 236.0, RT 0.5 min.
335: (S)-1-(4-bromo-2,3-difluorophenyl)ethanamine LCMS m/z (M + H)+ 238.1, RT 0.55 min.
336: (S)-1-(4-bromo-2-fluorophenyl)ethanamine LCMS m/z (M + H)+ 218.0, 220.1, RT
                                 0.47 min.
337: (S)-1-(4-chloro-2-fluorophenyl)ethanamine LCMS m/z (M + H)+ 174.2, RT 0.47 min.
338: (S)-1-(4-bromo-3-fluorophenyl)ethanamine LCMS m/z (M + H)+ 218.1, 220.1, RT
                                 0.52 min.
339: (S)-1-(3,4-dichlorophenyl)ethanamine LCMS m/z (M + H)+ 190.0, RT 0.57 min.
340: (S)-1-(6-chloro-5-fluoropyridin-3- LCMS m/z (M + H)+ 175.2, RT 0.37 min.
yl)ethanamine
341: (S)-1-(5,6-dichloropyridin-3-yl)ethanamine LCMS m/z (M + H)+ 191.1, RT 0.42 min.

Intermediate 342: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (112 mg, 0.40 mmol), (S)-1-phenylethanamine (58 mg, 0.48 mmol, 1.2 equiv), and DIPEA (153 mg, 1.2 mmol, 3.0 equiv) in DMSO (4.0 mL) was heated at 100° C. for 90 min. The reaction mixture was poured into 5 ml of water, extracted with EA (2×10 ml), the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) provided the pure product (142 mg, white solid) in a 93% yield. HRMS m/z 385.2231 (M+H)⁺, RT=3.35 min.

The Following Intermediates were prepared using a method similar to that described for the preparation of Intermediate 342 or Example 3

Intermediate 343: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=3.54 min; m/z 492.2485

Intermediate 344: (4R)-3-(2-((1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

HRMS (C) tR=1.76 min; MS m/z 561.43

Intermediate 345: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.94 min; m/z 480.2485

Intermediate 346: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.78 min; m/z 498.2391

Intermediate 347: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.71 min; m/z 480.2485

Intermediate 348: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=2.77 min; m/z 504.2337 (M+H)

Intermediate 349: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.96 min; m/z 554.1656

Intermediate 350: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=3.13 min; m/z 518.2089

Intermediate 351: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.97 min; m/z 536.1995

Intermediate 352: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.91 min; m/z 520.2046

Intermediate 353: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.87 min; m/z 520.2046

Intermediate 354: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.76 min; m/z 536.1995

Intermediate 355: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.76 min; m/z 550.2151

Intermediate 356: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=3.38 min; m/z 532.1882

Intermediate 357: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.63 min; m/z 480.2485

Intermediate 358: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=1.65 min; MS m/z 518.1 (M+H)

Intermediate 359: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=1.59 min; MS m/z 486.2

Intermediate 360: (4R)-3-(2-((1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

HRMS (C) tR=1.76 min; MS m/z 561.43

Intermediate 361: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.94 min; m/z 480.2485

Intermediate 362: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.96 min; m/z 512.2548

Intermediate 363: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.78 min; m/z 498.2391

Intermediate 364: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.71 min; m/z 480.2485

Intermediate 365: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=2.77 min; m/z 504.2337 (M+H)

Intermediate 366: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.96 min; m/z 554.1656

Intermediate 367: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=3.13 min; m/z 518.2089

Intermediate 368: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.97 min; m/z 536.1995

Intermediate 369: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.91 min; m/z 520.2046

Intermediate 370: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.87 min; m/z 520.2046

Intermediate 371

(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.76 min; m/z 536.1995

Intermediate 372: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.76 min; m/z 550.2151

Intermediate 373

(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=3.38 min; m/z 532.1882

Intermediate 374: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (C) tR=1.63 min; m/z 480.2485

Intermediate 375: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=1.65 min; MS m/z 518.1 (M+H)

Intermediate 376: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS (B) tR=1.59 min; MS m/z 486.2

Intermediate 377: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Anal. RP-HPLC tR=1.69 min; MS m/z 611.1 (M+H)⁺.

Intermediate 378: benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CD₂Cl₂) δ 8.18 (s, 1H), 7.41-7.30 (m, 5H), 5.15 (s, 2H), 5.03 (br s, 1H), 4.71-4.64 (m, 1H), 4.54-4.45 (m, 2H), 4.30-4.12 (m, 3H), 3.99-3.86 (m, 1H), 2.77 (br s, 2H), 1.87-1.57 (m, 3H), 1.36-1.24 (m, 2H), 1.20 (d, J=6.44 Hz, 3H), 1.16 (s, 9H), 1.09 (d, J=5.91 Hz, 3H). HRMS (C) tR=4.46 min; MS m/z 544.2964 (M+H)+

Intermediate 379: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.72 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.79 (dd, J=8.1, 2.4 Hz, 1H), 7.47 (d, J=5.8 Hz, 1H), 7.39-7.28 (m, 3H), 7.13-7.07 (m, 1H), 5.28 (p, J=6.9 Hz, 1H), 4.75 (dt, J=8.1, 3.5 Hz, 1H), 4.62 (dd, J=9.4, 3.1 Hz, 1H), 4.49-4.40 (m, 1H), 4.34 (t, J=9.0 Hz, 1H), 2.35 (d, J=1.9 Hz, 3H), 1.60 (d, J=6.7 Hz, 3H), 1.25 (s, 12H), 1.01 (d, J=6.5 Hz, 3H); MS m/z 492.6 (M−H).

Intermediate 380: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.86 min; MS m/z 528.5 (M−H)⁺.

Intermediate 381: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(4-fluoro-3-methylphenyl)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.69 min; MS m/z 494.0 (M+H)+.

Intermediate 382: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.74 min; MS m/z 530.0 (M+H)⁺.

Intermediate 383: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.86 (d, J=2.3 Hz, 1H), 8.83 (d, J=5.1 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 7.93 (dd, J=8.1, 2.4 Hz, 1H), 7.87 (s, 1H), 7.69 (dd, J=5.2, 1.7 Hz, 1H), 7.48 (d, J=5.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 6.37-5.79 (m, 1H), 5.33 (p, J=6.9 Hz, 1H), 4.74 (ddd, J=8.2, 4.6, 3.0 Hz, 1H), 4.62 (dd, J=9.3, 3.0 Hz, 1H), 4.43 (qd, J=6.4, 4.2 Hz, 1H), 4.34 (t, J=9.0 Hz, 1H), 1.67 (br s, 1H), 1.62 (d, J=6.8 Hz, 3H), 1.26 (s, 9H), 1.02 (d, J=6.4 Hz, 3H); MS m/z 531.3 (M+H).

Intermediate 384: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6′-(trifluoromethyl)-[2,3′-bipyridin]-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.51 min; MS m/z 531.1 (M+H).

Intermediate 385: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.51 min; MS m/z 531.3 (M+H).

Intermediate 386: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.59 min; MS m/z 531.2 (M+H).

Intermediate 387: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.60 min; MS m/z 545.2 (M+H).

Intermediate 388: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.65 min; MS m/z 545.2 (M+H).

Intermediate 389: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-fluoro-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.65 min; MS m/z 549.2 (M+H).

Intermediate 390: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.65 min; MS m/z 545.6 (M+H).

Intermediate 391: (R)-4-((S)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.63 min; MS m/z 543.5 (M+H).

Intermediate 392: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=0.94 min; MS m/z 486.0 (M−H).

Intermediate 393: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.81 min; MS m/z 534.5 (M−H).

Intermediate 394: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.74 min; MS m/z 531.0 (M+H).

Intermediate 395: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.71 min; MS m/z 495.0 (M+H).

Intermediate 396: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(2,4-dichlorophenyl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.84 min; MS m/z 536.0 (M+H).

Intermediate 397: (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

LCMS tR=1.77 min; MS m/z 548.0 (M+H).

Intermediate 398: 4-(2-((S)-1-((4-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)thiazol-4-yl)benzonitrile

LCMS tR=1.55 min; MS m/z 493.1 (M+H).

Intermediate 399: (R)-3-(2-(((S)-1-(5-bromopyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.61 (d, J=2.2 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H), 7.78 (dd, J=8.3, 2.3 Hz, 1H), 7.50 (d, J=5.9 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 5.22 (p, J=6.9 Hz, 1H), 4.72 (ddd, J=8.3, 4.7, 3.0 Hz, 1H), 4.62 (dd, J=9.3, 3.0 Hz, 1H), 4.41-4.31 (m, 2H), 1.56 (d, J=6.8 Hz, 3H), 1.21 (s, 9H), 1.00 (d, J=6.4 Hz, 3H). MS m/z 466.2 (M+H).

Intermediate 400: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Anal. RP-HPLC tR=1.54, 1.56 min (Column=Acquity BEH C18 1.7 μm 2.1×50 mm. Column Temperature=50° C. Eluents=A: Water (3.75 mM Ammonium formate, 2% ACN); B: ACN (3.75 mM Ammonium formate, 5% Water). Flow Rate=1 mL/min. Gradient=2% to 98% B in 1.70 min.; MS m/z 549.3 (M+H)⁺.

Intermediate 401: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

Anal. RP-HPLC tR=1.69 min; MS m/z 549.4 (M+H)⁺.

Intermediate 402: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one (0.146 g, 0.371 mmol), (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (91 mg, 0.41 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.097 mL, 0.56 mmol, 1.5 equiv) in DMSO (2.0 mL) was heated at 85° C. for 18 h. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20% to 60%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-one as a yellow oily solid in 37% yield. MS m/z 537.2 (M+H)⁺; Rt-1.22 min.

Intermediate 403: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (70 mg, 0.209 mmol), (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (60 mg, 0.23 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.091 mL, 0.52 mmol, 2.5 equiv) in DMSO (1.0 mL) was heated at 85-110° C. for 3-5 h. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 520.2 (M+H)⁺; Rt-1.31 min.

The intermediates in Table 24a were prepared using a method similar to that described for the preparation of Intermediate 403.

TABLE 24a
Intermediate 405
Intermediate 406
Intermediate 407
Intermediate 408
Intermediate 409
Intermediate 410
Intermediate 411
Intermediate 412
Intermediate 413
Intermediate 414
Intermediate 415
Intermediate 416
Intermediate 417
Intermediate 418
Intermediate 419
Intermediate 420
Intermediate 421
Intermediate 422
Intermediate 423
Intermediate 424
Intermediate 425
Intermediate 426
Intermediate 427
Intermediate 428
Intermediate 429
Intermediate 430
Intermediate 431
Intermediate 432
Intermediate 433
Intermediate 434
Intermediate 435
Intermediate 436
Intermediate 437
Intermediate 438
Intermediate 439
Intermediate 440
Intermediate 441
Intermediate 442
Intermediate 443
Intermediate 444
Intermediate 445
Intermediate 446
Intermediate 447
Intermediate 448
Intermediate 449
Intermediate 450
Intermediate 451
Intermediate 452
Intermediate 453
Intermediate 454
Intermediate 455
Intermediate 456
Intermediate 457
Intermediate 458
Intermediate 459
Intermediate 460
Intermediate 461
Intermediate 462
Intermediate 463
Intermediate 464
Intermediate 465
Intermediate 466
Intermediate 467
Intermediate 468
Intermediate 469
Intermediate 470

TABLE 24b
Chemical name and analytical data for
each intermediate listed in Table 24a.
Intermediate: Name               Analytical data
405: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 521.1
((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5- (M + H)+;
yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.29 min
406: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 505.3
((S)-1-(2-fluoro-4-              (M + H)+;
(trifluoromethyl)phenyl)ethylamino)pyrimidin-4- Rt-1.29 min
yl)oxazolidin-2-one
407: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 517.2
((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2- Rt-1.13 min
one
408: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 535.2
(((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- Rt-1.14 min
one
409: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 486.3
(((S)-1-(5-phenylisoxazol-3-     (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.25 min
410: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 537.2
(((S)-1-(2-(4-chlorophenyl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.33 min
411: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 520.2
(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5- (M + H)+;
fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.16 min
412: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 504.2
(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-5- (M + H)+;
fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.16 min
413: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 537.2
(((S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.28 min
414: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 519.3
(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.30 min
415: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 503.4
(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-5- (M + H)+;
fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.11 min
416: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 518.2
(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6- (M + H)+;
(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one Rt-1.18 min
417: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 534.2
(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6- (M + H)+;
(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one Rt-1.21 min
418: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 502.2
(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin- (M + H)+;
4-yl)oxazolidin-2-one            Rt-0.99 min
419: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 485.4
(4-chlorophenyl)-1H-pyrazol-4-   (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.93 min
420: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 520.2
(((S)-1-(3-(4-chlorophenyl)isoxazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.30 min
421: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3- MS m/z 504.3
(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)-5- (M + H)+;
fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.13 min
422: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 504.3
(((S)-1-(5-(4-fluorophenyl)isoxazol-3- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.22 min
423: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 509.4
(((S)-1-(5-(morpholinomethyl)isoxazol-3- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.80 min
424: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 509.4
(((R)-1-(5-(morpholinomethyl)isoxazol-3- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.83 min
425: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3
(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6- (M + H)+;
methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.98 min
426: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.2
(((S)-1-(2-(pyridin-2-yl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.19 min
427: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.3
(((S)-1-(2-(pyridin-3-yl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.92 min
428: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.3
(((S)-1-(2-(pyridin-4-yl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.89 min
429: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 500.4
(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6- (M + H)+;
methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.02 min
430: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 516.3
(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6- (M + H)+;
methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.04 min
431: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3
(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6- (M + H)+;
methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.76 min
432: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3- MS m/z 501.3
(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)- (M + H)+;
6-methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.04 min
433: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3
(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)amino)-6- (M + H)+;
methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.02 min
434: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 500.2
(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)amino)- (M + H)+;
6-methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.88 min
435: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 520.2
(((S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.14 min
436: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 486.3
(4-chlorophenyl)-1H-1,2,3-triazol-4- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.87 min
437: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4- MS m/z 481.4
(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-6- (M + H)+;
methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.94 min
438: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 533.4
(2,5-difluoro-4-(2,2,2-          (M + H)+;
trifluoroethoxy)phenyl)ethyl)amino)-6- Rt-0.96 min
methylpyrimidin-4-yl)oxazolidin-2-one
439: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-methyl-2- MS m/z 497.3
(((S)-1-(2-(6-methylpyridin-3-yl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.63 min
440: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 537.3
(6-(trifluoromethyl)pyridin-3-yl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.95 min
441: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 537.3
(2-(trifluoromethyl)pyridin-4-yl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.80 min
442: methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2- MS m/z 560.3
oxooxazolidin-3-yl)-2-(((S)-1-(2-(4- (M + H)+;
chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidine-4- Rt-1.20 min
carboxylate
443: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.2
(4-chlorophenyl)-2-methyl-1H-imidazol-4- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.77 min
444: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 518.3
(4-(difluoromethyl)phenyl)thiazol-5- (M + H)+;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.89 min
445: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4- MS m/z 499.2
chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6- (M + H)+;
(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one Rt-1.27 min.
446: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 471.3
fluoro-4-(trifluoromethyl)phenyl)ethylamino) (M + H)+;
pyrimidin-4-yl)oxazolidin-2-one  Rt-1.01 min
447: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-(1- MS m/z 487.3
ethoxycyclopropyl)-2-fluorophenyl)ethylamino) (M + H)+;
pyrimidin-4-yl)oxazolidin-2-one  Rt-1.02 min
448: 4-((S)-1-(4-((R)-4-((R)-1-tert-butoxyethyl)-2- MS m/z 530.3
oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)-2- (M + H)+;
chloro-N-cyclopentylbenzamide    Rt-0.91 min
449: 1-(4-((S)-1-(4-((R)-4-((R)-1-tert-butoxyethyl)-2- MS m/z 468.3
oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)-3- (M + H)+;
fluorophenyl)cyclopropanecarbonitrile Rt-0.91 min
450: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 483.3
fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl) (M + H)+;
ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.86 min
451:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-(1- MS m/z 465.3
methyl-1H-pyrazol-4-yl)phenyl)ethylamino) (M + H)+;
pyrimidin-4-yl)oxazolidin-2-one  Rt-0.83 min
452: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 469.3
fluoro-4-(1H-pyrazol-4-yl)phenyl)ethylamino) (M + H)+;
pyrimidin-4-yl)oxazolidin-2-one  Rt-0.80 min
453: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 489.3
((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl) (M + H)+;
ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.15 min
454: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 457.4
fluoro-4-(1-methylcyclopropyl)phenyl) (M + H)+;
ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.06 min
455: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 445.3
fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4- (M + H)+;
yl)oxazolidin-2-one              Rt-1.05 min
456: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 501.3
((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2- Rt-0.98 min
one
457: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 475.3
((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl) (M + H)+;
ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.20 min
458: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 487.2
((S)-1-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl) (M + H)+;
ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.90 min
459: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 463.3
((S)-1-(2-fluoro-4-isopropylphenyl)ethylamino) (M + H)+;
pyrimidin-4-yl)oxazolidin-2-one  Rt-1.20 min
460: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2- MS m/z 461.3
(((S)-1-(2-fluoro-4-(2-hydroxypropan-2- (M + H)+;
yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- Rt-1.14 min
one
461: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 519.3
(2,5-difluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- Rt-0.98 min
yl)oxazolidin-2-one
462: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 502.3
(4-chlorophenyl)thiazol-5-yl)ethyl)amino) pyrimidin- (M + H)+;
4-yl)oxazolidin-2-one            Rt-0.95 min
463: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 457.4
(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4- (M + H)+;
yl)oxazolidin-2-one              Rt 1.04 min
464: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2- MS m/z 451.3
(((S)-1-(2-fluoro-4-             (M + H)+;
methoxyphenyl)ethyl)amino)pyrimidin-4- Rt 1.03 min
yl)oxazolidin-2-one
465: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 421.2
(2,3-difluorophenyl)ethyl)amino)pyrimidin-4- (M + H)+;
yl)oxazolidin-2-one              Rt = 0.91 min
466: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2
(2,3-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
4-yl)oxazolidin-2-one            Rt = 1.05 min;
467: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2
(3,4-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
4-yl)oxazolidin-2-one            Rt = 1.03 min;
468: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.3
(2,4-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
4-yl)oxazolidin-2-one            Rt = 1.04 min;
469: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2
(3,5-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
4-yl)oxazolidin-2-one            Rt = 1.04 min;
470: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-chloro-2- MS m/z 565.4
(((S)-1-(5-(2-(trifluoromethyl)pyridin-4-yl)pyrimidin- (M + H)+;
2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt = 0.98 min;

Intermediate 473: (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol

A solution of (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine (80 mg, 0.25 mmol), (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (55 mg, 0.28 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.63 mmol, 2.5 equiv) in DMSO (1.3 mL) was heated at 85° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (0.058 g, white solid) in 50% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.66 (s, 1H), 7.61 (m, 2H), 7.13 (t, J=8.6 Hz, 2H), 5.35 (s, 1H), 5.30-5.14 (m, 2H), 5.04 (m, 1H), 3.94 (m, 1H), 3.77-3.65 (m, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.21 (s, 9H), 1.15 (d, J=6.0 Hz, 3H). MS m/z 461.3 (M+H)⁺; Rt-0.88 min.

Intermediate 474: (2R,3R)-3-(tert-butoxy)-2-((2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)amino)butan-1-ol

(2R,3R)-3-(tert-butoxy)-2-((2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)amino)butan-1-ol was prepared using a method similar to that described for the preparation of Intermediate 473. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82 (s, 1H), 7.67 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 5.35 (s, 1H), 5.27 (m, 1H), 5.19 (m, 1H), 5.07 (m, 1H), 3.94 (m, 1H), 3.71 (m, 2H), 1.57 (d, J=6.8 Hz, 3H), 1.21 (s, 9H), 1.14 (d, J=5.9 Hz, 3H). MS m/z 477.3 (M+H)⁺; Rt-0.96 min

Intermediate 475: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Triphosgene (18 mg, 0.062 mmol, 0.5 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (57 mg, 0.12 mmol) in DCM (1.2 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.058 mL, 0.49 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 30 min. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 487.4 (M+H)⁺; Rt-1.12 min.

Intermediate 476: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)oxazolidin-2-one

(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)oxazolidin-2-one was prepared using a method similar to that described for the preparation of Intermediate 475. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.17 (s, 1H), 5.31 (m, 1H), 4.70 (m, 1H), 4.62 (dd, J=9.2, 3.0 Hz, 1H), 4.33 (m, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.13 (br s, 9H), 1.02 (d, J=6.5 Hz, 3H). MS m/z 503.3 (M+H)⁺; Rt-1.21 min.

Intermediate 477

To a microwave vial with a stir bar was added (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (43.6 mg, 0.145 mmol) and (S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethanamine (25.1 mg, 0.121 mmol), followed by DMSO (605 uL) and DIEA (63.5 ul, 0.363 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 110° C. for 21 hr. The mixture was diluted with water and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one, as a brown solid film, (yield assumed quantitative). LCMS m/z 471.4 (M+H)⁺, Rt 0.85 min.

The compounds in Table 25 were prepared using methods similar to those described for the preparation of Intermediate 477.

TABLE 25
Intermediate: Name	Structure	LCMS
478: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(3- isobutoxyphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one		MS m/z 457.4 (M + H)+, Rt 1.04 min.
479: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(3- phenoxyphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one		MS m/z 477.3 (M +H)+, Rt 1.00 min.
480: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(4- isopropoxyphenyl)ethylamino)pyrimidin- 4-yl)oxazolidin-2-one		MS m/z 443.4 (M + H)+, Rt 0.94 min.
481: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(4-isobutoxy-3- methylphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one		MS m/z 471.4 (M + H)+, Rt 1.09 min.
482: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 487.3 (M + H)+, Rt 1.18 min.
483: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 505.4 (M + H)+, Rt 1.16 min.
484: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4- (difluoromethoxy)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one		MS m/z 469.3 (M + H)+, Rt 1.05 min.
485: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 505.4 (M + H)+, Rt 1.14 min.
486: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-3- fluorophenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one		MS m/z 487.3 (M + H)+, Rt 1.08 min.
487: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-2- fluorophenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one		MS m/z 487.3 (M + H)+, Rt 1.04 min.
488: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 487.3 (M + H)+, Rt 1.10 min.
489: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3- (difluoromethoxy)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one		MS m/z 469.3 (M + H)+, Rt 1.03 min.

Intermediate 490

To a microwave vial with a stir bar was added (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (75.0 mg, 0.224 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (59.7 mg, 0.247 mmol), followed by DMSO (0.9 mL) and DIEA (118 ul, 0.673 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 85° C. for 2 hr. The mixture was diluted with brine and extracted with EtOAc two times. The combined organic phases were dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a brown solid film, (yield assumed quantitative). LCMS m/z 503.2 (M+H)⁺, Rt 1.24 min.

The compounds in Table 26 were prepared using methods similar to those described for the preparation of Intermediate 490

TABLE 26
Intermediate: Name	Structure	LCMS
491: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 521.3 (M + H)+, Rt 1.33 min.
492: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(4- (difluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 485.2 (M + H)+, Rt 1.20 min.
493: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 521.3 (M + H)+, Rt 1.31 min.

Intermediate 494

To a suspension of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (30.0 mg, 0.106 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (38.4 mg, 0.159 mmol) in DMSO (0.53 mL), was added DIEA (64.7 ul, 0.371 mmol) in a microwave vial. The vial was capped and the reaction mixture heated in a preheated oil bath at 100° C. for 3 hr.

The mixture was diluted with dilute brine and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a clear colorless oil which was used without further purification (yield assumed quantitative). LCMS m/z 469.3 (M+H)⁺, Rt 0.98 min.

The compounds in Table 27 were prepared using methods similar to those described for the preparation of Intermediate 494.

TABLE 27
Intermediate: Name	Structure	LCMS
495: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 487.3 (M + H)+, Rt 0.99 min.
496: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 487.3 (M + H)+, Rt 1.00 min.
497: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-3- fluorophenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one		MS m/z 469.4 (M + H)+, Rt 0.91 min.
498: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4- (cyclopropylmethoxy)phenyl)ethyl)amino)- pyrimidin-4-yl)oxazolidin-2-one		MS m/z 455.3 (M + H)+, Rt 0.96 min.
499: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(2-fluoro-4- isobutoxyphenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one		MS m/z 475.3 (M + H)+, Rt 1.07 min.
500: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4- (difluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 451.3 (M + H)+, Rt 0.90 min.
501: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-2- fluorophenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one		MS m/z 469.3 (M + H)+, Rt 0.90 min.
502: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 469.3 (M + H)+, Rt 0.94 min.
503: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3- (difluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one		MS m/z 451.3 (M + H)+, Rt 0.87 min.

Intermediate 504: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To a Parshaker flask were added benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (1 g, 1.90 mmole) and 20% Pd(OH)₂ in activated carbon (1 g, 1.42 mmole), then was added MeOH (100 mL) under nitrogen gas. The reaction mixture was shaked under 50 spi hydrogen overnight. The reaction mixture was filtered through a celite. The celite cake was washed with MeOH and the filtrate was concentrate in vacuo to afford the title product as a white solid (630 mg). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.18-8.15 (m, 1H), 7.42-7.37 (m, 1H), 4.99 (br, s, 1H), 4.77-4.70 (m, 1H), 4.64-4.57 (m, 1H), 4.52-4.38 (m, 1H), 4.38-4.31 (m, 1H), 4.12-3.93 (m, 2H), 3.40-3.31 (m, 1H), 3.12-3.29 (m, 2H), 2.81-2.70 (m, 1H), 2.02-1.29 (m, 5H), 1.25 (s, 9H), 1.23-1.16 (m, 3H), 1.05-1.00 (m, 3H). HRMS (C) tR=2.65 min; MS m/z 392.2655 (M+H)+

Intermediate 505: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methyl propan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Intermediate 505 was prepared using a method similar to that described for the preparation of Intermediate 329. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.23-8.12 (m, 1H), 7.87 (d, J=7.45 Hz, 1H), 7.69 (d, J=6.22 Hz, 1H), 6.81-6.74 (m, 2H), 4.67 (m, 1H), 4.61-4.55 (m, 1H), 4.37-4.29 (m, 1H), 4.25-4.16 (m, 2H), 4.14-4.04 (m, 2H), 3.97-3.85 (m, 1H), 3.21-3.09 (m, 2H), 2.11-1.87 (m, 3H), 1.61 (s, 6H), 1.39-1.23 (m, 1H), 1.21 (d, J=7.45 Hz, 3H), 1.15-1.07 (m, 1H), 1.06 (s, 9H), 0.96 (d, J=6.62 Hz, 3H), HRMS (C) tR=4.80 min; MS m/z 579.3273 (M+H)+

Intermediate 506: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoro methoxy)phenyl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Intermediate 506 was prepared using a method similar to that described for the preparation of Intermediate 329. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.17 (br, s, 1H), 7.41 (d, J=6.14 Hz, 1H), 7.31 (d, J=7.98 Hz, 1H), 6.87-6.80 (m, 2H), 4.77-4.71 (m, 1H), 4.64-4.58 (m, 1H), 4.49-4.40 (m, 1H), 4.39-4.32 (m, 1H), 4.11-3.97 (m, 1H), 3.79-3.70 (m, 2H), 2.82-2.71 (m, 2H), 2.04-1.91 (m, 1H), 1.90-1.80 (m, 1H), 1.66-1.35 (m, 3H), 1.34-1.15 (m, 13H), 1.03 (d, J=7.36 Hz, 3H), HRMS (C) tR=5.68 min; MS m/z 586.2419 (M+H)+

Intermediate 507: benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate

Intermediate 507 was prepared using a method similar to that described for the preparation of Intermediate 342. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.16 (d, J=5.77 Hz, 1H), 7.41-7.31 (m, 6H), 5.15 (s, 2H), 4.76-4.71 (m, 1H), 4.64-4.58 (m, 1H), 4.48-4.41 (m, 1H), 4.38-4.31 (m, 1H), 4.30-4.18 (m, 2H), 4.09-3.96 (m, 1H), 2.77 (br s, 2H), 1.94-1.54 (m, 3H), 1.37-1.25 (m, 3H), 1.23 (s, 9H), 1.20 (d, J=6.53 Hz, 3H), 1.03 (d, J=5.91 Hz, 3H). HRMS (C) tR=4.64 min; MS m/z 526.3012 (M+H)+

The intermediates in Table 27b were prepared using methods similar to those described for the preparation of Intermediate 303.

TABLE 27b
Intermediate: Name	Structure	LCMS
508: (S)-1-(1-(3,4- difluorophenyl)-1H- imidazol-4-yl) ethanamine		LCMS(B) m/z (M + H)+ 224.1, RT 0.39 min.
509: (S)-1-(1-(4- chloro-3- fluorophenyl)-1H- imidazol-4-yl) ethanamine		LCMS(B) m/z (M + H)+ 240.0, RT 0.48 min.
510: (S)-1-(1-(3- chloro-4- fluorophenyl)-1H- imidazol-4-yl) ethanamine		LCMS(B) m/z (M + H)+ 240.1, RT 0.46 min.
511: (S)-1-(1-(4- (difluoromethyl) phenyl)-1H- imidazol-4-yl) ethanamine		LCMS(B) m/z (M + H)+ 238.1, RT 0.41 min.
512: (S)-1-(1-(4- (difluoromethyl)-3- fluorophenyl)-1H- imidazol-4-yl) ethanamine		LCMS(B) m/z (M + H)+ 256.0, RT 0.47 min.
513: (S)-1-(1-(3,5- difluorophenyl)- 1H-imidazol-4-yl) ethanamine		LCMS(B) m/z (M + H)+ 224.1, RT 0.41 min.

EXAMPLES

Example 1

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To a solution of 1-(3-(4-chlorophenyl)isoxazol-5-yl)ethanamine (610 mg, 2.74 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (774 mg, 2.74 mmol) in DMSO (5 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.96 mL, 5.48 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (50 ml), wash with water (50 ml), brine (50 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-25% EtOAc/DCM afforded 500 mg of white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 1.6 Hz, 1H), 7.80-7.65 (m, 2H), 7.58 (dd, J=5.8, 1.6 Hz, 1H), 7.49-7.37 (m, 2H), 6.48-6.35 (m, 1H), 5.66-5.44 (m, 1H), 4.71 (dddd, J=9.8, 8.5, 4.6, 3.0 Hz, 1H), 4.63 (ddd, J=9.4, 3.1, 2.1 Hz, 1H), 4.50-4.26 (m, 2H), 1.71 (s, 1H), 1.25 (s, 5H), 1.15 (s, 5H), 1.03 (dd, J=22.4, 6.4 Hz, 3H), 5.44-5.13 (m, 1H). HRMS (B) tR=3.36 min; m/z 485.1830

Example 2

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 75 mg, 0.337 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (101 mg, 0.337 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.118 mL, 0.674 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 124 mg yellow foam: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=2.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.45-7.36 (m, 2H), 7.28 (d, J=6.2 Hz, 1H), 5.65 (d, J=8.9 Hz, 1H), 5.43-5.27 (m, 1H), 4.69 (qd, J=5.6, 2.9 Hz, 1H), 4.62-4.35 (m, 2H), 4.23-4.01 (m, 1H), 1.68 (d, J=12.8 Hz, 2H), 1.26-1.16 (m, 2H), 1.12 (s, 8H), 1.05 (d, J=6.4 Hz, 3H). HRMS (C) tR=1.55 min; m/z 503.1736

Example 3

To a solution of (S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine (150 mg, 0.488 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (138 mg, 0.488 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 170 uL, 0.975 mmol) and heated in a microwave at 115° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-5% EtOAc/DCM afforded 140 mg. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.19 (m, 4H), 8.01 (dd, J=8.6, 2.1 Hz, 2H), 7.54 (d, J=5.7 Hz, 2H), 7.45 (dq, J=8.4, 1.5 Hz, 2H), 4.53 (dd, J=9.3, 2.4 Hz, 2H), 4.05 (p, J=6.1 Hz, 1H), 3.51 (s, 5H), 1.80 (s, 1H), 1.22 (t, J=6.5 Hz, 12H). Anal. RP-HPLC tR=2.73 min (Gradient: 2 to 98% B in 4.4 min-flow 1 mL/min. Eluent A: Water+3.75 mM NH₄Ac+0.001% formic acid. Eluent B: ACN. Column: Acquity CSH 1.7 μm 2.1×50 mm−50° C.) HRMS m/z 514.1039

The Following Examples were prepared using a method similar to that described for the preparation of Intermediate 342 or Example 3

Example 4

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.6, 2.2 Hz, 3H), 7.96 (d, J=2.0 Hz, 3H), 7.84 (dd, J=8.3, 2.1 Hz, 3H), 7.59 (dd, J=5.8, 3.0 Hz, 3H), 7.46 (d, J=8.3 Hz, 3H), 5.71-5.42 (m, 3H), 5.32 (s, 1H), 4.75 (dtd, J=10.3, 5.2, 2.9 Hz, 3H), 1.67-1.60 (m, 3H), 4.64 (ddd, J=9.2, 6.2, 2.9 Hz, 3H), 4.49-4.31 (m, 6H), 4.14 (q, J=7.1 Hz, 1H), 2.46 (s, 9H), 2.07 (s, 1H), 1.77 (dd, J=6.8, 3.2 Hz, 9H), 1.27 (d, J=23.6 Hz, 29H), 1.05 (dd, J=11.3, 6.5 Hz, 9H). HRMS (C) tR=2.00 min; MS m/z 500.98

Example 5

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 2.4 Hz, 3H), 8.02-7.83 (m, 6H), 7.59 (dd, J=5.8, 2.9 Hz, 3H), 7.12 (t, J=8.9 Hz, 3H), 5.72-5.47 (m, 5H), 5.32 (s, 1H), 4.75 (dtd, J=8.7, 4.8, 2.9 Hz, 3H), 4.64 (ddd, J=9.3, 6.2, 2.9 Hz, 3H), 4.49-4.28 (m, 6H), 3.52 (s, 2H), 2.36 (d, J=2.0 Hz, 9H), 1.78 (s, 2H), 1.65 (s, 3H), 1.30 (s, 22H), 1.24 (d, J=2.4 Hz, 6H), 1.05 (dd, J=11.3, 6.4 Hz, 10H). HRMS (C) tR=1.95 min; m/z 484.2234

Example 6

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 1.7 Hz, 3H), 7.74-7.57 (m, 9H), 7.53-7.44 (m, 3H), 5.61 (qt, J=16.2, 9.7, 8.6 Hz, 7H), 5.32 (s, 1H), 4.75 (ddd, J=8.6, 4.6, 2.9 Hz, 3H), 4.64 (ddd, J=8.8, 5.8, 2.9 Hz, 3H), 4.50-4.30 (m, 6H), 4.14 (q, J=7.2 Hz, 2H), 4.01 (s, 9H), 2.07 (s, 2H), 1.85-1.73 (m, 9H), 1.62 (s, 2H), 1.36-1.18 (m, 30H), 1.05 (dd, J=10.8, 6.5 Hz, 9H). HRMS (C) tR=1.61 min; m/z 516.1888

Example 7

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.2 Hz, 1H), 8.11-7.93 (m, 2H), 7.70-7.54 (m, 2H), 5.80-5.40 (m, 2H), 4.75 (dtd, J=8.6, 4.3, 2.2 Hz, 1H), 1.67-1.60 (m, 1H), 4.64 (ddd, J=9.4, 4.2, 2.9 Hz, 1H), 4.50-4.30 (m, 2H), 1.77 (dd, J=6.9, 3.4 Hz, 3H), 1.27 (d, J=21.9 Hz, 9H), 1.06 (dd, J=9.8, 6.5 Hz, 3H). HRMS (C) tR=2.05 min; m/z 570.1605

Example 8

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.7 Hz, 3H), 8.10 (d, J=1.3 Hz, 3H), 7.84 (dd, J=8.3, 1.4 Hz, 3H), 7.71 (d, J=8.3 Hz, 3H), 7.64-7.55 (m, 3H), 7.20 (d, J=3.1 Hz, 3H), 6.55 (dd, J=3.1, 0.8 Hz, 3H), 5.64 (p, J=7.2 Hz, 5H), 5.32 (s, 1H), 1.69-1.61 (m, 4H), 4.77 (ddd, J=8.7, 4.7, 2.9 Hz, 3H), 4.65 (td, J=8.8, 8.4, 2.9 Hz, 3H), 4.52-4.27 (m, 6H), 3.90 (s, 9H), 3.51 (s, 2H), 1.89-1.75 (m, 9H), 1.28 (d, J=23.5 Hz, 27H), 1.06 (dd, J=10.9, 6.4 Hz, 10H). HRMS (C) tR=1.77 min; m/z 505.2437

Example 9

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 4.64 (ddd, J=9.9, 7.1, 2.9 Hz, 1H), 4.47-4.30 (m, 2H), 1.06 (dd, J=9.3, 6.4 Hz, 3H), 1.85-1.72 (m, 3H), 1.63 (s, 1H), 1.39 (s, 9H), 1.28 (d, J=21.1 Hz, 9H), 4.84-4.71 (m, 1H), 8.25 (d, J=5.7 Hz, 1H), 8.11 (q, J=2.0 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7.66-7.52 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 5.63 (p, J=7.3 Hz, 2H), 5.39-5.29 (m, OH). HRMS (C) tR=2.02 min; m/z 508.2798

Example 10

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.7, 2.9 Hz, 1H), 8.04 (dq, J=7.8, 1.3 Hz, 1H), 7.95 (dt, J=2.5, 1.2 Hz, 1H), 7.67-7.49 (m, 2H), 7.39 (ddt, J=8.2, 2.5, 1.2 Hz, 1H), 5.62 (h, J=6.7, 6.1 Hz, 2H), 4.75 (dtd, J=9.1, 4.7, 2.9 Hz, 1H), 4.64 (ddd, J=9.3, 4.9, 2.9 Hz, 1H), 4.49-4.26 (m, 2H), 1.78 (dd, J=6.8, 3.6 Hz, 3H), 1.61 (s, 1H), 1.27 (d, J=23.8 Hz, 9H), 1.06 (dd, J=10.0, 6.5 Hz, 3H). HRMS (C) tR=1.82 min; m/z 536.1995

Example 11

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.3 Hz, 1H), 8.13-7.99 (m, 2H), 7.60 (dd, J=5.8, 2.0 Hz, 1H), 5.72-5.56 (m, 1H), 5.48 (s, 1H), 4.85-4.69 (m, 1H), 1.67-1.56 (m, 1H), 4.64 (ddd, J=9.5, 4.5, 2.9 Hz, 1H), 4.53-4.28 (m, 2H), 1.77 (dd, J=7.0, 3.4 Hz, 3H), 1.27 (d, J=22.0 Hz, 9H), 1.06 (dd, J=9.8, 6.4 Hz, 3H). HRMS (C) tR=1.87 min; m/z 554.1901

Example 12

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.9, 1.9 Hz, 1H), 8.09-7.92 (m, 2H), 7.59 (dd, J=5.7, 3.1 Hz, 1H), 7.43-7.32 (m, 2H), 5.60 (dt, J=15.5, 7.8 Hz, 2H), 4.75 (dtd, J=8.4, 5.0, 2.9 Hz, 1H), 4.64 (ddd, J=9.5, 7.1, 2.9 Hz, 1H), 4.49-4.27 (m, 2H), 2.99 (hept, J=6.9 Hz, 1H), 1.76 (dd, J=7.0, 2.8 Hz, 3H), 1.60 (dd, J=6.9, 2.8 Hz, 1H), 1.40-1.19 (m, 15H), 1.05 (dd, J=11.0, 6.5 Hz, 3H). HRMS (C) tR=2.23 min; m/z 494.2642

Example 13

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.8 Hz, 1H), 7.91 (dd, J=7.5, 0.9 Hz, 1H), 7.60 (d, J=5.8 Hz, 1H), 7.44 (dt, J=8.2, 1.1 Hz, 1H), 7.33-7.20 (m, 1H), 6.99-6.89 (m, 1H), 5.66 (p, J=7.3 Hz, 1H), 4.77 (ddd, J=8.7, 4.7, 3.0 Hz, 1H), 1.66-1.60 (m, 1H), 4.66 (dd, J=9.5, 3.0 Hz, 1H), 4.53-4.44 (m, 1H), 4.38 (q, J=9.0, 8.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d, J=0.9 Hz, 3H), 1.84-1.76 (m, 3H), 1.28 (d, J=26.5 Hz, 9H), 1.04 (d, J=6.5 Hz, 3H). HRMS (C) tR=1.65 min; MS m/z 519.60

Example 14

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

135 mg orangish-red resin (solidified upon standing). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=5.7 Hz, 1H), 7.62-7.46 (m, 3H), 7.45-7.36 (m, 2H), 4.85-4.69 (m, 1H), 4.64 (ddd, J=9.1, 5.6, 3.0 Hz, 1H), 4.44 (qd, J=6.4, 4.6 Hz, 1H), 4.34 (dt, J=15.4, 9.0 Hz, 1H), 2.40 (d, J=1.3 Hz, 3H), 1.79-1.60 (m, 3H), 1.34-1.18 (m, 11H), 1.04 (dd, J=14.8, 6.5 Hz, 3H). HRMS (C) tR=2.00 min; m/z 499.1986

Example 15

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.6, 2.2 Hz, 3H), 7.96 (d, J=2.0 Hz, 3H), 7.84 (dd, J=8.3, 2.1 Hz, 3H), 7.59 (dd, J=5.8, 3.0 Hz, 3H), 7.46 (d, J=8.3 Hz, 3H), 5.71-5.42 (m, 3H), 5.32 (s, 1H), 4.75 (dtd, J=10.3, 5.2, 2.9 Hz, 3H), 1.67-1.60 (m, 3H), 4.64 (ddd, J=9.2, 6.2, 2.9 Hz, 3H), 4.49-4.31 (m, 6H), 4.14 (q, J=7.1 Hz, 1H), 2.46 (s, 9H), 2.07 (s, 1H), 1.77 (dd, J=6.8, 3.2 Hz, 9H), 1.27 (d, J=23.6 Hz, 29H), 1.05 (dd, J=11.3, 6.5 Hz, 9H). HRMS (C) tR=2.00 min; MS m/z 500.98

Example 16

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 2.4 Hz, 3H), 8.02-7.83 (m, 6H), 7.59 (dd, J=5.8, 2.9 Hz, 3H), 7.12 (t, J=8.9 Hz, 3H), 5.72-5.47 (m, 5H), 5.32 (s, 1H), 4.75 (dtd, J=8.7, 4.8, 2.9 Hz, 3H), 4.64 (ddd, J=9.3, 6.2, 2.9 Hz, 3H), 4.49-4.28 (m, 6H), 3.52 (s, 2H), 2.36 (d, J=2.0 Hz, 9H), 1.78 (s, 2H), 1.65 (s, 3H), 1.30 (s, 22H), 1.24 (d, J=2.4 Hz, 6H), 1.05 (dd, J=11.3, 6.4 Hz, 10H). HRMS (C) tR=1.95 min; m/z 484.2234

Example 17

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 1.7 Hz, 3H), 7.74-7.57 (m, 9H), 7.53-7.44 (m, 3H), 5.61 (qt, J=16.2, 9.7, 8.6 Hz, 7H), 5.32 (s, 1H), 4.75 (ddd, J=8.6, 4.6, 2.9 Hz, 3H), 4.64 (ddd, J=8.8, 5.8, 2.9 Hz, 3H), 4.50-4.30 (m, 6H), 4.14 (q, J=7.2 Hz, 2H), 4.01 (s, 9H), 2.07 (s, 2H), 1.85-1.73 (m, 9H), 1.62 (s, 2H), 1.36-1.18 (m, 30H), 1.05 (dd, J=10.8, 6.5 Hz, 9H). HRMS (C) tR=1.61 min; m/z 516.1888

Example 18

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.2 Hz, 1H), 8.11-7.93 (m, 2H), 7.70-7.54 (m, 2H), 5.80-5.40 (m, 2H), 4.75 (dtd, J=8.6, 4.3, 2.2 Hz, 1H), 1.67-1.60 (m, 1H), 4.64 (ddd, J=9.4, 4.2, 2.9 Hz, 1H), 4.50-4.30 (m, 2H), 1.77 (dd, J=6.9, 3.4 Hz, 3H), 1.27 (d, J=21.9 Hz, 9H), 1.06 (dd, J=9.8, 6.5 Hz, 3H). HRMS (C) tR=2.05 min; m/z 570.1605

Example 19

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.7 Hz, 3H), 8.10 (d, J=1.3 Hz, 3H), 7.84 (dd, J=8.3, 1.4 Hz, 3H), 7.71 (d, J=8.3 Hz, 3H), 7.64-7.55 (m, 3H), 7.20 (d, J=3.1 Hz, 3H), 6.55 (dd, J=3.1, 0.8 Hz, 3H), 5.64 (p, J=7.2 Hz, 5H), 5.32 (s, 1H), 1.69-1.61 (m, 4H), 4.77 (ddd, J=8.7, 4.7, 2.9 Hz, 3H), 4.65 (td, J=8.8, 8.4, 2.9 Hz, 3H), 4.52-4.27 (m, 6H), 3.90 (s, 9H), 3.51 (s, 2H), 1.89-1.75 (m, 9H), 1.28 (d, J=23.5 Hz, 27H), 1.06 (dd, J=10.9, 6.4 Hz, 10H). HRMS (C) tR=1.77 min; m/z 505.2437

Example 20

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 4.64 (ddd, J=9.9, 7.1, 2.9 Hz, 1H), 4.47-4.30 (m, 2H), 1.06 (dd, J=9.3, 6.4 Hz, 3H), 1.85-1.72 (m, 3H), 1.63 (s, 1H), 1.39 (s, 9H), 1.28 (d, J=21.1 Hz, 9H), 4.84-4.71 (m, 1H), 8.25 (d, J=5.7 Hz, 1H), 8.11 (q, J=2.0 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7.66-7.52 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 5.63 (p, J=7.3 Hz, 2H), 5.39-5.29 (m, OH). HRMS (C) tR=2.02 min; m/z 508.2798

Example 21

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.7, 2.9 Hz, 1H), 8.04 (dq, J=7.8, 1.3 Hz, 1H), 7.95 (dt, J=2.5, 1.2 Hz, 1H), 7.67-7.49 (m, 2H), 7.39 (ddt, J=8.2, 2.5, 1.2 Hz, 1H), 5.62 (h, J=6.7, 6.1 Hz, 2H), 4.75 (dtd, J=9.1, 4.7, 2.9 Hz, 1H), 4.64 (ddd, J=9.3, 4.9, 2.9 Hz, 1H), 4.49-4.26 (m, 2H), 1.78 (dd, J=6.8, 3.6 Hz, 3H), 1.61 (s, 1H), 1.27 (d, J=23.8 Hz, 9H), 1.06 (dd, J=10.0, 6.5 Hz, 3H). HRMS (C) tR=1.82 min; m/z 536.1995

Example 22

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.3 Hz, 1H), 8.13-7.99 (m, 2H), 7.60 (dd, J=5.8, 2.0 Hz, 1H), 5.72-5.56 (m, 1H), 5.48 (s, 1H), 4.85-4.69 (m, 1H), 1.67-1.56 (m, 1H), 4.64 (ddd, J=9.5, 4.5, 2.9 Hz, 1H), 4.53-4.28 (m, 2H), 1.77 (dd, J=7.0, 3.4 Hz, 3H), 1.27 (d, J=22.0 Hz, 9H), 1.06 (dd, J=9.8, 6.4 Hz, 3H). HRMS (C) tR=1.87 min; m/z 554.1901

Example 23

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.9, 1.9 Hz, 1H), 8.09-7.92 (m, 2H), 7.59 (dd, J=5.7, 3.1 Hz, 1H), 7.43-7.32 (m, 2H), 5.60 (dt, J=15.5, 7.8 Hz, 2H), 4.75 (dtd, J=8.4, 5.0, 2.9 Hz, 1H), 4.64 (ddd, J=9.5, 7.1, 2.9 Hz, 1H), 4.49-4.27 (m, 2H), 2.99 (hept, J=6.9 Hz, 1H), 1.76 (dd, J=7.0, 2.8 Hz, 3H), 1.60 (dd, J=6.9, 2.8 Hz, 1H), 1.40-1.19 (m, 15H), 1.05 (dd, J=11.0, 6.5 Hz, 3H). HRMS (C) tR=2.23 min; m/z 494.2642

Example 24

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.8 Hz, 1H), 7.91 (dd, J=7.5, 0.9 Hz, 1H), 7.60 (d, J=5.8 Hz, 1H), 7.44 (dt, J=8.2, 1.1 Hz, 1H), 7.33-7.20 (m, 1H), 6.99-6.89 (m, 1H), 5.66 (p, J=7.3 Hz, 1H), 4.77 (ddd, J=8.7, 4.7, 3.0 Hz, 1H), 1.66-1.60 (m, 1H), 4.66 (dd, J=9.5, 3.0 Hz, 1H), 4.53-4.44 (m, 1H), 4.38 (q, J=9.0, 8.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d, J=0.9 Hz, 3H), 1.84-1.76 (m, 3H), 1.28 (d, J=26.5 Hz, 9H), 1.04 (d, J=6.5 Hz, 3H). HRMS (C) tR=1.65 min; MS m/z 519.60

Example 25

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

135 mg orange-red resin (solidified upon standing). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=5.7 Hz, 1H), 7.62-7.46 (m, 3H), 7.45-7.36 (m, 2H), 4.85-4.69 (m, 1H), 4.64 (ddd, J=9.1, 5.6, 3.0 Hz, 1H), 4.44 (qd, J=6.4, 4.6 Hz, 1H), 4.34 (dt, J=15.4, 9.0 Hz, 1H), 2.40 (d, J=1.3 Hz, 3H), 1.79-1.60 (m, 3H), 1.34-1.18 (m, 11H), 1.04 (dd, J=14.8, 6.5 Hz, 3H). HRMS (C) tR=2.00 min; m/z 499.1986

Example 26

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(4-(4-chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

200 mg (white solid). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=2.9, 1.0 Hz, 1H), 7.68-7.52 (m, 2H), 7.47-7.35 (m, 2H), 5.99-5.65 (m, 1H), 5.49-5.20 (m, 1H), 4.67 (ddt, J=21.5, 8.9, 5.4 Hz, 1H), 4.58-4.40 (m, 2H), 4.22-4.05 (m, 1H), 2.53 (d, J=6.0 Hz, 3H), 1.74 (s, 1H), 1.16 (s, 5H), 1.13-1.05 (m, 6H), 1.01 (d, J=6.4 Hz, 3H). HRMS (B) tR=5.16 min; m/z 534.1744

Example 27

(4R)-3-(2-((1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

210 mg (white solid). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=2.9, 1.9 Hz, 1H), 7.87-7.71 (m, 2H), 7.62-7.50 (m, 2H), 7.40 (d, J=8.7 Hz, 1H), 5.85 (d, J=15.8 Hz, 1H), 5.58-5.36 (m, 1H), 4.81-4.57 (m, 1H), 4.57-4.39 (m, 2H), 4.23-4.00 (m, 1H), 2.07 (s, 2H), 1.77 (s, 1H), 1.16 (s, 5H), 1.11 (d, J=6.4 Hz, 2H), 1.06 (s, 5H), 0.98 (d, J=6.4 Hz, 2H). HRMS (B) tR=5.15 min; m/z 566.1079 (M+H).

Example 28

(R)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.058 mmole) was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water 2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation to afford 28 mg of the title product as a yellow oil (ratio of two peaks with same MS: 96/4% by LC-MS). (400 MHz, CD₂Cl₂) δ 8.22 (d, J=2.27 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.88-6.79 (m, 2H), 5.12 (br s, 1H), 4.61-4.50 (m, 2H), 4.46-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.93 (br s, 1H), 3.77-3.68 (m, 2H), 3.20 (br s, 1H), 2.79-2.67 (m, 2H), 1.96-1.78 (m, 2H), 1.70-1.58 (m, 1H), 1.55-1.28 (m, 2H), 1.23 (d, J=6.63 Hz, 3H), 1.19 (d, J=7.19 Hz, 3H), HRMS (C) tR=4.47 min; MS m/z 548.1689 (M+H)+

Example 29

(R)-3-(5-fluoro-2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21 mg, 0.051 mmol), 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (14 mg, 0.051 mmol), Pd(OAc)₂ (1 mg, 5 umol), BINAP (3 mg, 5 umol), and Cs₂CO₃ (25 mg, 0.077 mmol) in 6 mL toluene was heated at 90° C. overnight. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The resulting crude was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water (2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (5 mg) (ratio of two peaks with same MS: 93/7% by LC-MS). (400 MHz, CD₂Cl₂) δ 8.16-8.08 (m, 2H), 6.79-6.75 (m, 1H), 6.57-6.52 (m, 1H), 4.97-4.86 (m, 1H), 4.47-4.39 (m, 2H), 4.33-4.25 (m, 1H), 4.11-4.02 (m, 1H), 3.89-3.75 (m, 3H), 2.97 (br s, 1H), 2.80-2.67 (m, 2H), 1.84-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.48 (s, 6H), 1.38-1.15 (m, 2H), 1.11 (d, J=5.91 Hz, 3H), 1.07 (d, J=5.91 Hz, 3H), HRMS (C) tR=3.59 min; MS m/z 541.2557 (M+H)+

Examples 30, 31, 32, and 33

3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 72 mg, 0.322 mmol) and 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (90 mg, 0.322 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.113 mL, 0.645 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column (silica, 40 g, 50μ) eluting w/0-5% EtOAc/DCM followed by Flash column (silica, 80 g, 15μ) eluting w/0-5% EtOAc/heptane separated 2 major peaks which were further separated via chiral SFC chromatography on an ID column (75 g/min, 120 bar, 21×250 mm) eluting 35% IPA/CO₂ (v/v) to give: Example 30, Peak 1: 10 mg (white foam): ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=5.8 Hz, 1H), 8.09-7.95 (m, 2H), 7.58 (d, J=5.7 Hz, 1H), 7.54-7.41 (m, 2H), 5.83 (s, 1H), 5.28 (s, 1H), 4.72 (s, 1H), 4.54 (dd, J=9.6, 2.5 Hz, 1H), 4.37 (d, J=9.5 Hz, 1H), 3.44-3.15 (m, 1H), 1.78 (d, J=7.0 Hz, 3H), 1.63 (s, 1H), 1.32 (d, J=7.3 Hz, 3H), 1.23 (d, J=6.1 Hz, 3H). HRMS m/z 482.1081, RT=2.90 min. Chiral RT=2.15 min

Example 31, Peak 2: 38 mg (white foam): ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=5.7 Hz, 1H), 8.09-7.93 (m, 2H), 7.58 (d, J=5.7 Hz, 1H), 7.53-7.41 (m, 2H), 5.84 (s, 1H), 5.33 (s, 1H), 4.72 (s, 1H), 4.55 (dd, J=9.6, 2.4 Hz, 1H), 4.35 (t, J=8.8 Hz, 1H), 3.39-3.17 (m, 1H), 1.78 (d, J=7.0 Hz, 3H), 1.62 (d, J=6.9 Hz, 1H), 1.32 (d, J=7.3 Hz, 3H), 1.23 (d, J=6.2 Hz, 1H). HRMS m/z 482.1081, RT=2.89 min. Chiral RT=2.43 min

Example 32, Peak 3: 45 mg (white foam) ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=5.8 Hz, 1H), 8.09-7.91 (m, 2H), 7.59 (d, J=5.7 Hz, 1H), 7.52-7.38 (m, 2H), 6.22 (s, 1H), 5.38 (d, J=48.6 Hz, 1H), 4.86 (dd, J=8.2, 4.2 Hz, 1H), 1.83-1.75 (m, 3H), 4.56 (dd, J=9.3, 2.5 Hz, 1H), 4.43 (t, J=9.2 Hz, 1H), 3.50 (s, 1H), 2.97 (d, J=46.0 Hz, 1H), 1.23 (d, J=6.2 Hz, 1H), 1.12 (d, J=7.6 Hz, 3H). HRMS m/z 482.1081, RT=2.86 min. Chiral RT=2.55 min

Example 33, Peak 4: 12 mg (white foam) ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=5.8 Hz, 1H), 8.11-7.92 (m, 2H), 7.60 (d, J=5.6 Hz, 1H), 7.53-7.40 (m, 2H), 5.77 (s, 1H), 5.45 (s, 1H), 4.96-4.77 (m, 1H), 4.57 (dd, J=9.5, 2.4 Hz, 1H), 4.44 (t, J=9.1 Hz, 1H), 2.94 (s, 1H), 1.79 (d, J=7.1 Hz, 3H), 1.63 (d, J=7.1 Hz, 1H), 1.23 (d, J=6.1 Hz, 2H), 1.20-1.08 (m, 3H). HRMS m/z 482.1081, RT=2.86 min. Chiral RT=2.66 min

Example 34

3-(5-fluoro-2-(((S)-1-(3-fluoro-4-(hydroxymethyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

To a solution of (S)-(4-(1-aminoethyl)-2-fluorophenyl)methanol (62.6 mg, 0.37 mmol) and 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (110 mg, 0.37 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.129 mL, 0.74 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column (silica, 40 g, 50μ) eluting w/5-50% EtOAc/DCM afforded 155 mg (white foam):¹H NMR (400 MHz, CDCl₃) δ 8.22 (dd, J=6.6, 2.6 Hz, 1H), 7.40 (td, J=7.8, 5.2 Hz, 1H), 7.12 (ddd, J=7.8, 4.6, 1.6 Hz, 1H), 7.03 (ddd, J=10.9, 6.3, 1.7 Hz, 1H), 5.52 (d, J=22.7 Hz, 1H), 4.90 (p, J=7.0 Hz, 1H), 4.75 (d, J=9.6 Hz, 3H), 4.59 (dt, J=15.7, 9.1 Hz, 1H), 4.41 (ddd, J=12.4, 9.1, 6.2 Hz, 1H), 1.89 (d, J=18.6 Hz, 1H), 1.16 (d, J=7.2 Hz, 1H), 1.04-0.74 (m, 2H). HRMS m/z 446.1377, RT=2.03 min.

Example 35

A solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (18.6 mg, 0.082 mmol) and 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine (22 mg, 0.082 mmol) in DMSO (2 mL) was heated at 100° C. for 2 h. The reaction mixture was poured into water (20 mL), and extracted with EtOAc (2×20 mL). Combined organics were dried over Na₂SO₄, filtered and concentrated. Silica gel column chromatography ((25% MeOH in EtOAc)/Heptane 10 to 100%) provided (4R)-3-(2-(1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (12 mg, approx 1:1 mixture of diastereomers) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 4H), 8.15 (d, J=5.7 Hz, 2H), 7.51 (ddd, J=8.1, 2.8, 1.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.07-5.96 (m, 2H), 5.32 (t, J=7.4 Hz, 1H), 5.09 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.43 (dd, J=7.3, 4.8 Hz, 2H), 4.33 (dd, J=9.4, 8.3 Hz, 1H), 4.18 (d, J=9.0 Hz, 2H), 3.62 (s, 1H), 3.23 (s, 1H), 1.62-1.58 (m, 6H), 1.07-0.97 (m, 3H), 0.87-0.77 (m, 3H). HRMS m/z 475.1039 and 475.1042 (M+H)⁺.

Example 36

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (68 mg, 0.18 mmol) in 3 ml of DCM was cooled to 0° C., treated with 1 ml of TFA, it was stirred at same temperature for 4 hours, the solvent was removed to yield the product as a TFA salt form, it was dissolved in 2 ml of MeOH, the TFA was removed by using a PL-HCO3 MP SPE (0.9 mmol) cartridge, the solvent was removed to yield the pure product (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid (52 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=5.8 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.40-7.31 (m, 4H), 7.31-7.24 (m, 1H), 5.84 (s, 1H), 4.94 (s, 1H), 4.58 (q, J=4.9, 3.2 Hz, 1H), 4.40 (dd, J=9.3, 2.8 Hz, 1H), 4.31 (t, J=8.9 Hz, 1H), 1.56 (d, J=7.0 Hz, 3H), 0.98-0.74 (m, 3H).HRMS m/z 329.1619 (M+H)⁺, RT=2.23 min.

Example 37 and 38

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (97 mg, 0.17 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 58 mg of (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1-hydroxyethyl)oxazolidin-2-one as a waxy off-white foam. Separated the diastereomers via chiral SFC chromatography on an AD-H column (75 g/min, 120 bar, 21×250 mm) eluting 25% IPA/CO₂ (v/v) to give (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

Example 37 Peak 1: 23 mg (off-white foam). ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.17 (m, 4H), 8.01 (dd, J=8.6, 2.1 Hz, 2H), 7.54 (d, J=5.7 Hz, 2H), 7.45 (dq, J=8.4, 1.5 Hz, 2H), 6.16 (s, 2H), 5.32 (s, 3H), 4.82-4.60 (m, 2H), 4.53 (dd, J=9.3, 2.4 Hz, 2H), 4.43 (s, 2H), 4.29 (q, J=8.9 Hz, 2H), 4.05 (p, J=6.1 Hz, 1H), 3.51 (s, 5H), 1.80 (s, 1H), 1.22 (t, J=6.5 Hz, 12H). HRMS (B) tR=2.75 min. MS m/z 514.0979 Chiral RT=2.10 min

Example 38 Peak 2: 58 mg (off-white foam). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (dd, J=12.4, 3.9 Hz, 8H), 8.01 (dd, J=8.5, 2.1 Hz, 4H), 7.71-7.36 (m, 8H), 6.29 (s, 4H), 5.37 (d, J=37.2 Hz, 5H), 4.86 (ddd, J=7.7, 4.9, 2.4 Hz, 4H), 4.55 (dd, J=9.5, 2.6 Hz, 4H), 4.41 (t, J=8.9 Hz, 4H), 4.19-3.77 (m, 5H), 3.51 (s, 3H), 1.83 (s, 1H), 1.23 (d, J=6.1 Hz, 4H), 1.12-0.95 (m, 12H). HRMS (B) tR=2.73 min. MS m/z 514.0979 Chiral RT=3.70 min

The compounds in Table 28a were prepared using methods similar to those described for the preparation of Examples 35, 36, or 37/38.

TABLE 28a
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79

TABLE 28b
Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 28a.
Example: Name	1H NMR (400 MHz) δ ppm	LCMS
39: (4R)-3-(2-(1-(5-(5-fluoro-2-	(CDCl3) δ 8.71 (d, J = 1.8 Hz, 4H),	HRMS (B)
methylphenyl)pyrimidin-2-	8.23 (dd, J = 5.8, 1.0 Hz, 2H), 7.44	m/z
yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-	(dd, J = 12.1, 5.7 Hz, 2H), 7.35-7.26	439.1865
hydroxyethyl)oxazolidin-2-one	(m, 3H), 7.08 (tt, J = 8.4, 2.8 Hz, 2H),	and
	6.95 (dt, J = 9.0, 2.7 Hz, 2H), 6.16 (t,	439.1865 (M +
	J = 8.5 Hz, 2H), 5.41 (p, J = 7.0 Hz,	H)+
	1H), 5.20 (s, 1H), 4.91 (s, 1H), 4.78
	(s, 1H), 4.58-4.49 (m, 2H), 4.42 (dd,
	J = 9.4, 8.3 Hz, 2H), 4.29 (s, 2H), 3.84
	(s, 1H), 3.48 (br s, 1H), 2.27 (s, 6H),
	1.95 (br s, 2H), 1.71-1.67 (m, 3H),
	1.38-1.18 (m, 6H), 1.12 (br s, 3H)
	(approx 1:1 mixture of diastereomers)
40: (4R)-4-((R)-1-hydroxyethyl)-3-(2-	(CDCl3) δ 8.95 (s, 4H), 8.41 (d, J =	HRMS (B)
((1-(5-(4-	5.8, 1H), 8.21 (d, J = 5.8 Hz, 1H), 7.92-	m/z
(trifluoromethyl)phenyl)pyrimidin-2-	7.66 (m, 7H), 7.48-7.44 (m, 3H),	475.1684 (M +
yl)ethyl)amino)pyrimidin-4-	6.45-6.35 (m, 2H), 5.41 (p, J = 6.9	H)+
yl)oxazolidin-2-one	Hz, 1H), 5.22 (br s, 1H), 4.94-4.90
	(m, 2H), 4.78 (br s, 1H), 4.65-4.35
	(m, 4H), 4.30 (br s, 1H), 3.49 (br s,
	1H), 2.77 (br s, 1H), 1.70-1.66 (m,
	6H), 1.25-1.21 (m, 3H), 1.09 (br s,
	3H) (approx 1:1 mixture of
	diastereomers)
41: (4R)-3-(2-(1-(5-(4-fluoro-3-	(CDCl3) δ 8.85-8.75 (m, 4H), 8.16-	HRMS (B)
methylphenyl)pyrimidin-2-	8.08 (m,2H), 7.38-7.20 (m, 6H),	m/z
yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-	7.09-7.05 (m, 2H), 6.08-6.04 (m,	439.1875 (M +
hydroxyethyl)oxazolidin-2-one	2H), 5.34-5.25 (m, 1H), 5.14-5.10	H)+.
	(m, 1H), 4.86-4.78 (m, 1H), 4.57
	(dd, J = 9.5, 2.8 Hz, 1H), 4.49-4.28
	(m, 3H), 3.54 (br s, 1H), 2.29 (br s,
	6H), 1.58-1.53 (m, 6H), 1.19-1.12
	(m, 3H), 1.00 (br s, 3H) (approx 1:1
	mixture of diastereomers)
42: (4R)-3-(2-((1-(5-(tert-	(CDCl3) δ 8.74-8.72 (m, 4H), 8.20 (d,	HRMS (B)
butyl)pyrimidin-2-	J = 5.8 Hz, 2H), 7.46-7.40 (m, 2H),	m/z
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	6.19-6.15 (m, 2H), 5.37-5.29 (m,	387.2135 (M +
hydroxyethyl)oxazolidin-2-one	1H), 5.30 (s, 1H), 4.98-4.86 (m, 1H),	H)+
	4.82 (s, 1H), 4.61-4.50 (m, 3H), 4.47-
	4.37 (m, 2H), 4.32-4.21 (m, 2H),
	3.84 (s, 1H), 1.63-1.58 (m, 6H), 1.39-
	1.37 (m, 18H), 1.24-1.20 (m, 3H),
	1.14-1.00 (m, 3H) (approx 1:1
	mixture of diastereomers)
43: (4R)-4-((R)-1-hydroxyethyl)-3-(2-	(CDCl3) δ 8.94 (d, J = 4.4 Hz, 4H),	HRMS (B)
(1-(5-(3-	8.23 (dd, J = 5.8, 2.2 Hz, 2H), 7.86-	m/z
(trifluoromethyl)phenyl)pyrimidin-2-	7.63 (m, 8H), 7.44 (dd, J = 13.5, 5.7	475.1682
yl)ethylamino)pyrimidin-4-	Hz, 2H), 6.12 (dd, J = 15.1, 7.4 Hz,	and
yl)oxazolidin-2-one	2H), 5.41 (t, J = 7.4 Hz, 1H), 5.20 (br	475.1689 (M +
	s, 1H), 4.89 (d, J = 6.7 Hz, 1H), 4.80	H)+.
	(s, 1H), 4.58-4.48 (m, 2H), 4.43 (dd,
	J = 9.3, 8.2 Hz, 2H), 4.30 (br s, 1H),
	3.77 (br s, 1H), 3.36 (br s, 1H), 1.90
	(br s, 3H), 1.69 (d, J = 2.2 Hz, 3H),
	1.37-1.17 (m, 3H), 1.12 (br s, 3H)
	(approx 1:1 mixture of diastereomers)
44: (R)-4-((R)-1-hydroxyethyl)-3-(2-	(CDCl3) δ 8.21 (d, J = 5.9 Hz, 1H),	HRMS (B)
(((S)-1-(4-phenoxyphenyl)ethyl)amino)	7.45 (d, J = 5.7 Hz, 1H), 7.42-7.26	m/z
pyrimidin-4-yl)oxazolidin-2-one	(m, 4H), 7.13 (dd, J = 8.1, 6.7 Hz,	421.1875,
	1H), 7.07-6.88 (m, 4H), 5.66 (b, 1H),	(M + H)+,
	4.97 (s, 1H), 4.67 (ddd, J = 8.2, 5.1,	RT = 2.56
	2.5 Hz, 1H), 4.51-4.25 (m, 2H), 3.61	min.
	(b, 1H), 1.56 (d, J = 6.9 Hz, 3H), 0.95
	(d, J = 22.9 Hz, 3H).
45: (4R)-3-(2-((1-(5-(4-		HRMS (B)
fluorophenoxy)pyrimidin-2-		m/z
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-		441.1676,
hydroxyethyl)oxazolidin-2-one		(M + H)+,
		RT = 2.13
		min.
46: (4R)-3-(2-((1-(3-(4-chlorophenyl)-		HRMS (B)
1,2,4-oxadiazol-5-		m/z
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-		431.1219,
hydroxyethyl)oxazolidin-2-one.		(M + H)+,
		RT = 2.16
		min.
47: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 9.13 (d,	HRMS m/z
(((S)-1-(5-(3-	J = 1.5 Hz, 1H), 8.73 (d, J = 1.4 Hz,	475.1686 (M +
(trifluoromethyl)phenyl)pyrazin-2-	1H), 8.39 (s, 1H), 8.32 (d, J = 7.9 Hz,	H)+.
yl)ethyl)amino)pyrimidin-4-	1H), 8.16 (d, J = 5.9 Hz, 1H), 7.78 (d,
yl)oxazolidin-2-one	J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz,
	1H), 7.39 (d, J = 5.8 Hz, 1H), 5.28 (q,
	J = 7.0 Hz, 1H), 4.51 (dd, J = 9.2, 2.8
	Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.81
	(br s, 0H), 1.65 (d, J = 7.1 Hz, 3H),
	0.80 (br s, 3H);
48: (R)-3-(2-((S)-1-(3-fluoro-4-((3,3,4-	1H NMR (400 MHz, MeOD) δ 8.11 (d,	HRMS m/z
trimethylpiperazin-1-	J = 5.8 Hz, 1H), 7.40-7.30 (m, 2H),	487.2808 (M +
yl)methyl)phenyl)ethylamino)pyrimidin-	7.16 (dd, J = 8.0, 1.7 Hz, 1H), 7.07	H)+.
4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-	(dd, J = 11.2, 1.7 Hz, 1H), 5.08 (q, J =
2-one	7.0 Hz, 1H), 4.80 (br s, 1H), 4.52 (dd,
	J = 9.2, 2.8 Hz, 1H), 4.38 (t, J = 8.9
	Hz, 1H), 3.99 (br s, 1H), 3.48 (s, 2H),
	2.55 (t, J = 4.9 Hz, 2H), 2.48 (br s,
	2H), 2.20-2.18 (m, 5H), 1.50 (d, J =
	7.0 Hz, 3H), 1.04 (s, 6H), 0.78 (br s,
	3H);
49: (R)-3-(2-((S)-1-(4-((4,4-	1H NMR (400 MHz, MeOD) δ 8.11 (d,	HRMS m/z
difluoropiperidin-1-yl)methyl)-3-	J = 5.8 Hz, 1H), 7.38-7.30 (m, 2H),	480.2204 (M +
fluorophenyl)ethylamino)pyrimidin-4-	7.18 (dd, J = 7.9, 1.7 Hz, 1H), 7.10 (d,	H)+.
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-	J = 11.3 Hz, 1H), 5.08 (q, J = 6.9 Hz,
one	1H), 4.80 (br s, 1H), 4.52 (dd, J = 9.1,
	2.8 Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H),
	4.01 (br s, 1H), 3.60 (s, 2H), 2.60-
	2.58 (m, 4H), 2.05-1.89 (m, 4H),
	1.50 (d, J = 7.0 Hz, 3H), 0.77 (br s,
	3H)
50: (R)-3-(2-(((S)-1-(5-(4-fluoro-3-	1H NMR (400 MHz, MeOD) δ 8.70 (d,	HRMS m/z
methylphenyl)pyridin-2-	J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.97 (dd,	438.1927 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	J = 8.2, 2.3 Hz, 1H), 7.55-7.43 (m,	H)+.
hydroxyethyl)oxazolidin-2-one	3H), 7.36 (d, J = 5.8 Hz, 1H), 7.13
	(dd, J = 9.5, 8.5 Hz, 1H), 5.16 (q, J =
	7.0 Hz, 1H), 4.78 (br s, 1H), 4.51 (dd,
	J = 9.3, 2.7 Hz, 1H), 4.37 (t, J = 8.9
	Hz, 1H), 3.67 (br s, 1H), 2.33 (d, J =
	1.9 Hz, 3H), 1.59 (d, J = 7.1 Hz, 3H),
	0.68 (br s, 3H);
51: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.79 (d,	HRMS m/z
(((S)-1-(5-(3-	J = 2.5 Hz, 1H), 8.14 (s, 1H), 8.06 (dd,	474.1739 (M +
(trifluoromethyl)phenyl)pyridin-2-	J = 8.3, 2.4 Hz, 1H), 7.95-7.89 (m,	H)+.
yl)ethyl)amino)pyrimidin-4-	2H), 7.74-7.64 (m, 2H), 7.55 (d, J =
yl)oxazolidin-2-one	8.2 Hz, 1H), 7.36 (d, J = 5.7 Hz, 1H),
	5.18 (q, J = 7.0 Hz, 1H), 4.79 (s, 1H),
	4.51 (dd, J = 9.1, 2.7 Hz, 1H), 4.37 (t,
	J = 8.9 Hz, 1H), 3.63 (br s, 1H), 1.60
	(d, J = 7.0 Hz, 3H), 0.68 (br s, 3H);
52: (R)-3-(2-(((S)-1-(6-(4-fluoro-3-	1H NMR (400 MHz, MeOD) δ 8.60 (d,	HRMS m/z
methylphenyl)pyridin-3-	J = 2.2 Hz, 1H), 8.13 (d, J = 6.0 Hz,	438.1985 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 7.88 (dd, J = 8.3, 2.3 Hz, 1H),	H)+.
hydroxyethyl)oxazolidin-2-one	7.84-7.69 (m, 3H), 7.35 (d, J = 5.8
	Hz, 1H), 7.12 (t, J = 9.0 Hz, 1H), 5.17
	(q, J = 7.0 Hz, 1H), 4.83 (br s, 1H),
	4.52 (dd, J = 9.3, 2.7 Hz, 1H), 4.39 (t,
	J = 8.9 Hz, 1H), 3.87 (br s, 1H), 2.33
	(d, J = 1.9 Hz, 3H), 1.59 (d, J = 7.0
	Hz, 3H), 0.76 (br s, 3H);
53: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.68 (d,	HRMS m/z
(((S)-1-(6-(3-	J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.19 (d,	474.1816 (M +
(trifluoromethyl)phenyl)pyridin-3-	J = 7.7 Hz, 1H), 8.14 (d, J = 5.8 Hz,	H)+.
yl)ethyl)amino)pyrimidin-4-	1H), 7.98-7.85 (m, 2H), 7.76-7.62
yl)oxazolidin-2-one	(m, 2H), 7.35 (d, J = 5.8 Hz, 1H), 5.19
	(q, J = 7.0 Hz, 1H), 4.83 (s, 1H), 4.52
	(dd, J = 9.1, 2.7 Hz, 1H), 4.39 (t, J =
	8.9 Hz, 1H), 3.84 (br s, 1H), 1.60 (d, J =
	7.1 Hz, 3H), 0.75 (br s, 3H);
54: (R)-3-(2-(((S)-1-(5-(4-fluoro-3-	1H NMR (400 MHz, MeOD) δ 9.00 (d,	HRMS m/z
methylphenyl)pyrazin-2-	J = 1.5 Hz, 1H), 8.65 (d, J = 1.5 Hz,	439.1872 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 8.15 (d, J = 5.9 Hz, 1H), 7.94	H)+.
hydroxyethyl)oxazolidin-2-one	(ddd, J = 7.3, 2.3, 0.9 Hz, 1H), 7.87
	(ddd, J = 7.7, 4.9, 2.4 Hz, 1H), 7.38
	(d, J = 5.8 Hz, 1H), 7.16 (dd, J = 9.5,
	8.6 Hz, 1H), 5.25 (q, J = 7.0 Hz, 1H),
	4.82 (br s, 1H), 4.51 (dd, J = 9.3, 2.8
	Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H), 3.84
	(br s, 1H), 2.35 (d, J = 1.8 Hz, 3H),
	1.63 (d, J = 7.1 Hz, 3H), 0.80 (br s,
	3H);
55: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.95 (d,	HRMS m/z
(((S)-1-(2′-(trifluoromethyl)-[3,4′-	J = 2.3 Hz, 1H), 8.79 (d, J = 5.1 Hz,	475.1685 (M +
bipyridin]-6-yl)ethyl)amino)pyrimidin-4-	1H), 8.22 (dd, J = 8.3, 2.4 Hz, 1H),	H)+.
yl)oxazolidin-2-one	8.19-8.11 (m, 2H), 7.99 (dd, J = 5.1,
	1.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),
	7.37 (d, J = 5.8 Hz, 1H), 5.19 (q, J =
	7.0 Hz, 1H), 4.78 (s, 1H), 4.55-4.45
	(m, 1H), 4.37 (t, J = 8.9 Hz, 1H), 3.73-
	3.44 (m, 1H), 1.60 (d, J = 7.0 Hz,
	3H), 0.69 (br s, 3H);
56: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 9.30 (d,	HRMS m/z
(((S)-1-(6′-(trifluoromethyl)-[2,3′-	J = 2.0 Hz, 1H), 8.75 (s, 1H), 8.60 (dd,	475.1689 (M +
bipyridin]-5-yl)ethyl)amino)pyrimidin-4-	J = 8.2, 2.1 Hz, 1H), 8.14 (d, J = 5.8	H)+.
yl)oxazolidin-2-one	Hz, 5H), 7.98 (t, J = 1.4 Hz, 2H), 7.93
	(d, J = 8.4 Hz, 1H), 7.36 (d, J = 5.8
	Hz, 1H), 5.20 (q, J = 7.0 Hz, 1H), 4.83
	(br s, 1H), 4.52 (dd, J = 9.2, 2.7 Hz,
	1H), 4.39 (t, J = 8.9 Hz, 1H), 3.80 (br
	s, 1H), 1.61 (d, J = 7.0 Hz, 3H), 0.75
	(br s, 3H);
57: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 9.03 (d,	HRMS m/z
(((S)-1-(6′-(trifluoromethyl)-[3,3′-	J = 2.2 Hz, 1H), 8.88 (d, J = 1.8 Hz,	475.1689 (M +
bipyridin]-6-yl)ethyl)amino)pyrimidin-4-	1H), 8.34 (dd, J = 8.3, 2.2 Hz, 1H),	H)+.
yl)oxazolidin-2-one	8.15 (dd, J = 8.1, 2.5 Hz, 2H), 7.93 (d,
	J = 8.4 Hz, 1H), 7.63-7.58 (m, 1H),
	7.37 (d, J = 5.8 Hz, 1H), 5.19 (q, J =
	7.1 Hz, 1H), 4.79 (br s, 1H), 4.51 (dd,
	J = 9.1, 2.7 Hz, 1H), 4.38 (t, J = 8.9
	Hz, 1H), 3.71-3.47 (m, 1H), 1.61 (d,
	J = 7.1 Hz, 3H), 0.70 (br s, 3H);
58: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 9.24-	HRMS m/z
(((S)-1-(6-(trifluoromethyl)-[2,3′-	9.19 (m, 1H), 8.47 (dd, J = 8.3, 2.3	475.1721 (M +
bipyridin]-6′-yl)ethyl)amino)pyrimidin-	Hz, 1H), 8.24-8.07 (m, 3H), 7.79 (dd,	H)+.
4-yl)oxazolidin-2-one	J = 7.7, 0.9 Hz, 1H), 7.60 (d, J = 8.2
	Hz, 2H), 7.39 (d, J = 5.9 Hz, 1H), 5.21
	(q, J = 7.0 Hz, 1H), 4.80 (br s, 1H),
	4.58-4.44 (m, 1H), 4.38 (t, J = 8.8
	Hz, 1H), 3.69 (br s, 1H), 1.61 (d, J =
	7.1 Hz, 3H), 0.69 (br s, 3H);
59: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.81 (d,	HRMS m/z
(((S)-1-(4-methyl-2′-(trifluoromethyl)-	J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.15 (d,	489.1881 (M +
[3,4′-bipyridin]-6-	J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.72 (dd,	H)+.
yl)ethyl)amino)pyrimidin-4-	J = 5.0, 1.6 Hz, 1H), 7.45 (s, 1H), 7.37
yl)oxazolidin-2-one	(d, J = 5.8 Hz, 1H), 5.14 (q, J = 7.0
	Hz, 1H), 4.79 (br s, 1H), 4.52 (dd, J =
	9.3, 2.7 Hz, 1H), 4.38 (t, J = 8.9 Hz,
	1H), 3.65 (br s, 1H), 2.32 (s, 3H), 1.58
	(d, J = 7.1 Hz, 3H), 0.77 (br s, 3H);
60: (R)-3-(2-(((S)-1-(5-fluoro-2′-	1H NMR (400 MHz, MeOD) δ 8.82-	HRMS m/z
(trifluoromethyl)-[3,4′-bipyridin]-6-	8.80 (m,2H), 8.19 (d, J = 1.5 Hz, 1H),	493.1575 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	8.14 (d, J = 5.8 Hz, 1H), 8.10 (dd, J =	H)+.
hydroxyethyl)oxazolidin-2-one	10.8, 1.9 Hz, 1H), 8.00 (dd, J = 5.2,
	1.7 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H),
	5.54 (q, J = 6.9 Hz, 1H), 4.64 (s, 1H),
	4.55 (dd, J = 9.3, 2.7 Hz, 1H), 4.41 (t,
	J = 8.8 Hz, 1H), 3.93 (br s, 1H), 1.60
	(d, J = 6.9 Hz, 3H) 0.87 (br s, 3H);
61: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.79 (s,	HRMS m/z
(((S)-1-(5-methyl-2′-(trifluoromethyl)-	1H), 8.78 (d, J = 4.6 Hz, 1H), 8.15 (s,	489.1829 (M +
[3,4′-bipyridin]-6-	1H), 8.14 (d, J = 6.3 Hz, 1H), 8.05 (s,	H)+.
yl)ethyl)amino)pyrimidin-4-	1H), 7.98 (d, J = 5.0 Hz, 1H), 7.37 (d,
yl)oxazolidin-2-one	J = 5.8 Hz, 0H), 5.49-5.38 (m, 1H),
	4.90-4.84 (m, 1H), 4.55 (dd, J = 9.2,
	2.6 Hz, 1H), 4.41 (t, J = 8.8 Hz, 1H),
	3.96 (br s, 1H), 2.57 (s, 3H), 1.53 (d, J =
	6.7 Hz, 3H), 0.87 (br s, 3H);
62: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.79 (d,	HRMS m/z
(((S)-1-(2-methyl-2′-(trifluoromethyl)-	J = 5.0 Hz, 1H), 8.15 (d, J = 5.9 Hz,	489.1840
[3,4′-bipyridin]-6-	1H), 7.88 (s, 1H), 7.74-7.65 (m, 2H),	(M + H)+.
yl)ethyl)amino)pyrimidin-4-	7.39 (d, J = 8.0 Hz, 1H), 7.37 (d, J =
yl)oxazolidin-2-one	5.8 Hz, 1H), 5.14 (t, J = 7.1 Hz, 1H),
	4.79 (br s, 1H), 4.52 (dd, J = 9.3, 2.7
	Hz, 1H), 4.38 (t,J = 8.9 Hz, 1H), 3.61
	(br s, 1H), 2.53 (s, 3H), 1.59 (d, J =
	7.0 Hz, 3H), 0.76 (br s, 3H);
63: (R)-3-(2-(((S)-1-(2′-(tert-butyl)-	1H NMR (400 MHz, MeOD) δ 8.85 (d,	HRMS m/z
[3,4′-bipyridin]-6-	J = 1.8 Hz, 1H), 8.56 (dd, J = 5.3, 0.8	463.2439 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	Hz, 1H), 8.16-8.08 (m, 1H), 7.73 (d,	H)+.
hydroxyethyl)oxazolidin-2-one	J = 0.7 Hz, 1H), 7.58 (d, J = 8.2 Hz,
	1H), 7.54 (dd, J = 5.2, 1.7 Hz, 1H),
	7.36 (d, J = 5.8 Hz, 1H), 5.18 (q, J =
	7.0 Hz, 1H), 4.78 (br s, 1H), 4.56-
	4.46 (m, 1H), 4.37 (t, J = 8.8 Hz, 1H),
	3.59 (br s, 1H), 1.60 (d, J = 7.1 Hz,
	3H), 1.42 (s, 9H), 0.67 (br s, 3H);
64: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.84 (d,	HRMS m/z
(((S)-1-(2′-(1,1,1-trifluoro-2-	J = 2.2 Hz, 1H), 8.64 (d, J = 5.1 Hz,	517.2167 (M +
methylpropan-2-yl)-[3,4′-bipyridin]-6-	1H), 8.16-8.03 (m, 2H), 7.86 (s, 1H),	H)+.
yl)ethyl)amino)pyrimidin-4-	7.64 (dd, J = 5.1, 1.6 Hz, 1H), 7.58 (d,
yl)oxazolidin-2-one	J = 8.2 Hz, 1H), 7.35 (d, J = 5.8 Hz,
	1H), 5.18 (q, J = 7.0 Hz, 1H), 4.78 (br
	s, 1H), 4.50 (dd, J = 9.3, 2.7 Hz, 1H),
	4.37 (t, J = 8.8 Hz, 1H), 3.57 (br s,
	1H), 1.68 (s, 6H), 1.60 (d, J = 7.1 Hz,
	3H), 0.67 (br s, 3H);
65: 4-(2-((S)-1-((4-((R)-4-((R)-1-	1H NMR (400 MHz, MeOD) δ 8.19 (d,	HRMS m/z
hydroxyethyl)-2-oxooxazolidin-3-	J = 5.8 Hz, 1H), 8.15-8.09 (m, 2H),	437.1375 (M +
yl)pyrimidin-2-yl)amino)ethyl)thiazol-4-	7.90 (s, 1H), 7.80-7.74 (m, 2H), 7.43	H)+.
yl)benzonitrile	(d, J = 5.8 Hz, 1H), 5.51 (q, J = 7.5
	Hz, 1H), 4.82 (br s, 1H), 4.49 (dd, J =
	9.0, 3.1 Hz, 1H), 4.38 (t, J = 8.9 Hz,
	1H), 4.10 (br s, 1H), 1.73 (d, J = 7.1
	Hz, 3H), 0.78 (br s, 3H);
66: (R)-3-(2-(((S)-1-(5-(4-	1H NMR (400 MHz, MeOD) δ 8.16 (d,	HRMS m/z
chlorophenyl)isoxazol-3-	J = 5.8 Hz, 1H), 7.82-7.76 (m, 2H),	430.1260 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	7.53-7.47 (m, 2H), 7.40 (d, J = 5.8	H)+.
hydroxyethyl)oxazolidin-2-one	Hz, 1H), 6.78 (s, 1H), 5.34 (q, J = 7.1
	Hz, 1H), 4.87 (ddd, J = 8.4, 4.2, 2.7
	Hz, 1H), 4.54 (dd, J = 9.2, 2.7 Hz,
	1H), 4.41 (t, J = 8.9 Hz, 1H), 4.31 (br
	s, 1H), 1.63 (d, J = 7.0 Hz, 3H), 0.93
	(br s, 3H);
67: (R)-3-(2-(((R)-1-(4-(2,4-	1H NMR (400 MHz, MeOD) δ 8.18 (d,	HRMS m/z
dichlorophenyl)thiazol-2-	J = 5.8 Hz, 1H), 7.86 (d, J = 8.4 Hz,	480.0639 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 7.78 (s, 1H), 7.58 (d, J = 2.2 Hz,	H)+.
hydroxyethyl)oxazolidin-2-one	1H), 7.44-7.39 (m, 2H), 5.43 (q, J =
	7.0 Hz, 1H), 4.64 (br s, 1H), 4.56-
	4.49 (m, 2H), 4.30 (br s, 1H), 1.71 (d,
	J = 7.0 Hz, 3H), 1.06 (d, J = 6.5 Hz,
	3H);
68: (R)-3-(2-(((S)-1-(4-(2,4-	1H NMR (400 MHz, MeOD) δ 8.19 (d,	HRMS m/z
dichlorophenyl)thiazol-2-	J = 5.8 Hz, 1H), 7.91 (d, J = 8.5 Hz,	480.0637 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 7.81 (s, 1H), 7.58 (d, J = 2.1 Hz,	H)+.
hydroxyethyl)oxazolidin-2-one	1H), 7.46-7.39 (m, 2H), 5.50 (q, J =
	7.0 Hz, 1H), 4.82 (br s, 1H), 4.51 (dd,
	J = 9.0, 2.7 Hz, 1H), 4.38 (t, J = 8.9
	Hz, 1H), 4.04 (br s, 1H), 1.72 (d, J =
	7.0 Hz, 3H), 0.82 (br s, 3H);
69: (R)-3-(2-(((R)-1-(4-(4-	1H NMR (400 MHz, MeOD) δ 8.17 (d,	HRMS m/z
bromophenyl)thiazol-2-	J = 5.8 Hz, 1H), 7.86-7.81 (m, 2H),	490.0533 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	7.69 (s, 1H), 7.59-7.54 (m, 2H), 7.42	H)+.
hydroxyethyl)oxazolidin-2-one	(d, J = 5.8 Hz, 1H), 5.44 (q, J = 7.0
	Hz, 1H), 4.69 (br s, 1H), 4.52 (ddt, J =
	19.3, 9.1, 4.6 Hz, 2H), 4.26 (br s, 1H),
	1.71 (d, J = 7.0 Hz, 3H), 1.08 (d, J =
	6.5 Hz, 3H);
70: (R)-3-(2-(((S)-1-(4-(4-	1H NMR (400 MHz, MeOD) δ 8.21 (d,	HRMS m/z
bromophenyl)thiazol-2-	J = 5.8 Hz, 1H), 7.89-7.84 (m, 2H),	490.0533 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	7.71 (s, 1H), 7.61-7.56 (m, 2H), 7.44	H)+.
hydroxyethyl)oxazolidin-2-one	(d, J = 5.8 Hz, 1H), 5.52 (t, J = 3.5 Hz,
	1H), 4.84 (br s, 1H), 4.52 (dd, J = 9.4,
	2.8 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H),
	4.13 (br s, 1H), 1.74 (d, J = 7.0 Hz,
	3H), 0.81 (br s, 3H);
71: 4-(2-((R)-1-((4-((R)-4-((R)-1-	1H NMR (400 MHz, MeOD) δ 8.17 (d,	HRMS m/z
hydroxyethyl)-2-oxooxazolidin-3-	J = 5.8 Hz, 1H), 8.14-8.09 (m, 2H),	437.1382 (M +
yl)pyrimidin-2-yl)amino)ethyl)thiazol-4-	7.91 (s, 1H), 7.80-7.74 (m, 2H), 7.42	H)+.
yl)benzonitrile	(d, J = 5.8 Hz, 1H), 5.46 (q, J = 7.0
	Hz, 1H), 4.70 (br s, 1H), 4.59-4.45
	(m, 2H), 4.27 (br s, 1H), 1.73 (d, J =
	7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H);
72: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 8.12 (d,	HRMS m/z
((S)-1-(4-((4-methylpiperazin-1-	J = 5.8 Hz, 1H), 7.41-7.22 (m, 5H),	441.2593 (M +
yl)methyl)phenyl)ethylamino)pyrimidin-	5.09 (q, J = 7.0 Hz, 1H), 4.53 (dd, J =	H)+.
4-yl)oxazolidin-2-one	9.3, 2.8 Hz, 1H), 4.39 (t, J = 8.9 Hz,
	1H), 3.99 (s, 1H), 3.52 (d, J = 1.5 Hz,
	2H), 2.56 (bs, 8H), 2.28 (s, 3H), 1.52
	(d, J = 7.0 Hz, 3H), 0.78 (s,3H).
73: (4R)-3-(2-((1-(3-fluoro-4-(4-	1H NMR (400 MHz, MeOD) δ 8.14 (t,	HRMS m/z
methyl-1H-pyrazol-1-	J = 5.7 Hz, 1H), 7.86-7.77 (m, 1H),	427.1870 (M +
yl)phenyl)ethyl)amino)pyrimidin-4-yl)-	7.64 (td, J = 8.3, 2.2 Hz, 1H), 7.56 (d,	H)+.
4-((R)-1-hydroxyethyl)oxazolidin-2-one	J = 3.0 Hz, 1H), 7.42-7.28 (m, 3H),
	5.20-4.99 (m, 1H), 4.75-4.47 (m,
	2H), 4.37 (dt,J = 17.1, 8.9 Hz, 1H),
	2.17 (s, 3H), 1.56 (d,J = 7.1 Hz, 3H),
	1.10 (d, J = 6.5 Hz, 1.5H), 0.82 (br s,
	1.5H).
74: (4R)-3-(2-((1-(5-(3,4-	1H NMR (400 MHz, MeOD) δ 8.27 (d,	HRMS m/z
dichlorophenyl)-1H-imidazol-2-	J = 3.1 Hz, 1H), 7.63 (d, J = 5.0 Hz,	481.0930 (M +
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-	1H), 7.50 (dd,J = 8.4, 1.6 Hz, 1H),	H)+.
4-((R)-1-hydroxyethyl)oxazolidin-2-one	7.41 (s, 1H), 5.14 (q, J = 7.0 Hz, 1H),
	4.72 (td, J = 7.1, 5.1 Hz, 1H), 4.56-
	4.42 (m, 2H), 4.16 (qd, J = 6.4, 5.1
	Hz, 1H), 1.63 (dd, J = 10.1, 7.1 Hz,
	3H), 1.11 (d, J = 6.5 Hz, 3H).
75: (4R)-3-(2-((1-(5-(3,4-	1H NMR (400 MHz, MeOD) δ 8.19 (d,	HRMS m/z
dichlorophenyl)-1H-imidazol-2-	J = 5.8 Hz, 1H), 7.91 (s, 1H), 7.63 (s,	463.1018 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41 (d,	H)+
hydroxyethyl)oxazolidin-2-one	J = 5.8 Hz, 1H), 5.27-5.12 (m, 1H),
	4.67 (s, 1H), 4.62-4.47 (m, 2H), 4.26
	(s, 1H), 1.65 (d, J = 7.1 Hz, 3H), 1.08
	(d, J = 6.5 Hz, 3H).
76: (R)-3-(2-(((S)-1-(5-((4,4-	1H NMR (400 MHz, MeOD) δ 8.47 (d,	HRMS m/z
difluoropiperidin-1-yl)methyl)pyridin-2-	J = 2.0 Hz, 1H), 8.15 (d, J = 5.9 Hz,	463.2250 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 7.78 (dd, J = 8.0, 2.2 Hz, 1H),	H)+.
hydroxyethyl)oxazolidin-2-one	7.45 (d, J = 8.1 Hz, 1H), 7.37 (d, J =
	5.7 Hz, 1H), 5.26-5.08 (m, 1H),
	4.81 (d, J = 6.4 Hz, 1H), 4.53 (dd, J =
	9.1, 2.7 Hz, 1H), 4.39 (t, J = 8.9 Hz,
	1H), 3.95-3.64 (m, 1H), 3.61 (s, 2H),
	2.59 (t, J = 5.6 Hz, 4H), 1.99 (tt, J =
	13.7, 5.6 Hz, 4H), 1.56 (d, J = 7.0 Hz,
	3H), 0.77 (s, 3H).
77: (R)-3-(2-(((S)-1-(6-((4,4-	1H NMR (400 MHz, MeOD) δ 8.52 (d,	HRMS m/z
difluoropiperidin-1-yl)methyl)pyridin-3-	J = 2.3 Hz, 1H), 8.14 (d, J = 5.9 Hz,	463.2267 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 7.85 (dd, J = 8.1, 2.3 Hz, 1H),	H)+.
hydroxyethyl)oxazolidin-2-one	7.51 (d, J = 8.0 Hz, 1H), 7.36 (d, J =
	5.8 Hz, 1H), 5.16 (q, J = 7.1 Hz, 1H),
	4.83 (d, J = 4.5 Hz, 1H), 4.54 (dd, J =
	9.3, 2.7 Hz, 1H), 4.40 (t, J = 8.9 Hz,
	1H), 4.16-3.76 (br s, 1H), 3.69 (s, 2H),
	2.61 (t, J = 5.7 Hz, 4H), 1.99 (tt, J =
	13.5, 5.6 Hz, 4H), 1.57 (d, J = 7.0 Hz,
	3H), 0.83 (s, 3H).
78: (R)-4-((R)-1-hydroxyethyl)-3-(2-	1H NMR (400 MHz, MeOD) δ 9.13 (d,	HRMS m/z
(((R)-1-(5-(3-	J = 1.5 Hz, 1H), 8.79 (d, J = 1.5 Hz,	475.1685 (M +
(trifluoromethyl)phenyl)pyrazin-2-	1H), 8.40 (s, 1H), 8.33 (d, J = 7.8 Hz,	H)+.
yl)ethyl)amino)pyrimidin-4-	1H), 8.15 (d, J = 5.8 Hz, 1H), 7.78 (d,
yl)oxazolidin-2-one	J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz,
	1H), 7.38 (d, J = 5.8 Hz, 1H), 5.25 (q,
	J = 7.0 Hz, 1H), 4.59-4.51 (m, 2H),
	4.33 (br s, 1H), 1.64 (d, J = 7.0 Hz,
	3H), 1.09 (d, J = 6.5 Hz, 3H);
79: (R)-3-(2-(((R)-1-(5-(4-fluoro-3-	1H NMR (400 MHz, MeOD) δ 8.99 (d,	HRMS m/z
methylphenyl)pyrazin-2-	J = 1.5 Hz, 1H), 8.70 (d, J = 1.6 Hz,	439.1869 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	1H), 8.14 (d, J = 5.8 Hz, 1H), 7.99-	H)+.
hydroxyethyl)oxazolidin-2-one	7.92 (m, 1H), 7.88 (ddd, J = 8.4, 4.9,
	2.4 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H),
	7.16 (dd, J = 9.5, 8.6 Hz, 1H), 5.22 (q,
	J = 7.0 Hz, 1H), 4.64 (br s, 1H), 4.60-
	4.51 (m, 2H), 4.32 (t, J = 8.7 Hz, 1H),
	2.35 (d, J = 2.0 Hz, 3H), 1.62 (d, J =
	7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H);

The compounds in Table 29a were prepared using methods similar to those described for the preparation of Examples 35, 36, or 37/38.

TABLE 29a
80 and 81
82 and 83
84 and 85
86 and 87
88 and 89
90 and 91
92 and 93
94 and 95
96 and 97
98 and 99
100 and 101
102 and 103
104 and 105
106 and 107
108 and 109
110 and 111
112 and 113
114 and 115
116 and 117
118 and 119
120 and 121
122 and 123
124 and 125
126 and 127
128 and 129
130 and 131
132 and 133
134 and 135
136 and 137
138 and 139
140 and 141
142 and 143
144 and 145
146 and 147
148 and 149
150 and 151
152 and 153
154 and 155
156 and 157
158 and 159
160 and 161
162 and 163
164 and 165
166 and 167
168 and 169
170 and 171
172 and 173
174 and 175
176 and 177
178 and 179
180 and 181
182 and 183
184 and 185
186 and 187
188 and 189
190 and 191
192 and 193
194 and 195
196 and 197
198 and 199
200 and 201

TABLE 29b
Chemical name, NMR chemical shifts, chiral separation
conditions and LCMS signal for compounds listed in Table 29a.
                                 Chiral separation conditions, peak identification and
Example: Name                    analytical data
80 and 81:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(4-fluoro-3-     chromatography (Column AD-H 20 × 250 mm 35% IPA 10 mM
(trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 232 nm UV collection) to
2-yl)ethyl)amino)pyrimidin-4-yl)- give (R)-3-(2-(((S)-1-(5-(4-fluoro-3-
4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
2-one                            4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
                                 (((R)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 80: First eluted product (40 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.90 (s, 2H), 8.22 (d, J = 5.76 Hz, 1H), 7.83-7.70 (m,
                                 2H), 7.49-7.35 (m, 2H), 6.12 (d, J = 8.09 Hz, 1H), 5.40 (p,
                                 J = 7.25 Hz, 1H), 4.89 (s, 1H), 4.51 (dd, J = 2.70, 9.45 Hz,
                                 1H), 4.42 (dd, J = 8.23, 9.37 Hz, 1H), 3.30 (s, 1H), 1.68 (d,
                                 J = 7.25 Hz, 3H), 1.12 (br s, 3H). HRMS(B) m/z 493.1599
                                 (M + H)+.
                                 81: Second eluted product (45 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.91 (s, 2H), 8.22 (d, J = 5.7 Hz, 1H), 7.84-7.71
                                 (m, 2H), 7.40 (dd, J = 11.6, 7.2 Hz, 2H), 6.14 (d, J = 6.8 Hz,
                                 1H), 5.21 (s, 1H), 4.79 (s, 1H), 4.58-4.48 (m, 1H), 4.30 (s,
                                 1H), 3.81 (s, 1H), 1.66 (m, 3H), 1.24 (m, 3H). HRMS(B) m/z
                                 493.1600 (M + H)+.
82 and 83:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(4-chloro-3-     chromatography (Column AD-H 20 × 250 mm 30% IPA 10 mM
(trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 232 nm UV collection) to
2-yl)ethyl)amino)pyrimidin-4-yl)- give (R)-3-(2-(((S)-1-(5-(4-chloro-3-
4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
2-one                            4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
                                 (((R)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 82: First eluted product (13 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.91 (s, 2H), 8.22 (d, J = 5.8 Hz, 1H), 7.90-7.85 (m, 1H),
                                 7.68 (d, J = 1.8 Hz, 2H), 7.45 (d, J = 5.7 Hz, 1H), 6.08 (d, J =
                                 8.2 Hz, 1H), 5.40 (q, J = 7.5 Hz, 1H), 4.89 (s, 1H), 4.51
                                 (dd, J = 9.4, 2.7 Hz, 1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H),
                                 4.09 (s, 1H), 3.29 (s, 1H), 1.68 (d, J = 7.5 Hz, 3H), 1.12 (br
                                 s, 3H). HRMS(B) m/z 509.1306 (M + H)+.
                                 83: Second eluted product (12 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.93 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.88 (d, J =
                                 1.7 Hz, 1H), 7.69 (d, J = 1.4 Hz, 2H), 7.42 (d, J = 5.7 Hz,
                                 1H), 6.09 (d, J = 6.8 Hz, 1H), 5.21 (s, 1H), 4.78 (s, 1H),
                                 4.53 (d, J = 8.9 Hz, 1H), 4.31 (s, 1H), 3.70 (s, 1H), 1.66 (m,
                                 3H), 1.24 (m, 3H). HRMS(B) m/z 509.1312 (M + H)+.
84 and 85:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(3,4-            chromatography (Column C6 AD-H 20 × 250 mm 35% IPA 5
dichlorophenyl)pyrimidin-2-      mM NH4OH in CO2, flow 80 mL/min, 232 nm UV collection)
yl)ethyl)amino)pyrimidin-4-yl)-4- to give (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-
                                 dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-
                                 ((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 84: First eluted product (28 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.89 (s, 2H), 8.22 (d, J = 5.7 Hz, 1H), 7.70-7.58 (m, 2H),
                                 7.49-7.37 (m, 2H), 6.03 (d, J = 7.5 Hz, 1H), 5.39 (t, J =
                                 7.4 Hz, 1H), 4.89 (s, 1H), 4.55-4.47 (m, 1H), 4.42 (dd, J =
                                 9.4, 8.3 Hz, 1H), 3.25 (s, 1H), 1.67 (dd, J = 7.0, 4.3 Hz,
                                 3H), 1.12 (br s, 3H). HRMS(B) m/z 475.1026 (M + H)+.
                                 85: Second eluted product (22 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.90 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.71-7.57
                                 (m, 2H), 7.46-7.38 (m, 2H), 6.01 (s, 1H), 5.18 (s, 1H),
                                 4.78 (s, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.31 (s, 2H), 3.64 (s,
                                 1H), 1.66 (d, J = 6.9 Hz, 3H), 1.26-1.21 (m, 3H).
                                 HRMS(B) m/z 475.1032 (M + H)+.
86 and 87: (R)-4-((R)-1-         Chiral separation was achieved by chiral SFC column
hydroxyethyl)-3-(2-((1-(5-(3-    chromatography (Column AD-H 20 × 250 mm 35% IPA 10 mM
(trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 232 nm UV collection) to
2-yl)ethyl)amino)pyrimidin-4-    give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-
yl)oxazolidin-2-one              (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
                                 4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-
                                 (((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
                                 86:: First eluted product (80 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.94 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.85-7.63
                                 (m, 4H), 7.46 (d, J = 5.7 Hz, 1H), 6.11 (d, J = 8.2 Hz, 1H),
                                 5.41 (p, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.52 (dd, J = 9.5, 2.6
                                 Hz, 1H), 4.43 (dd, J = 9.4, 8.3 Hz, 1H), 3.34 (s, 1H), 1.67
                                 (d, J = 7.2 Hz, 3H), 1.12 br(s, 3H). HRMS(B) m/z 475.1681
                                 (M + H)+.
                                 87: Second eluted product (67 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.95 (s, 2H), 8.20 (d, J = 5.9 Hz, 1H), 7.86-7.64
                                 (m, 4H), 7.46 (d, J = 5.9 Hz, 1H), 6.48 (br s, 1H), 5.20 (br s,
                                 1H), 4.79 (br s, 1H), 4.55 (d, J = 8.6 Hz, 1H), 4.34-4.30 (m,
                                 2H), 3.65 (br s, 1H), 1.67 (d, J = 7.2 Hz, 3H), 1.25 (d, J =
                                 6.5 Hz, 3H). HRMS(B) m/z 475.1677 (M + H)+.
88 and 89:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(4-chloro-3-     chromatography (Column C6 AD-H 20 × 250 mm 35% IPA 5
methylphenyl)pyrimidin-2-        mM NH4OH in CO2, flow 80 mL/min, 232 nm UV collection)
yl)ethyl)amino)pyrimidin-4-yl)-4- to give (R)-3-(2-(((S)-1-(5-(4-chloro-3-
((R)-1-hydroxyethyl)oxazolidin-2- methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-
one                              ((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-
                                 (5-(4-chloro-3-methylphenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 88: First eluted product (16 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.79 (s, 2H), 8.13 (d, J = 5.7, 1H), 7.44-7.17 (m, 4H),
                                 6.07-5.96 (m, 1H), 5.29 (t, J = 7.7 Hz, 1H), 5.12 (s, 1H),
                                 4.81 (d, J = 7.3 Hz, 1H), 4.55 (s, 1H), 4.43 (dd, J = 9.4, 2.6
                                 Hz, 1H), 3.38 (s, 1H), 2.39 (s, 3H), 1.57 (d, J = 7.7 Hz, 3H),
                                 1.02 (br s, 3H). HRMS(B) m/z 455.1575 (M + H)+.
                                 89: Second eluted product (9 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.80 (s, 2H), 8.13 (d, J = 5.7 Hz, 1H), 7.41 (d, J =
                                 8.3 Hz, 1H), 7.37-7.23 (m, 3H), 5.97 (br s, 1H), 5.08 (br s,
                                 1H), 4.71 (br s, 1H), 4.45 (d, J = 9.0 Hz, 1H), 4.40-4.18
                                 (m, 2H), 3.86 (br s, 1H), 2.39 (s, 3H), 1.57 (d, J = 7.7 Hz,
                                 3H), 1.16-1.13 (m, 3H). HRMS(B) m/z 455.1578 (M + H)+.
90 and 91:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(3-chloro-5-     chromatography (Column Coated 1 P9: AD-H 4.6 × 100 mm
(trifluoromethyl)phenyl)pyrimidin- 5-55% IPA 5 mM NH3 in CO2, flow 5 mL/min, 177 nm UV
2-yl)ethyl)amino)pyrimidin-4-yl)- collection) to give (R)-3-(2-(((S)-1-(5-(3-chloro-5-
4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
2-one                            4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
                                 (((R)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 90: First eluted product (4 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.83 (s, 2H), 8.14 (d, J = 5.8 Hz, 1H), 7.69-7.57 (m, 3H),
                                 7.37 (d, J = 5.8 Hz, 1H), 5.99 (d, J = 7.7 Hz, 1H), 5.32 (p, J =
                                 7.1 Hz, 1H), 4.81 (d, J = 7.5 Hz, 1H), 4.42 (dd, J = 9.4,
                                 2.4 Hz, 1H), 4.33 (dd, J = 9.4, 8.3 Hz, 1H), 3.18 (br s, 1H),
                                 1.57 (d, J = 9.5 Hz, 3H), 1.03 (br s, 3H). HRMS(B) m/z
                                 509.1299 (M + H)+.
                                 91: Second eluted product (4 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.83 (s, 2H), 8.13 (d, J = 5.7 Hz, 1H), 7.69-7.58
                                 (m, 3H), 7.34 (d, J = 5.7 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H),
                                 5.35-5.31 (m, 1H), 5.13 (br s, 1H), 4.45 (d, J = 9.0 Hz, 1H),
                                 4.35-4.24 (m, 1H), 4.22 (s, 1H), 3.62 (br s, 1H), 1.57 (d, J =
                                 7.0 Hz, 3H), 1.19-1.16 (m, 3H). HRMS(B) m/z 509.1298
                                 (M + H)+.
92 and 93:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(3-(4-chlorophenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
1,2,4-oxadiazol-5-               60 bar, eluting 25% IPA with 5 mM NH4OH/CO2 (v/v) to
yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 92: First eluted product (12.4 mg). HRMS(B) m/z 431.1225
                                 (M + H)+. RT = 2.39 min.
                                 93: Second eluted product (14.3 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.25 (d, J = 6.0 Hz, 1H), 8.10-7.94 (m, 2H), 7.57
                                 (d, J = 5.7 Hz, 1H), 7.53-7.43 (m, 2H), 5.96 (b, 1H), 5.38
                                 (s, 1H), 4.84 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.54 (dd, J =
                                 9.4, 2.5 Hz, 1H), 4.40 (dd, J = 9.4, 8.3 Hz, 1H), 4.18-3.59
                                 (b, 1H), 1.79 (d, J = 7.1 Hz, 3H), 1.01 (b, 3H). HRMS(B)
                                 m/z 431.1219 (M + H)+, RT = 2.40 min.
94 and 95:                       Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(4-fluorophenyl)- chromatography ID-H, 5 UM, 20 × 250 MM column, 80
1,3,4-oxadiazol-2-               ml/min, 99 bar, eluting 30% IPA with 5 mM NH4OH/CO2
yl)ethyl)amino)pyrimidin-4-yl)-4- (v/v) to give (R)-3-(2-(((R)-1-(5-(4-fluorophenyl)-1,3,4-
((R)-1-hydroxyethyl)oxazolidin-2- oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-
                                 fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 94: First eluted product (30.1 mg). HRMS (B) m/z 415.1519
                                 (M + H)+. RT = 1.80 min.
                                 95: Second eluted product (32.3 mg). HRMS(B) m/z
                                 415.1521 (M + H)+, RT = 1.79 min.
96 and 97:                       Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
((1-(3-(2-phenoxyethyl)-1,2,4-   99 bar, eluting 20% IPA with 5 mM NH4OH/CO2 (v/v) to
oxadiazol-5-                     give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(2-
yl)ethyl)amino)pyrimidin-4-      phenoxyethyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
yl)oxazolidin-2-one              yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-
                                 (((S)-1-(3-(2-phenoxyethyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
                                 96: First eluted product (19.2 mg). HRMS(B) m/z 441.1867
                                 (M + H)+. RT = 1.90 min.
                                 97: Second eluted product (31.2 mg). HRMS(B) m/z
                                 441.1864 (M + H)+, RT = 1.94 min.
98 and 99:                       Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
((1-(5-(p-tolyl)-1,3,4-oxadiazol-2- 100 bar, eluting 15% IPA with 0.5% NH4OH/CO2 (v/v) to
yl)ethyl)amino)pyrimidin-4-      give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(p-tolyl)-
yl)oxazolidin-2-one.             1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
                                 2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(p-
                                 tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)oxazolidin-2-one.
                                 98: First eluted product (48 mg). HRMS(B) m/z 411.1768 (M +
                                 H)+. RT = 1.82 min.
                                 99: Second eluted product (50 mg). HRMS(B) m/z
                                 411.1768 (M + H)+, RT = 1.82 min.
100 and 101:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(3-(4-fluorophenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
1,2,4-oxadiazol-5-               100 bar, eluting 15% IPA with 0.5% NH4OH/CO2 (v/v) to
yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 100: First eluted product (40 mg). HRMS(B) m/z 415.1516
                                 (M + H)+. RT = 1.96 min.
                                 101: Second eluted product (13 mg). HRMS(B) m/z
                                 415.1518 (M + H)+. RT = 1.97 min.
102 and 103:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(2-fluorophenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
1,3,4-oxadiazol-2-               99 bar, eluting 35% IPA with 5 mM NH4OH/CO2 (v/v) to
yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one.                             hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(2-
                                 fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 102: First eluted product (44 mg). HRMS(B) m/z 415.1514
                                 (M + H)+. RT = 1.58 min.
                                 103: Second eluted product (51 mg). HRMS(B) m/z
                                 415.1510 (M + H)+. RT = 1.58 min.
104 and 105:                     Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
((1-(5-(m-tolyl)-1,3,4-oxadiazol- 99 bar, eluting 35% IPA with 5 mM NH4OH/CO2 (v/v) to
2-yl)ethyl)amino)pyrimidin-4-    give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(m-tolyl)-
yl)oxazolidin-2-one              1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
                                 2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(m-
                                 tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)oxazolidin-2-one.
                                 104: First eluted product (42 mg). HRMS(B) m/z 411.1762
                                 (M + H)+. RT = 1.78 min.
                                 105: Second eluted product (51 mg). HRMS(B) m/z
                                 411.1762 (M + H)+. RT = 1.82 min.
106 and 107:                     Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
((1-(5-(o-tolyl)-1,3,4-oxadiazol-2- 99 bar, eluting 35% IPA with 5 mM NH4OH/CO2 (v/v) to
yl)ethyl)amino)pyrimidin-4-      give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(o-tolyl)-
yl)oxazolidin-2-one              1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
                                 2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(o-
                                 tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)oxazolidin-2-one.
                                 106: First eluted product (44 mg). HRMS(B) m/z 411.1766
                                 (M + H)+. RT = 1.80 min.
                                 107: Second eluted product (42 mg). HRMS(B) m/z
                                 411.1764 (M + H)+. RT = 1.80 min.
108 and 109:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(4-(4-chlorophenyl)- chromatography ID, 5 UM, 20 × 250 MM column, 89 ml/min,
5-methylthiazol-2-               99 bar, eluting 22% MeOH/CO2 (v/v) to give (R)-3-(2-(((R)-
yl)ethyl)amino)pyrimidin-4-yl)-4- 1-(4-(4-chlorophenyl)-5-methylthiazol-2-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(4-(4-
                                 chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 108: First eluted product (44 mg). HRMS(B) m/z 411.1766
                                 (M + H)+. RT = 1.80 min.
                                 109: Second eluted product (34 mg). HRMS(B) m/z
                                 460.1198 (M + H)+. RT = 2.41 min.
110 and 111:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[5-(3-fluoro-phenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
[1,3,4]oxadiazol-2-yl]-          eluting 20% IPA with 5 mM NH4OH/CO2 (v/v) to give (R)-3-
ethylamino}-pyrimidin-4-yl)-4-   (2-{(R)-1-[5-(3-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-
((R)-1-hydroxy-ethyl)-oxazolidin- ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-
2-one.                           oxazolidin-2-one and (R)-3-(2-{(S)-1-[5-(3-fluoro-phenyl)-
                                 [1,3,4]oxadiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-
                                 hydroxy-ethyl)-oxazolidin-2-one.
                                 110: First eluted product (34.1 mg). HRMS(B) m/z
                                 415.1510 (M + H)+. RT = 1.70 min.
                                 111: Second eluted product (41.9 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.23 (s, 1H), 7.82 (dt, J = 7.7, 1.2 Hz, 1H), 7.72
                                 (ddd, J = 9.1, 2.6, 1.6 Hz, 1H), 7.64-7.42 (m, 2H), 7.35-
                                 7.17 (m, 1H), 6.21 (s, 1H), 5.57-5.35 (m, 1H), 4.93 (dt, J =
                                 6.7, 2.9 Hz, 1H), 4.61 (dd, J = 9.5, 2.4 Hz, 2H), 4.42 (dd, J =
                                 9.3, 8.3 Hz, 2H), 3.98 (s, 1H), 1.08 (d, J = 6.4 Hz, 3H),
                                 0.92-0.77 (m, 3H). HRMS(B) m/z 415.1515 (M + H)+,
                                 RT = 1.70 min.
112 and 113:                     Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-Hydroxy-ethyl)-3-{2- chromatography AD-H 20 × 250 mm, 20% MeOH in CO2,
[1-(5-pyridin-3-yl-              80 g/min, UV220 nm to give (R)-4-((R)-1-Hydroxy-ethyl)-3-
[1,3,4]oxadiazol-2-yl)-          {2-[(R)-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-ethylamino]-
ethylamino]-pyrimidin-4-yl}-     pyrimidin-4-yl}-oxazolidin-2-one and (R)-4-((R)-1-Hydroxy-
oxazolidin-2-one                 ethyl)-3-{2-[(S)-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-
                                 ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one.
                                 112: First eluted product (39.9 mg). HRMS(B) m/z
                                 398.1566 (M + H)+. RT = 1.18 min.
                                 113: Second eluted product (40.2 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 9.26 (s, 1H), 8.80 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H),
                                 8.23 (s, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.48 (dd, J = 8.2, 4.6
                                 Hz, 1H), 6.17 (s, 1H), 5.46 (s, 1H), 4.99-4.84 (m, 1H),
                                 4.60 (dd, J = 9.3, 2.3 Hz, 2H), 4.42 (dd, J = 9.3, 8.3 Hz,
                                 2H), 4.01 (s, 1H), 1.09 (d, J = 6.5 Hz, 3H), 0.91-0.81 (m,
                                 3H). HRMS(B) m/z 398.1660, (M + H)+. RT = 1.17 min.
114 and 115:                     Chiral separation was achieved by chiral SFC column
(R)-3-{2-[1-(5-Benzyl-           chromatography AD-H 21 × 250 mm, 25% MeOH in CO2,
[1,2,4]oxadiazol-3-yl)-          75 g/min, UV224 nm to give (R)-3-{2-[(R)-1-(5-Benzyl-
ethylamino]-pyrimidin-4-yl}-4-   [1,2,4]oxadiazol-3-yl)-ethylamino]-pyrimidin-4-yl}-4-((R)-1-
((R)-1-hydroxy-ethyl)-oxazolidin- hydroxy-ethyl)-oxazolidin-2-one and (R)-3-{2-[(S)-1-(5-
2-one                            Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-pyrimidin-4-yl}-4-
                                 ((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
                                 114: First eluted product (48.9 mg). HRMS(B) m/z
                                 411.1855 (M + H)+. RT = 1.85 min.
                                 115: Second eluted product (52.2 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.13 (d, J = 5.7 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H),
                                 7.31-7.13 (m, 5H), 6.09 (s, 1H), 5.21 (dq, J = 14.4, 7.1
                                 Hz, 1H), 4.90-4.69 (m, 1H), 4.42 (dd, J = 9.4, 2.5 Hz, 1H),
                                 4.33-4.20 (m, 1H), 4.12 (s, 2H), 3.99 (d, J = 24.4 Hz, 1H),
                                 1.54 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). HRMS(B)
                                 m/z 411.1864, (M + H)+. RT = 1.86 min.
116 and 117:                     Chiral separation was achieved by chiral SFC column
(R)-3-{2-[1-(5-Benzyl-           chromatography AD-H 21 × 250 mm, 25% MeOH in CO2,
[1,2,4]oxadiazol-3-yl)-          75 g/min, UV231 nm to give (R)-3-{2-[(R)-1-(5-Benzyl-
ethylamino]-5-fluoro-pyrimidin-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-
yl}-4-((R)-1-hydroxy-ethyl)-     ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-{2-[(S)-1-
oxazolidin-2-one                 (5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-
                                 pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
                                 116: First eluted product (29.4 mg). HRMS(B) m/z 429.1667
                                 (M + H)+. RT = 1.84 min.
                                 117: Second eluted product (52.2 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.14 (d, J = 2.8 Hz, 1H), 7.38-7.13 (m, 5H), 5.64
                                 (d, J = 8.3 Hz, 1H), 5.25-5.08 (m, 1H), 4.66 (s, 1H), 4.44
                                 (t, J = 9.0 Hz, 1H), 4.28 (dd, J = 9.1, 5.8 Hz, 1H), 4.12 (s,
                                 2H), 3.84 (s, 1H), 1.58-1.50 (m, 3H), 0.99 (d, J = 6.4 Hz,
                                 3H). HRMS(B) m/z 429.1671, (M + H)+. RT = 1.84 min.
118 and 119:                     Chiral separation was achieved by chiral SFC column
(R)-3-{2-[1-(5-Benzyl-           chromatography AD-H 21 × 250 mm, 25% IPA in CO2,
[1,2,4]oxadiazol-3-yl)-          75 g/min, UV240 nm to give (R)-3-{2-[(R)-1-(5-Benzyl-
ethylamino]-5-fluoro-pyrimidin-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-
yl}-4-((R)-1-hydroxy-ethyl)-     ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-{2-[(S)-1-
oxazolidin-2-one                 (5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-
                                 pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
                                 118: First eluted product (34.3 mg). HRMS(B) m/z
                                 477.0856 (M + H)+. RT = 2.31 min.
                                 119: Second eluted product (33.5 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H), 8.04-7.81 (m, 2H), 7.76-
                                 7.58 (m, 2H), 7.55 (d, J = 5.8 Hz, 1H), 5.38 (s, 1H), 4.84
                                 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.54 (dd, J = 9.4, 2.5 Hz,
                                 1H), 4.39 (dd, J = 9.4, 8.3 Hz, 1H), 3.92 (s, 1H), 1.78 (d, J =
                                 7.1 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H). HRMS(B) m/z
                                 477.0856 (M + H)+. RT = 2.32 min.
120 and 121:                     Chiral separation was achieved by chiral SFC column
(R)-3-{2-[1-(5-Benzyl-           chromatography OJ-H 21 × 250 mm, 15% MeOH in CO2,
[1,2,4]oxadiazol-3-yl)-          80 g/min, UV233 nm to give and (R)-3-{2-[(S)-1-(5-Benzyl-
ethylamino]-5-fluoro-pyrimidin-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-
yl}-4-((R)-1-hydroxy-ethyl)-     ((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
oxazolidin-2-one                 120: First eluted product (40.1 mg). HRMS(B) m/z
                                 429.1785 (M + H)+. RT = 2.23 min.
                                 121: Second eluted product (42.9 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H), 7.87-7.63 (m, 2H), 7.55
                                 (d, J = 5.8 Hz, 1H), 7.39-7.13 (m, 1H), 6.13 (s, 1H), 5.34
                                 (d, J = 20.8 Hz, 1H), 4.84 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H),
                                 4.54 (dd, J = 9.4, 2.5 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.86
                                 (d, J = 36.7 Hz, 1H), 2.34 (d, J = 1.9 Hz, 3H), 1.77 (d, J =
                                 7.1 Hz, 3H), 1.01 (d, J = 6.8 Hz, 4H). HRMS(B) m/z
                                 429.1783 (M + H)+. RT = 2.24 min.
122 and 123:                     Chiral separation was achieved by chiral SFC column
(R)-3-(5-Fluoro-2-{1-[3-(3-fluoro- chromatography OJ-H 21 × 250 mm, 15% MeOH in CO2,
4-methyl-phenyl)-                80 g/min, UV233 nm to give (R)-3-(5-Fluoro-2-{(R)-1-[3-(3-
[1,2,4]oxadiazol-5-yl]-          fluoro-4-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-
ethylamino}-pyrimidin-4-yl)-4-   pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and
((R)-1-hydroxy-ethyl)-oxazolidin- (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-
2-one                            5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-
                                 one.
                                 122: First eluted product (58.7 mg). HRMS(B) m/z 447.1573
                                 (M + H)+. RT = 2.22 min.
                                 123: Second eluted product (36.4 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.17 (d, J = 2.7 Hz, 1H), 7.63 (dddd, J = 17.6, 9.8,
                                 8.0, 1.7 Hz, 2H), 7.32-7.14 (m, 1H), 5.96-5.72 (m, 1H),
                                 5.22 (q, J = 6.9, 5.9 Hz, 1H), 4.69-4.57 (m, 1H), 4.45 (t, J =
                                 9.0 Hz, 1H), 4.35 (dd, J = 9.2, 5.6 Hz, 1H), 4.14-3.96
                                 (m, 1H), 2.25 (d, J = 1.9 Hz, 3H), 1.67 (dd, J = 11.7, 7.0 Hz,
                                 3H), 0.95 (t, J = 7.8 Hz, 3H). HRMS(B) m/z 447.1573 (M +
                                 H)+. RT = 2.22 min.
124 and 125:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[3-(3,4-Difluoro-    chromatography AD-H 21 × 250 mm, 25% IPA in CO2,
phenyl)-[1,2,4]oxadiazol-5-yl]-  75 g/min, UV226 nm to give (R)-3-(2-{(R)-1-[3-(3,4-Difluoro-
ethylamino}-pyrimidin-4-yl)-4-   phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-
((R)-1-hydroxy-ethyl)-oxazolidin- ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-1-
2-one                            [3-(3,4-Difluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-
                                 pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
                                 124: First eluted product (43.2 mg). HRMS(B) m/z
                                 443.1112 (M + H)+. RT = 2.09 min.
                                 125: Second eluted product (40.7 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.16 (d, J = 5.8 Hz, 1H), 7.93-7.67 (m, 2H), 7.47
                                 (d, J = 5.7 Hz, 1H), 7.30-7.10 (m, 1H), 6.07 (s, 1H), 5.30
                                 (s, 1H), 4.76 (ddd, J = 8.3, 4.6, 2.5 Hz, 1H), 4.45 (dd, J =
                                 9.4, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.4 Hz, 1H), 4.02-3.52
                                 (m, 1H), 1.69 (d, J = 7.1 Hz, 3H), 1.07-0.88 (m, 3H).
                                 HRMS(B)m/z 433.1109, (M + H)+. RT = 2.18 min.
126 and 127:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[3-(3,4-Dichloro-    chromatography IA. 21 × 250 mm, 30% (70%
phenyl)-isoxazol-5-yl]-          MeOH: 30% DCM) in CO2, 70 g/min, UV239 nm to give (R)-3-
ethylamino}-pyrimidin-4-yl)-4-   (2-{(R)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-
((R)-1-hydroxy-ethyl)-oxazolidin- ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-
2-one                            oxazolidin-2-one and (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-
                                 phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-
                                 hydroxy-ethyl)-oxazolidin-2-one.
                                 126: First eluted product (37.4 mg). HRMS(B) m/z
                                 464.0869 (M + H)+. RT = 2.63 min.
                                 127: Second eluted product (27.3 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.15 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.53 (dd, J =
                                 8.3, 2.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 6.37 (s, 1H),
                                 5.70 (s, 1H), 5.11 (s, 1H), 4.77 (ddd, J = 7.4, 4.6, 2.6 Hz,
                                 1H), 4.46 (dd, J = 9.4, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.4
                                 Hz, 1H), 1.61 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 7.5 Hz, 3H).
                                 HRMS(B) m/z 464.0855, (M + H)+. RT = 2.56 min.
128 and 129:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[3-(2,4-Dichloro-    chromatography OJ-H. 21 × 250 mm, 15% MeOH in CO2,
phenyl)-isoxazol-5-yl]-          75 g/min, UV231 nm to give (R)-3-(2-{(R)-1-[3-(2,4-Dichloro-
ethylamino}-pyrimidin-4-yl)-4-   phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-
((R)-1-hydroxy-ethyl)-oxazolidin- hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-1-[3-(2,4-
2-one                            Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-
                                 4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
                                 128: First eluted product (72.9 mg). HRMS(B) m/z
                                 464.0869 (M + H)+. RT = 2.54 min.
                                 129: Second eluted product (36.5 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.39-8.11 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56-
                                 7.47 (m, 2H), 7.42-7.28 (m, 1H), 6.60 (s, 1H), 5.80 (s,
                                 1H), 5.27 (d, J = 37.0 Hz, 1H), 4.72-4.45 (m, 3H), 4.31 (t,
                                 J = 8.7 Hz, 1H), 1.71 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.4
                                 Hz, 3H). HRMS(B) m/z 464.0876, (M + H)+. RT = 2.55 min.
130 and 131:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[3-(3,4-Difluoro-    chromatography ID 21 × 250 mm, 30% iIPA in CO2,
phenyl)-[1,2,4]oxadiazol-5-yl]-  75 g/min, UV233 nm to give and (R)-3-(2-{(S)-1-[3-(3,4-
ethylamino}-5-fluoro-pyrimidin-4- Difluorophenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-5-fluoro-
yl)-4-((R)-1-hydroxy-ethyl)-     pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
oxazolidin-2-one                 130: First eluted product (63.9 mg). HRMS(B) m/z
                                 451.1324 (M + H)+. RT = 2.20 min.
                                 131: Second eluted product (58.1 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.25 (d, J = 2.8 Hz, 1H), 7.97-7.72 (m, 2H), 7.27
                                 (dt, J = 9.9, 8.4 Hz, 1H), 6.09 (s, 1H), 5.47-5.16 (m, 1H),
                                 4.84-4.64 (m, 1H), 4.54 (t, J = 9.0 Hz, 1H), 4.43 (dd, J =
                                 9.1, 5.4 Hz, 1H), 3.87 (s, 1H), 1.76 (d, J = 7.1 Hz, 3H), 1.04
                                 (d, J = 6.5 Hz, 3H). HRMS(B) m/z 451.1324 (M + H)+.
                                 RT = 2.20 min.
132 and 133:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[3-(3,4-Dichloro-    chromatography IC. 21 × 250 mm, 40% MeOH in CO2,
phenyl)-isoxazol-5-yl]-          80 g/min, UV239 nm to give (R)-3-(2-{(R)-1-[3-(3,4-Dichloro-
ethylamino}-5-fluoro-pyrimidin-4- phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-
yl)-4-((R)-1-hydroxy-ethyl)-     4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-
oxazolidin-2-one                 1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-
                                 fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-
                                 one.
                                 132: First eluted product (107 mg). HRMS(B) m/z 482.0781
                                 (M + H)+. RT = 2.63 min.
                                 133: Second eluted product (61.1 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.22 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H),
                                 7.61 (dd, J = 8.3, 2.0 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.45
                                 (s, 1H), 5.72 (d, J = 7.6 Hz, 1H), 5.25 (t, J = 7.1 Hz, 1H),
                                 4.66-4.42 (m, 2H), 4.26 (t, J = 6.2 Hz, 1H), 1.68 (d, J =
                                 6.9 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H). HRMS(B) m/z
                                 482.0777 (M + H)+. RT = 2.63 min.
134 and 135:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[3-(2,4-Dichloro-    chromatography AD-H, 21 × 250 mm, 35% IPA in CO2,
phenyl)-isoxazol-5-yl]-          75 g/min, UV237 nm to give (R)-3-(2-{(R)-1-[3-(2,4-Dichloro-
ethylamino}-5-fluoro-pyrimidin-4- phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-
yl)-4-((R)-1-hydroxy-ethyl)-     4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-
oxazolidin-2-one                 1-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-
                                 fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-
                                 one.
                                 134: First eluted product (53.4 mg). HRMS(B) m/z
                                 482.0778 (M + H)+. RT = 2.54 min.
                                 135: Second eluted product (107 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.21 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H),
                                 7.50 (d, J = 2.0 Hz, 1H), 7.42-7.22 (m, 1H), 6.60 (s, 1H),
                                 5.88 (s, 1H), 5.24 (t, J = 6.7 Hz, 1H), 4.98-4.71 (m, 1H),
                                 4.63-4.40 (m, 2H), 3.83 (s, 1H), 1.70 (d, J = 7.1 Hz, 3H),
                                 1.05 (d, J = 6.4 Hz, 3H). HRMS(B) m/z 482.0774 (M + H)+.
                                 RT = 2.53 min.
136 and 137:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-{1-[4-(3-Chloro-4-fluoro- chromatography OD-H, 21 × 250 mm, 30% IPA in CO2,
phenyl)-thiazol-2-yl]-ethylamino}- 75 g/min, UV220 nm to give (R)-3-(2-{(R)-1-[4-(3-Chloro-4-
pyrimidin-4-yl)-4-((R)-1-hydroxy- fluoro-phenyl)-thiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-
ethyl)-oxazolidin-2-one          ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-1-
                                 [4-(3-Chloro-4-fluoro-phenyl)-thiazol-2-yl]-ethylamino}-
                                 pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
                                 136: First eluted product (76.9 mg). HRMS(B) m/z
                                 464.0930 (M + H)+. RT = 2.50 min.
                                 137: Second eluted product (88.6 mg). 1H NMR (400 MHz,
                                 CDCl3) δ 8.22 (d, J = 6.0 Hz, 1H), 7.95 (dd, J = 7.0, 2.2 Hz,
                                 1H), 7.72 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 7.50 (d, J = 5.7
                                 Hz, 1H), 7.34 (s, 1H), 7.18 (t, J = 8.6 Hz, 1H), 5.61-5.35
                                 (m, 1H), 4.75 (ddd, J = 8.1, 4.4, 2.4 Hz, 1H), 4.45 (dd, J =
                                 9.3, 2.7 Hz, 1H), 4.34 (t, J = 8.9 Hz, 1H), 3.87 (s, 1H), 1.73
                                 (d, J = 6.9 Hz, 3H), 0.90 (q, J = 6.9, 6.3 Hz, 3H). HRMS(B)
                                 m/z 464.0940 (M + H)+. RT = 2.49 min.
138 and 139:                     Chiral separation was achieved by chiral SFC column
(R)-3-(5-fluoro-2-((1-(5-(3-     chromatography (Column AD-H 20 × 250 mm 45% IPA 10 mM
(trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 238 nm UV collection) to
2-yl)ethyl)amino)pyrimidin-4-yl)- give (R)-3-(5-fluoro-2-(((S)-1-(5-(3-
4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
2-one                            4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(5-
                                 fluoro-2-(((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 138: First eluted product (6 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.84 (s, 2H), 8.15 (d, J = 2.8 Hz, 1H), 7.76-7.55 (m, 3H),
                                 6.17 (br s, 1H), 5.24 (t, J = 7.1 Hz, 1H), 4.56 (d, J = 7.4 Hz,
                                 1H), 4.47 (t, J = 8.8 Hz, 1H), 4.33 (dd, J = 9.0, 5.1 Hz, 1H),
                                 4.00 (br s, 1H), 1.59 (d, J = 6.9 Hz, 3H), 1.06 (br d, J = 5.7
                                 Hz, 3H). HRMS(B) m/z 493.1587 (M + H)+.
                                 139: Second eluted product (10 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.86 (s, 2H), 8.14 (d, J = 2.9 Hz, 1H), 7.77-7.55
                                 (m, 4H), 6.32 (br s, 1H), 5.18 (br s, 1H), 4.49-4.29 (m,
                                 3H), 3.96 (p, J = 6.1 Hz, 1H), 2.69 (br s, 1H), 1.58 (d, J =
                                 7.0 Hz, 3H), 1.15 (d, J = 5.9 Hz, 3H). HRMS(B) m/z
                                 493.1591 (M + H)+.
140 and 141:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column OD 20 × 250 mm 25% MeOH in
((1-(2-phenylthiazol-5-          CO2, flow 75 g/min, 238 nm UV collection) to give(R)-4-
yl)ethyl)amino)pyrimidin-4-      ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(2-phenylthiazol-5-
yl)oxazolidin-2-one              yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
                                 ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(2-phenylthiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 140: First eluted product (48 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 10.83 (s, 1H), 8.13-7.69 (m, 5H), 7.47 (d, J = 4.6
                                 Hz, 4H), 5.31-5.14 (m, 1H), 4.82 (d, J = 7.7 Hz, 1H), 4.66
                                 (dd, J = 9.6, 2.2 Hz, 1H), 4.46 (dd, J = 9.6, 8.0 Hz, 1H),
                                 3.38 (d, J = 9.6 Hz, 1H), 1.84 (d, J = 6.8 Hz, 3H), 1.55-
                                 1.09 (m, 1H), 1.03-0.71 (m, 4H). HRMS(B) m/z 411.1365.
                                 Chiral RT = 2.90 min
                                 141: Second eluted product (46 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 11.03 (s, 1H), 8.11-7.64 (m, 5H), 7.49 (d, J = 4.9
                                 Hz, 3H), 5.52-5.10 (m, 1H), 4.70 (dd, J = 23.0, 8.0 Hz,
                                 2H), 4.42 (t, J = 8.6 Hz, 2H), 1.86 (d, J = 6.8 Hz, 3H), 1.53-
                                 1.08 (m, 4H), 0.99-0.61 (m, 1H). HRMS(B) m/z
                                 411.1365. Chiral RT = 4.00 min
142 and 143:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(3-             chromatography (Column AD 20 × 250 mm 20% MeOH in
chlorophenyl)-1,2,4-oxadiazol-5- CO2, flow 90 g/min, 238 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-
                                 chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 142: First eluted product (15.5 mg): 1H NMR (400 MHz,
                                 CDCl3) δ 8.16 (d, J = 5.8 Hz, 4H), 7.79 (dd, J = 7.6, 1.8 Hz,
                                 4H), 7.56-7.26 (m, 15H), 5.83 (s, 4H), 5.17 (s, 4H), 4.57
                                 (q, J = 6.1 Hz, 4H), 4.39 (dd, J = 9.3, 2.5 Hz, 4H), 4.29-
                                 4.04 (m, 9H), 3.96 (p, J = 6.2 Hz, 1H), 2.96 (s, 4H), 1.88-
                                 1.56 (m, 5H), 1.49-1.01 (m, 28H), 0.93-0.59 (m, 4H).
                                 HRMS(B) m/z 430.1156. Chiral RT = 3.40 min
                                 143: Second eluted product (10 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.25 (d, J = 5.8 Hz, 3H), 7.91 (dd, J = 7.7, 1.8 Hz,
                                 3H), 7.62-7.52 (m, 6H), 7.43 (dtd, J = 25.2, 7.5, 1.6 Hz,
                                 6H), 6.30 (s, 3H), 5.40 (s, 3H), 4.87 (ddd, J = 8.3, 4.3, 2.3
                                 Hz, 3H), 4.55 (dd, J = 9.5, 2.5 Hz, 3H), 4.39 (t, J = 8.9 Hz,
                                 3H), 4.10-3.75 (m, 4H), 3.50 (s, 3H), 3.18-2.93 (m, 3H),
                                 1.72 (d, J = 6.8 Hz, 0H), 1.39-1.16 (m, 5H), 1.10-0.93
                                 (m, 9H), 0.93-0.76 (m,2H). HRMS(B) m/z 430.1156.
                                 Chiral RT = 4.80 min
144 and 145:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column ID 21 × 250 mm 25% MeOH in
((1-(3-(4-isopropylphenyl)-1,2,4- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
oxadiazol-5-                     ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(4-isopropylphenyl)-
yl)ethyl)amino)pyrimidin-4-      1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
yl)oxazolidin-2-one              2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-
                                 isopropylphenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 144: First eluted product (36 mg): (CDCl3) δ 8.24 (d, J =
                                 5.7 Hz, 1H), 8.06-7.88 (m, 2H), 7.50 (d, J = 5.8 Hz, 1H),
                                 7.41-7.32 (m, 2H), 6.05 (s, 1H), 5.22 (s, 1H), 4.71 (s, 1H),
                                 4.49 (dd, J = 9.3, 2.5 Hz, 1H), 4.43-4.14 (m, 2H), 4.12-
                                 3.99 (m, 0H), 3.51 (s, 1H), 3.37 (s, 1H), 2.98 (hept, J = 6.9
                                 Hz, 1H), 2.04-1.73 (m, 1H), 1.44-1.17 (m, 11H).
                                 HRMS(B) m/z 438.2016. Chiral RT = 3.20 min
                                 145: Second eluted product (36 mg): CDCl3) δ 8.25 (d, J =
                                 5.7 Hz, 1H), 8.05-7.91 (m, 2H), 7.54 (d, J = 5.7 Hz, 1H),
                                 7.42-7.31 (m, 2H), 6.23 (s, 1H), 5.33 (d, J = 10.8 Hz, 1H),
                                 4.85 (ddd, J = 8.5, 4.5, 2.3 Hz, 1H), 4.56 (dd, J = 9.4, 2.5
                                 Hz, 1H), 1.84-1.73 (m, 3H), 4.39 (t, J = 8.9 Hz, 1H), 3.86
                                 (s,1H), 3.51 (s, 1H), 3.15 (s,1H), 2.97 (hept, J = 7.0 Hz,
                                 1H), 1.94 (d, J = 7.1 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 0.99
                                 (d, J = 6.9 Hz, 3H). HRMS(B) m/z 438.2016. Chiral RT =
                                 4.60 min
146 and 147:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% MeOH in
((1-(3-(2-                       CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
(trifluoromethoxy)phenyl)-1,2,4- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(2-
oxadiazol-5-                     (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
yl)ethyl)amino)pyrimidin-4-      yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
yl)oxazolidin-2-one              ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(2-
                                 (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 146: First eluted product (8.3 mg): (CDCl3) δ 8.25 (d, J =
                                 5.9 Hz, 1H), 8.07 (dd, J = 7.8, 1.8 Hz, 1H), 7.69-7.39 (m,
                                 4H), 5.73 (s, 1H), 5.26 (s, 1H), 4.78-4.57 (m, 1H), 4.48
                                 (dd, J = 9.3, 2.3 Hz, 1H), 4.39-4.00 (m, 2H), 3.52 (s, 1H),
                                 2.93 (s, 1H), 1.80 (d, J = 7.1 Hz, 3H), 1.62 (s, 3H), 1.21 (dd,
                                 J = 18.6, 6.3 Hz, 5H). HRMS(B) m/z 480.1369. Chiral RT =
                                 2.10 min
                                 147: Second eluted product (38.5 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 8.10 (dd, J = 8.0, 1.7 Hz, 1H), 7.67-7.52
                                 (m, 2H), 7.51-7.40 (m, 2H), 5.88 (s, 1H), 5.39 (s, 1H),
                                 4.86 (ddd, J = 8.5, 4.6, 2.5 Hz, 1H), 1.75-1.64 (m, 1H),
                                 4.55 (dd, J = 9.4, 2.5 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 4.14-
                                 3.58 (m, 1H), 2.86 (s, 1H), 1.80 (d, J = 7.1 Hz, 3H), 1.23
                                 (d, J = 6.1 Hz, 1H), 1.00 (s, 3H). HRMS(B) m/z 480.1369.
                                 Chiral RT = 2.55 min
148 and 149:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-fluoro-3-    chromatography (Column AD-H 21 × 250 mm 15% MeOH in
methylphenyl)-1,2,4-oxadiazol-5- CO2, flow 80 g/min, 238 nm UV collection) to give(R)-3-(2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 148: First eluted product (13 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 8.03-7.80 (m, 2H), 7.52 (d, J = 5.7 Hz, 1H),
                                 7.13 (t, J = 8.9 Hz, 1H), 5.85 (s, 1H), 5.23 (s, 1H), 4.69 (d, J =
                                 8.4 Hz, 1H), 4.50 (dd, J = 9.5, 2.5 Hz, 1H), 4.41-4.04
                                 (m, 2H), 3.51 (s, 2H), 3.11 (s, 1H), 2.36 (d, J = 2.0 Hz, 3H),
                                 1.78 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 6.4 Hz, 4H). HRMS(B)
                                 m/z 428.1608 Chiral RT = 4.25 min
                                 149: Second eluted product (49 mg): (CDCl3) δ 8.25 (d, J =
                                 5.7 Hz, 1H), 8.01-7.80 (m, 2H), 7.56 (d, J = 5.7 Hz, 1H),
                                 7.12 (t, J = 8.9 Hz, 1H), 5.76 (s, 1H), 5.46-5.12 (m, 1H),
                                 4.85 (ddd, J = 8.4, 4.6, 2.4 Hz, 1H), 4.55 (dd, J = 9.5, 2.5
                                 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 2.89 (s, 1H), 2.35 (d, J =
                                 2.0 Hz, 3H), 1.79 (d,J = 7.1 Hz, 3H), 1.43-1.13 (m, 2H),
                                 1.16-0.74 (m, 3H). HRMS(B) m/z 428.1608 Chiral RT =
                                 6.15 min
150 and 151:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-ethylphenyl)- chromatography (Column ID 21 × 250 mm 40% MeOH +
1,2,4-oxadiazol-5-               10 mM NH4OH in CO2, flow 75 g/min, 238 nm UV
yl)ethyl)amino)-5-               collection) to give (R)-3-(2-(((R)-1-(3-(4-ethylphenyl)-1,2,4-
fluoropyrimidin-4-yl)-4-((R)-1-  oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-one    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-
                                 fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 150: First eluted product (106 mg): (CDCl3) δ 8.24 (d, J =
                                 2.9 Hz, 1H), 7.99-7.87 (m, 2H), 7.38-7.22 (m, 2H), 5.96
                                 (d, J = 7.1 Hz, 1H), 5.31 (d, J = 9.1 Hz, 1H), 4.56-4.25 (m,
                                 4H), 3.49 (s, 4H), 3.30 (d, J = 13.4 Hz, 1H), 2.72 (q, J = 7.6
                                 Hz, 2H), 1.68 (s, 0H), 1.66-1.38 (m, 2H), 1.35-1.08 (m,
                                 7H). HRMS(B) m/z 442.1765 Chiral RT = 2.80 min
                                 151: Second eluted product (10.6 mg): (CDCl3) δ 8.27 (d, J =
                                 2.7 Hz, 2H), 8.05-7.87 (m, 4H), 7.39-7.23 (m, 4H),
                                 5.77 (d, J = 6.7 Hz, 2H), 5.30-5.17 (m, 2H), 4.73 (dt, J =
                                 10.7, 5.1 Hz, 2H), 4.54 (t, J = 9.1 Hz, 2H), 1.85-1.73 (m,
                                 6H), 4.44 (dd, J = 9.2, 5.6 Hz, 2H), 3.86-3.59 (m, 2H),
                                 3.51 (s, 2H), 2.72 (q, J = 7.6 Hz, 6H), 1.37-1.19 (m, 8H),
                                 1.01 (d, J = 6.9 Hz, 8H), 0.92-0.69 (m, 1H). HRMS(B) m/z
                                 442.1765 Chiral RT = 4.05 min
152 and 153:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(5-(3,4-           chromatography (Column IC 4.6 × 100 mm 5-55% IPA + 20
dimethylphenyl)-1,3,4-oxadiazol- mM NH4OH/in CO2, flow 75 g/min, 238 nm UV collection)
2-yl)ethyl)amino)pyrimidin-4-yl)- to give(R)-3-(2-(((S)-1-(5-(3,4-dimethylphenyl)-1,3,4-
4-((R)-1-hydroxyethyl)oxazolidin- oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-
                                 dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-
                                 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 152: First eluted product (25 mg): (CDCl3) δ 8.22 (d, J =
                                 5.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.75 (dd, J = 8.0, 1.8 Hz,
                                 1H), 7.48 (d, J = 5.7 Hz, 1H), 7.34-7.20 (m, 1H), 5.90 (d, J =
                                 4.6 Hz, 1H), 5.18 (s, 1H), 4.93-4.74 (m, 1H), 1.85-1.71
                                 (m, 3H), 4.61 (dd, J = 9.3, 2.2 Hz, 1H), 4.50-4.38 (m, 1H),
                                 4.33 (t, J = 8.8 Hz, 1H), 4.21 (s, 1H), 4.11-4.00 (m, 0H),
                                 2.34 (s, 6H), 1.22 (dd, J = 10.3, 6.3 Hz, 5H). HRMS(B) m/z
                                 425.1982. Chiral RT = 1.75 min
                                 153: Second eluted product (25 mg): (CDCl3) δ 8.23 (d, J =
                                 5.7 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 7.8, 1.9
                                 Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H),
                                 5.67 (d, J = 6.0 Hz, 1H), 5.48-5.30 (m, 1H), 5.02-4.91
                                 (m, 1H), 4.62 (dd, J = 9.5, 2.3 Hz, 1H), 4.42 (dd, J = 9.4,
                                 8.3 Hz, 1H), 3.88 (s, 2H), 2.34 (s, 6H), 1.79 (d, J = 7.2 Hz,
                                 3H), 1.63 (s, 1H), 1.33-1.16 (m, 1H), 1.06 (d, J = 6.4 Hz,
                                 3H). HRMS(B) m/z 425.1981. Chiral RT = 2.15 min
154 and 155:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column OJ-H 21 × 250 mm 20% MeOH + 5
((1-(3-(isoquinolin-8-yl)-1,2,4- mM NH4OH/CO2/in CO2, flow 75 g/min, 238 nm UV
oxadiazol-5-                     collection) to give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-
yl)ethyl)amino)pyrimidin-4-      (isoquinolin-8-yl)-1,2,4-oxadiazol-5-
yl)oxazolidin-2-one              yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
                                 ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-
                                 oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 154: First eluted product (10 mg): (CDCl3) δ 8.47-8.11
                                 (m, 4H), 7.99 (d, J = 8.1 Hz, 2H), 7.83 (t, J = 7.9 Hz, 3H),
                                 7.57 (s, 4H), 5.94 (s, 2H), 5.47 (s, 2H), 4.95-4.65 (m, 2H),
                                 4.42 (d, J = 88.6 Hz, 6H), 3.52 (s, 5H), 2.09-1.51 (m, 1H),
                                 1.47-0.99 (m, 7H), 0.96-0.68 (m, 1H). HRMS(B) m/z
                                 447.1655. Chiral RT = 2.55 min
                                 155: Second eluted product (28.7 mg): (CDCl3) δ 10.26 (s,
                                 2H), 8.63 (s, 2H), 8.28 (d, J = 7.3 Hz, 4H), 7.97 (d, J = 8.2
                                 Hz, 2H), 7.77 (t, J = 7.8 Hz, 3H), 7.58 (d, J = 5.3 Hz, 2H),
                                 6.08 (s, 2H), 5.62 (p, J = 7.1 Hz, 2H), 5.11-4.84 (m, 2H),
                                 4.61 (dd, J = 8.8, 2.7 Hz, 2H), 4.41 (t, J = 8.9 Hz, 2H), 4.30
                                 (s, 2H), 3.89 (s, 2H), 3.63-3.43 (m, 8H), 1.73 (d, J = 33.4
                                 Hz, 0H), 1.32 (q, J = 5.2 Hz, 3H), 1.04 (d, J = 7.1 Hz, 6H).
                                 HRMS(B) m/z 447.1655. Chiral RT = 2.90 min
156 and 157:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-chloro-2-    chromatography (Column IC 4.6 × 100 mm 5-55% IPA + 20
(trifluoromethyl)phenyl)-1,2,4-  mM NH4OH in CO2, flow 75 g/min, 238 nm UV collection)
oxadiazol-5-                     to give(R)-3-(2-(((R)-1-(3-(4-chloro-2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 chloro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 156: First eluted product (50 mg): (CDCl3) δ 8.16 (d, J =
                                 5.9 Hz, 1H), 7.81-7.64 (m, 1H), 7.57 (dd, J = 8.3, 2.1 Hz,
                                 1H), 7.48 (d, J = 5.8 Hz, 1H), 6.50 (s, 1H), 5.35 (s, 1H),
                                 4.78 (ddd, J = 7.4, 4.6, 2.4 Hz, 1H), 4.45 (dd, J = 9.3, 2.5
                                 Hz, 1H), 4.31 (dd, J = 9.4, 8.3 Hz, 1H), 3.92 (d, J = 48.4 Hz,
                                 1H), 3.41 (s, 1H), 3.18-2.11 (m, 1H), 1.70 (d, J = 7.1 Hz,
                                 3H), 1.30-1.08 (m, 1H), 0.93 (d, J = 7.6 Hz, 3H).
                                 HRMS(B) m/z 498.1030. Chiral RT = 2.03 min
                                 157: Second eluted product (15 mg): (CDCl3) δ 8.15 (d, J =
                                 6.2 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.3 Hz,
                                 1H), 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H),
                                 5.96 (s, 1H), 5.17 (s, 1H), 4.73-4.47 (m, 1H), 4.40 (dd, J =
                                 9.2, 2.4 Hz, 1H), 4.21 (d, J = 37.9 Hz, 1H), 3.42 (s, 3H),
                                 1.60 (s, 3H), 1.33-0.99 (m, 1H), 0.92-0.64 (m, 1H).
                                 HRMS(B) m/z 498.1030. Chiral RT = 2.18 min
158 and 159:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(5-fluoro-2-((1-(3-(4-    chromatography (Column ID 21 × 250 mm 40% MeOH +
isopropylphenyl)-1,2,4-          10 mM NH4OH in CO2, flow 75 g/min, 238 nm UV
oxadiazol-5-                     collection) to give (R)-3-(5-fluoro-2-(((R)-1-(3-(4-
yl)ethyl)amino)pyrimidin-4-yl)-4- isopropylphenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(5-fluoro-2-(((S)-1-
                                 (3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 158: First eluted product (51 mg): (CDCl3) δ 8.17 (d, J =
                                 2.7 Hz, 1H), 7.92-7.83 (m, 2H), 7.30-7.21 (m, 2H), 5.83
                                 (d, J = 6.5 Hz, 1H), 5.21 (dd, J = 13.8, 6.9 Hz, 1H), 4.77-
                                 4.57 (m, 1H), 4.46 (t, J = 9.1 Hz, 1H), 4.36 (dd, J = 9.2, 5.6
                                 Hz, 1H), 3.96 (p, J = 6.1 Hz, 1H), 3.63 (s, 1H), 2.88 (hept, J =
                                 7.0 Hz, 1H), 1.76-1.60 (m, 3H), 1.19 (d, J = 7.0 Hz,
                                 7H), 1.14 (d, J = 6.1 Hz, 4H), 0.93 (d, J = 7.0 Hz, 3H).
                                 HRMS(B) m/z 456.1921 Chiral RT = 2.60 min
                                 159: Second eluted product (54 mg): (CDCl3) δ 8.24 (d, J =
                                 3.0 Hz, 1H), 8.02-7.89 (m, 2H), 7.39-7.30 (m, 2H), 5.98
                                 (d, J = 7.2 Hz, 1H), 5.31 (d, J = 8.6 Hz, 1H), 4.52-4.27 (m,
                                 4H), 1.83-1.67 (m, 3H), 3.49 (s, 1H), 2.97 (hept, J = 6.9
                                 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.21 (dd, J = 11.1, 6.2 Hz,
                                 5H). HRMS(B) m/z 456.1921. Chiral RT = 3.70 min
160 and 161:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% IPA in
((1-(3-(3-(trifluoromethyl)phenyl)- CO2, flow 75 g/min, 238 nm UV collection) to give(R)-4-
1,2,4-oxadiazol-5-               ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-
yl)ethyl)amino)pyrimidin-4-      (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)oxazolidin-2-one              yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
                                 ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-
                                 (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 160: First eluted product (15 mg): (CDCl3) δ 8.27 (d, J =
                                 2.0 Hz, 1H), 8.16 (t, J = 7.3 Hz, 2H), 7.71 (d, J = 7.9 Hz,
                                 1H), 7.56 (t, J = 7.8 Hz, 1H), 1.74-1.56 (m, 3H), 7.50-
                                 7.37 (m, 1H), 6.06 (s, 1H), 5.26 (d, J = 47.9 Hz, 1H), 4.59
                                 (d, J = 9.5 Hz, 1H), 4.52-4.23 (m,2H), 1.14 (dd, J = 6.3,
                                 4.8 Hz, 5H), 1.03-0.88 (m, 2H), 0.88-0.71 (m, 0H), 4.85-
                                 4.72 (m, 0H), 4.16 (s, 1H), 3.97 (p, J = 6.1 Hz, 0H), 2.88
                                 (s, 1H), 2.34-1.77 (m, 1H). HRMS(B) m/z 464.1420.
                                 Chiral RT = 2.10 min
                                 161: Second eluted product (38.5 mg): (CDCl3) δ 8.36 (d, J =
                                 1.8 Hz, 1H), 8.31-8.19 (m, 2H), 7.87-7.76 (m, 1H),
                                 7.64 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 5.7 Hz, 1H), 6.04 (s,
                                 1H), 5.42 (s, 1H), 4.87 (ddd, J = 8.4, 4.7, 2.5 Hz, 1H), 4.55
                                 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (dd, J = 9.5, 8.3 Hz, 1H),
                                 4.11-3.72 (m, 1H), 2.83 (s, 1H), 2.13-1.57 (m, 1H), 1.23
                                 (d, J = 6.1 Hz, 2H), 1.05 (d, J = 9.5 Hz, 3H). HRMS(B) m/z
                                 464.1420 Chiral RT = 2.55 min
162 and 163:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-fluoro-3-    chromatography (Column AD-H 21 × 250 mm 10% MeOH in
(trifluoromethoxy)phenyl)-1,2,4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
oxadiazol-5-                     (((R)-1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-
yl)ethyl)amino)pyrimidin-4-yl)-4- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
one                              fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 162: First eluted product (13 mg): CDCl3) δ 8.24 (d, J = 5.9
                                 Hz, 1H), 8.04 (ddt, J = 13.4, 6.5, 1.9 Hz, 2H), 7.55 (d, J =
                                 5.7 Hz, 1H), 7.35 (t, J = 9.0 Hz, 1H), 6.08 (s, 1H), 5.27 (s,
                                 1H), 4.78-4.58 (m, 1H), 4.52 (dd, J = 9.3, 2.5 Hz, 1H),
                                 4.44 (d, J = 15.7 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.51 (s,
                                 2H), 2.97 (s, 1H), 1.98-1.67 (m, 0H), 1.22 (d, J = 6.5 Hz,
                                 4H). HRMS(B) m/z 498.1275 Chiral RT = 3.60 min
                                 163: Second eluted product (40 mg): (CDCl3) δ 8.25 (d, J =
                                 6.2 Hz, 1H), 8.13-7.98 (m, 2H), 7.57 (d, J = 5.6 Hz, 1H),
                                 7.35 (dd, J = 9.4, 8.6 Hz, 1H), 5.77 (s, 1H), 5.40 (s, 1H),
                                 4.85 (ddd, J = 8.2, 4.7, 2.5 Hz, 1H), 4.54 (dd, J = 9.4, 2.5
                                 Hz, 1H), 4.41 (dd, J = 9.4, 8.3 Hz, 1H), 3.87 (t, J = 65.5 Hz,
                                 1H), 3.52 (s, 1H), 2.76 (s, 1H), 1.79 (d, J = 7.1 Hz, 3H),
                                 1.34-1.25 (m, 1H), 1.05 (s, 3H).). HRMS(B) m/z 498.1275
                                 Chiral RT = 4.80 min
164 and 165:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(3-             chromatography (Column AD-H 21 × 250 mm 35% IPA in
(difluoromethoxy)phenyl)-1,2,4-  CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
oxadiazol-5-                     (((R)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
yl)ethyl)amino)pyrimidin-4-yl)-4- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-
one                              (difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 164: First eluted product (18 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 7.92 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (t, J = 2.0
                                 Hz, 1H), 7.62-7.43 (m, 2H), 7.36-7.24 (m, 1H), 6.61 (t, J =
                                 73.3 Hz, 1H), 6.25 (d, J = 59.0 Hz, 1H), 5.36 (d, J = 30.2
                                 Hz, 1H), 4.86 (ddd, J = 8.5, 4.8, 2.5 Hz, 1H), 4.55 (dd, J =
                                 9.3, 2.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 1.83
                                 (s, 1H), 1.34-1.16 (m, 1H), 1.02 (s, 3H). HRMS(B) m/z
                                 462.1463 Chiral RT = 1.65 min
                                 165: Second eluted product (63 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 7.92 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (t, J = 2.0
                                 Hz, 1H), 7.62-7.43 (m, 2H), 7.36-7.24 (m, 1H), 6.61 (t, J =
                                 73.3 Hz, 1H), 6.25 (d, J = 59.0 Hz, 1H), 5.36 (d, J = 30.2
                                 Hz, 1H), 4.86 (ddd, J = 8.5, 4.8, 2.5 Hz, 1H), 4.55 (dd, J =
                                 9.3, 2.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 1.83
                                 (s, 1H), 1.34-1.16 (m, 1H), 1.02 (s, 3H). HRMS(B) m/z
                                 462.1463 Chiral RT = 2.10 min
166 and 167:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-chloro-3-    chromatography (Column AD-H 21 × 250 mm 30% MeOH in
methoxyphenyl)-1,2,4-oxadiazol-  CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
5-yl)ethyl)amino)pyrimidin-4-yl)- (((R)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-
4-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 166: First eluted product (10 mg): (CDCl3) δ 8.38-8.18
                                 (m, 1H), 7.61 (hept, J = 2.3, 1.9 Hz, 2H), 7.57-7.45 (m,
                                 2H), 5.89 (s, 1H), 5.33 (s, 2H), 4.70 (s, 1H), 4.50 (dd, J =
                                 9.4, 2.4 Hz, 1H), 4.00 (s, 2H), 3.07 (s, 1H), 1.75 (s, 2H),
                                 1.34-1.11 (m, 6H). HRMS(B) m/z 461.1464. RT = 2.24
                                 min. Chiral RT = 2.85 min
                                 167: Second eluted product (120 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 5.7 Hz,
                                 1H), 7.52-7.46 (m, 1H), 5.74 (s, 1H), 5.35 (d, J = 20.7 Hz,
                                 1H), 4.85 (ddd, J = 8.3, 4.7, 2.4 Hz, 1H), 4.54 (dd, J = 9.5,
                                 2.5 Hz, 1H), 4.40 (dd, J = 9.4, 8.3 Hz, 1H), 4.01 (s, 3H),
                                 3.52 (s, 3H), 2.85 (s, 1H), 1.88-1.76 (m, 2H), 1.67 (s, 1H),
                                 1.23 (d, J = 6.1 Hz, 1H), 1.03 (s, 3H). HRMS(B) m/z
                                 461.1464. RT = 2.23 min. Chiral RT = 3.55 min
168 and 169:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(2,2-           chromatography (Column AD-H 21 × 250 mm 35% IPA in
difluorobenzo[d][1,3]dioxol-5-yl)- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
1,2,4-oxadiazol-5-               (((R)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-
yl)ethyl)amino)pyrimidin-4-yl)-4- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(2,2-
one                              difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 168: First eluted product (14 mg): (CDCl3) δ 8.23 (d, J =
                                 6.2 Hz, 1H), 7.86 (dd, J = 8.2, 1.8 Hz, 1H), 7.78 (d, J = 1.7
                                 Hz, 1H), 7.55 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H),
                                 6.46 (s, 1H), 5.29 (d, J = 27.6 Hz, 1H), 4.90-4.58 (m, 1H),
                                 4.52 (dd, J = 9.4, 2.5 Hz, 1H), 4.46-4.17 (m, 2H), 3.51 (s,
                                 1H), 2.93 (s, 2H), 1.22 (dd, J = 8.8, 6.2 Hz, 4H). HRMS(B)
                                 m/z 476.1256. RT = 2.42 min. Chiral RT = 1.65 min
                                 169: Second eluted product (62 mg): (CDCl3) δ 8.15 (d, J =
                                 5.8 Hz, 1H), 7.79 (dd, J = 8.3, 1.7 Hz, 1H), 7.69 (d, J = 1.7
                                 Hz, 1H), 7.47 (d, J = 5.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H),
                                 6.38 (s, 1H), 5.26 (d, J = 24.5 Hz, 1H), 4.76 (ddd, J = 8.5,
                                 4.6, 2.4 Hz, 1H), 4.46 (dd, J = 9.3, 2.5 Hz, 1H), 4.32 (t, J =
                                 8.9 Hz, 1H), 4.06-3.60 (m, 1H), 3.42 (s, 2H), 1.86 (d, J =
                                 7.1 Hz, 3H), 1.14 (d, J = 6.1 Hz, 1H), 1.04-0.72 (m, 3H).
                                 HRMS(B) m/z 476.1256. RT = 2.43 min. Chiral RT = 1.95
                                 min
170 and 171:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-chloro-3-    chromatography (Column AD-H 21 × 250 mm 20% MeOH in
(trifluoromethyl)phenyl)-1,2,4-  CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
oxadiazol-5-                     (((R)-1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-
yl)ethyl)amino)pyrimidin-4-yl)-4- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
one                              chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 170: First eluted product (23 mg): (CDCl3) δ 8.42 (d, J =
                                 2.0 Hz, 1H), 8.25 (d, J = 5.9 Hz, 1H), 8.18 (dd, J = 8.4, 2.1
                                 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 5.7 Hz, 1H),
                                 5.81 (s, 1H), 5.33 (s, 2H), 4.66 (s, 1H), 4.52 (dd, J = 9.3,
                                 2.5 Hz, 1H), 4.46-4.14 (m, 2H), 2.84 (s, 1H), 1.79 (d, J =
                                 7.0 Hz, 3H), 1.23 (d, J = 6.5 Hz, 4H). HRMS(B) m/z
                                 498.1030. RT = 2.57 min. Chiral RT = 2.70 min
                                 171: Second eluted product (83 mg): (CDCl3) δ 8.42 (d, J =
                                 2.0 Hz, 1H), 8.31-8.12 (m, 2H), 7.62 (dd, J = 26.0, 7.1 Hz,
                                 2H), 1.92-1.70 (m, 3H), 6.31 (s, 1H), 5.32 (s, 2H), 4.86
                                 (ddd, J = 8.3, 4.8, 2.4 Hz, 1H), 4.54 (dd, J = 9.3, 2.5 Hz,
                                 1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H), 4.13-3.77 (m, 1H),
                                 2.71 (s, 2H), 1.44-0.84 (m, 4H). HRMS(B) m/z 498.1030.
                                 RT = 2.57 min. Chiral RT = 3.60 min
172 and 173:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-ethylphenyl)- chromatography (Column IA 21 × 250 mm 40% IPA + 10 mM
1,2,4-oxadiazol-5-               NH4OH in CO2, flow 75 g/min, 238 nm UV collection) to
yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 172: First eluted product (73 mg): (CDCl3) δ 8.24 (d, J =
                                 5.8 Hz, 1H), 8.05-7.87 (m, 2H), 7.50 (d, J = 5.8 Hz, 1H),
                                 7.41-7.30 (m, 2H), 5.98 (s, 1H), 1.57-1.47 (m, 0H), 5.22
                                 (s, 1H), 4.71 (s, 1H), 4.13-4.00 (m, 0H), 4.48 (dd, J = 9.5,
                                 2.4 Hz, 1H), 4.33 (s, 1H), 4.18 (s, 1H), 3.51 (d, J = 5.3 Hz,
                                 0H), 3.30 (s, 1H), 2.73 (q, J = 7.6 Hz, 2H), 1.78 (d, J = 7.1
                                 Hz, 3H), 1.39-1.08 (m, 7H). HRMS(B) m/z 424.1859. RT =
                                 2.39 min. Chiral RT = 2.15 min
                                 173: Second eluted product (17 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 2H), 8.04-7.89 (m, 4H), 7.54 (d, J = 5.8 Hz, 2H),
                                 7.39-7.29 (m, 4H), 5.97 (s, 2H), 5.53-5.22 (m, 2H), 4.85
                                 (ddd, J = 8.2, 4.4, 2.4 Hz, 2H), 4.55 (dd, J = 9.3, 2.5 Hz,
                                 2H), 4.39 (dd, J = 9.4, 8.3 Hz, 2H), 4.12-3.97 (m, 0H),
                                 3.76 (d, J = 62.5 Hz, 2H), 3.51 (s, 2H), 3.03 (s, 2H), 2.72 (q,
                                 J = 7.6 Hz, 4H), 1.98-1.71 (m, 1H), 1.45-1.13 (m, 10H),
                                 1.12-0.80 (m, 7H). HRMS(B) m/z 424.1859. RT = 2.40
                                 min. Chiral RT = 3.25 min
174 and 175:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% IPA in
((1-(3-(4-(trifluoromethyl)phenyl)- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
1,2,4-oxadiazol-5-               ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(4-
yl)ethyl)amino)pyrimidin-4-      (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)oxazolidin-2-one              yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
                                 ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-
                                 (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 174: First eluted product (55 mg): (CDCl3) δ 8.30-8.14
                                 (m, 3H), 7.76 (dd, J = 8.7, 2.5 Hz, 2H), 7.55 (dd, J = 12.4,
                                 5.8 Hz, 1H), 6.61 (s, 1H), 5.32 (s, 1H), 4.77-4.62 (m, 1H),
                                 4.62-4.46 (m, 1H), 4.40 (t, J = 8.8 Hz, 1H), 4.24 (t, J = 9.0
                                 Hz, 1H), 3.51 (s, 1H), 1.81 (s, 2H), 1.22 (dd, J = 9.6, 6.3
                                 Hz, 4H). HRMS(B) m/z 464.1420. RT = 2.43 min. Chiral RT =
                                 2.55 min
                                 175: Second eluted product (51 mg): (CDCl3) δ 8.22 (dd, J =
                                 21.0, 7.0 Hz, 3H), 7.75 (d, J = 8.1 Hz, 2H), 7.56 (d, J =
                                 5.8 Hz, 1H), 6.47 (s, 1H), 5.37 (d, J = 39.2 Hz, 1H), 4.86
                                 (ddd, J = 8.7, 4.7, 2.5 Hz, 1H), 4.55 (dd, J = 9.3, 2.5 Hz,
                                 1H), 4.40 (t, J = 8.9 Hz, 1H), 4.19-3.70 (m, 1H), 3.50 (s,
                                 1H), 2.01-1.70 (m, 0H), 1.23 (d, J = 6.1 Hz, 1H), 1.01 (s,
                                 3H). HRMS(B) m/z 464.1420. RT = 2.44 min. Chiral RT =
                                 3.25 min
176 and 177:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 15% IPA in
((1-(3-phenethyl-1,2,4-oxadiazol- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-4-
5-yl)ethyl)amino)pyrimidin-4-    ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-phenethyl-1,2,4-
yl)oxazolidin-2-one              oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-phenethyl-
                                 1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
                                 2-one
                                 176: First eluted product (17 mg): (CDCl3) δ 8.25 (d, J =
                                 6.2 Hz, 1H), 7.54 (d, J = 5.5 Hz, 1H), 7.36-7.07 (m, 5H),
                                 5.83 (s, 1H), 5.10 (s, 1H), 4.67 (d, J = 7.6 Hz, 1H), 4.57-
                                 4.41 (m, 1H), 4.10 (d,J = 38.8 Hz, 2H), 3.36-3.14 (m,
                                 1H), 3.07 (d, J = 2.1 Hz, 4H), 1.94-1.67 (m, 1H), 1.28 (d, J =
                                 3.8 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H). HRMS(B) m/z
                                 424.1859. RT = 2.24 min. Chiral RT = 4.50 min
                                 177: Second eluted product (19 mg): (CDCl3) δ 8.25 (d, J =
                                 5.9 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.38-7.08 (m, 5H),
                                 6.03 (s, 1H), 5.31 (d, J = 11.3 Hz, 1H), 4.84 (ddd, J = 8.3,
                                 4.5, 2.3 Hz, 1H), 4.56 (dd, J = 9.3, 2.5 Hz, 1H), 4.40 (dd, J =
                                 9.3, 8.3 Hz, 1H), 3.91-3.62 (m, 1H), 3.51 (s, 2H), 3.36-
                                 3.10 (m, 1H), 3.06 (s, 4H), 1.72 (d, J = 7.0 Hz, 3H), 1.59-
                                 1.35 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H).). HRMS(B) m/z
                                 424.1859. RT = 2.30 min. Chiral RT = 5.90 min
178 and 179:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(3-(4-chloro-3-    chromatography (Column AD-H 21 × 250 mm 20% IPA in
(trifluoromethoxy)phenyl)-1,2,4- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
oxadiazol-5-yl)ethyl)amino)-5-   (((R)-1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-
fluoropyrimidin-4-yl)-4-((R)-1-  oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-one    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 178: First eluted product (49 mg): (CDCl3) δ 8.26 (d, J = 2.8
                                 Hz, 1H), 8.05 (p, J = 1.4 Hz, 1H), 8.03-7.92 (m, 1H), 7.62
                                 (d, J = 8.4 Hz, 1H), 5.73 (d, J = 7.6 Hz, 1H), 5.44-5.25 (m,
                                 1H), 4.60-4.40 (m, 3H), 4.32 (p, J = 5.7, 5.3 Hz, 1H), 2.81-
                                 1.89 (m, 2H), 1.80 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H).).
                                 HRMS(B) m/z 533.1171. RT = 2.64 min. Chiral RT = 3.05
                                 min
                                 179: Second eluted product (81 mg): (CDCl3) δ 8.27 (d, J =
                                 2.7 Hz, 1H), 8.04 (p, J = 1.4 Hz, 1H), 7.97 (dd, J = 8.4, 1.9
                                 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 5.68 (t, J = 4.0 Hz, 1H),
                                 5.33 (s, 1H), 4.68 (dt, J = 10.9, 4.6 Hz, 1H), 4.56 (t, J = 9.0
                                 Hz, 1H), 4.44 (dd, J = 9.2, 5.3 Hz, 1H), 3.85 (s, 1H), 1.95
                                 (d, J = 7.0 Hz, 2H), 1.84-1.73 (m, 3H), 1.36-1.19 (m,
                                 1H), 1.08 (s, 3H). HRMS(B) m/z 533.1173. RT = 2.64 min.
                                 Chiral RT = 3.75 min
180 and 181:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% IPA in
((1-(3-(4-                       CO2, flow 80 g/min, 238 nm UV collection) to (R)-4-((R)-1-
(trifluoromethoxy)phenyl)-1,2,4- hydroxyethyl)-3-(2-(((R)-1-(3-(4-(trifluoromethoxy)phenyl)-
oxadiazol-5-                     1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
yl)ethyl)amino)pyrimidin-4-      2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-
yl)oxazolidin-2-one              (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 180: First eluted product (19 mg): (CDCl3) δ 8.24 (d, J =
                                 5.8 Hz, 1H), 8.16-8.06 (m, 2H), 7.53 (d, J = 5.8 Hz, 1H),
                                 7.34 (d, J = 8.3 Hz, 2H), 6.24 (s, 1H), 5.29 (d, J = 24.7 Hz,
                                 1H), 4.81-4.61 (m, 1H), 1.85-1.74 (m, 3H), 4.51 (dd, J =
                                 9.4, 2.4 Hz, 1H), 4.46-4.32 (m, 1H), 4.31-4.13 (m, 1H),
                                 3.51 (s, 1H), 3.25 (d, J = 66.2 Hz, 1H), 1.22 (dd, J = 8.9, 6.3
                                 Hz, 4H). HRMS(B) m/z 480.1369. RT = 2.50 min. Chiral
                                 RT = 2.20 min
                                 181: Second eluted product (44 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 8.17-8.05 (m, 2H), 7.55 (d, J = 5.7 Hz, 1H),
                                 7.33 (d, J = 8.3 Hz, 2H), 6.41 (s, 1H), 5.35 (d, J = 27.1 Hz,
                                 1H), 4.96-4.77 (m, 1H), 4.55 (dd, J = 9.3, 2.5 Hz, 1H),
                                 4.40 (t, J = 8.9 Hz, 1H), 4.16-3.55 (m, 1H), 3.03 (s, 1H),
                                 1.78 (d, J = 7.1 Hz, 3H), 1.23 (d, J = 6.1 Hz, 1H), 1.01 (s,
                                 3H). HRMS(B) m/z 480.1369. RT = 2.51 min. Chiral RT =
                                 2.45 min
182 and 183:                     Chiral separation was achieved by chiral SFC column
(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 30% IPA in
((1-(3-(3-(2,2,2-                CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
trifluoroethoxy)phenyl)-1,2,4-   ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-(2,2,2-
oxadiazol-5-                     trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-
yl)ethyl)amino)pyrimidin-4-      yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
yl)oxazolidin-2-one              ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-
                                 trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 182: First eluted product (13.8 mg): (CDCl3) δ 8.14 (d, J =
                                 5.9 Hz, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.60-7.52 (m, 1H),
                                 7.46 (dd, J = 14.2, 5.8 Hz, 1H), 7.37 (td, J = 8.0, 2.8 Hz,
                                 1H), 7.05 (dd, J = 8.2, 2.7 Hz, 1H), 4.71-4.51 (m, 1H),
                                 4.51-4.23 (m, 4H), 4.23-4.04 (m, 1H), 3.97 (hept, J = 6.1
                                 Hz, 1H), 1.64 (d, J = 1.5 Hz, 3H), 1.13 (dd, J = 10.4, 6.3 Hz,
                                 6H). HRMS(B) m/z 494.1526. RT = 2.38 min. Chiral RT =
                                 1.95 min
                                 183: Second eluted product (65 mg): (CDCl3) δ 8.25 (d, J =
                                 5.8 Hz, 1H), 7.77 (dt, J = 7.7, 1.2 Hz, 1H), 7.63 (dd, J = 2.7,
                                 1.4 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.45 (t, J = 8.0 Hz,
                                 1H), 7.14 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.06 (s, 1H), 5.35
                                 (d, J = 24.3 Hz, 1H), 4.85 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H),
                                 4.55 (dd, J = 9.3, 2.5 Hz, 1H), 4.51-4.34 (m, 4H), 4.05
                                 (hept, J = 6.1 Hz, 1H), 3.89 (s, 1H), 2.96 (s, 1H), 1.84-
                                 1.75 (m, 3H), 1.23 (d, J = 6.2 Hz, 6H), 1.02 (s, 3H).
                                 HRMS(B) m/z 494.1526. RT = 2.39 min. Chiral RT = 2.45
                                 min
184 and 185:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(5-(4-             chromatography (Column AD-H 21 × 250 mm 20% MeOH in
chlorophenyl)-4-methyloxazol-2-  CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-
                                 chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 184: First eluted product (48 mg): (CDCl3) δ 8.21 (d, J =
                                 5.7 Hz, 1H), 7.58-7.35 (m, 5H), 5.94 (s, 1H), 4.62 (dd, J =
                                 9.2, 2.5 Hz, 1H), 4.55-4.42 (m, 1H), 1.74-1.65 (m, 3H),
                                 4.32 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 2.38 (s, 3H), 2.27-
                                 1.93 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H). HRMS(B) m/z
                                 443.1360. RT = 2.51 min. Chiral RT = 2.90 min
                                 185: Second eluted product (31 mg): (CDCl3) δ 7.61-7.47
                                 (m, 3H), 7.45-7.35 (m, 2H), 5.84 (s, 1H), 5.31 (d, J = 10.0
                                 Hz, 1H), 4.94 (s, 1H), 4.58 (d, J = 9.8 Hz, 2H), 1.78-1.66
                                 (m, 3H), 4.44 (t, J = 8.8 Hz, 1H), 4.22 (s, 1H), 3.52 (s, 2H),
                                 2.38 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H). HRMS(B) m/z
                                 443.1360. RT = 2.52 min. Chiral RT = 4.00 min
186 and 187:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(5-(4-             chromatography (Column AD-H 21 × 250 mm 30% IPA in
chlorophenyl)-4-methyloxazol-2-  CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)-5-               (((R)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-
fluoropyrimidin-4-yl)-4-((R)-1-  yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-one    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-
                                 chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-
                                 fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 186: First eluted product (114 mg): (MeOD) δ 8.14 (dd, J =
                                 111.8, 3.1 Hz, 1H), 7.64-7.53 (m, 2H), 7.53-7.42 (m,
                                 2H), 5.35-5.18 (m, 1H), 5.18-5.05 (m, 1H), 4.80-4.70
                                 (m, 1H), 4.55-4.45 (m, 2H), 4.17 (td, J = 6.7, 3.9 Hz, 1H),
                                 4.07 (dt, J = 8.9, 5.4 Hz, 1H), 2.38 (d, J = 1.9 Hz, 3H), 1.67
                                 (dd, J = 7.1, 5.4 Hz, 3H), 1.14 (dd, J = 27.1, 6.3 Hz, 3H).
                                 HRMS(B) m/z 461.1266. RT = 2.29 min. Chiral RT = 3.60
                                 min
                                 187: Second eluted product (14 mg): (MeOD) δ 8.14 (dd, J =
                                 115.3, 3.2 Hz, 1H), 7.59 (ddt, J = 6.7, 4.3, 2.1 Hz, 2H),
                                 7.53-7.42 (m, 2H), 5.14 (dq, J = 30.9, 6.9 Hz, 1H), 4.71
                                 (dt, J = 9.6, 4.6 Hz, 1H), 4.39 (q, J = 7.4, 5.0 Hz, 1H), 3.98
                                 (ddt, J = 28.7, 12.3, 5.6 Hz, 2H), 2.37 (d, J = 2.3 Hz, 3H),
                                 1.67 (dd, J = 7.1, 4.0 Hz, 3H), 1.32 (d, J = 6.5 Hz, 2H), 1.17
                                 (d, J = 6.1 Hz, 2H), 1.08-0.76 (m, 2H). HRMS(B) m/z
                                 461.1266. RT = 2.37 min. Chiral RT = 6.05 min
188 and 189:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(4-(4-             chromatography (Column ID 21 × 250 mm 25% MeOH 10
chlorophenyl)-5-methylthiazol-2- mM NH4OH in CO2, flow 75 g/min, 230 nm UV collection)
yl)ethyl)amino)-5-               to give (R)-3-(2-(((R)-1-(4-(4-chlorophenyl)-5-methylthiazol-
fluoropyrimidin-4-yl)-4-((R)-1-  2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-one    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(4-(4-
                                 chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)-5-
                                 fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 188: First eluted product (61.8 mg): 1H NMR (400 MHz,
                                 CDCl3) δ 8.24 (d, J = 3.2 Hz, 1H), 7.64-7.53 (m, 2H), 7.49-
                                 7.38 (m, 2H), 5.75 (d, J = 6.1 Hz, 1H), 5.22 (s, 1H), 4.54-
                                 4.24 (m, 4H), 3.49 (s, 2H), 2.52 (s, 3H), 1.17 (d, J = 6.4 Hz,
                                 3H). HRMS(E) m/z 478.1114 (M + H). RT = 5.98 min. Chiral
                                 RT = 3.90 min.
                                 189: Second eluted product (82 mg): 1H NMR (400 MHz,
                                 CDCl3) δ 8.32-7.93 (m, 1H), 7.68-7.52 (m, 2H), 7.43
                                 (dd, J = 8.6, 2.5 Hz, 2H), 5.75 (d, J = 6.8 Hz, 1H), 5.35-
                                 5.21 (m, 1H), 4.58 (dt, J = 8.6, 5.3 Hz, 1H), 1.77-1.64 (m,
                                 3H), 4.53-4.43 (m, 1H), 4.38 (dd, J = 9.0, 5.0 Hz, 1H),
                                 3.96 (d, J = 11.1 Hz, 1H), 3.50 (s, 2H), 2.52 (d, J = 6.1 Hz,
                                 3H), 1.04 (d, J = 49.6 Hz, 3H). HRMS(B) m/z 477.1038. RT =
                                 2.48 min. Chiral RT = 5.80 min.
190 and 191:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(2-((1-(4-(4-             chromatography (Column ID 21 × 250 mm 30% MeOH 10
bromophenyl)thiazol-2-           mM NH4OH in CO2, flow 75 g/min, 230 nm UV collection)
yl)ethyl)amino)-5-               to give (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-
fluoropyrimidin-4-yl)-4-((R)-1-  yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-one    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(4-(4-
                                 bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-
                                 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
                                 190: First eluted product (63.7 mg): 1H NMR (400 MHz,
                                 CDCl3) δ 8.26 (d, J = 3.0 Hz, 1H), 7.86-7.71 (m, 2H), 7.62-
                                 7.50 (m, 2H), 7.41 (s, 1H), 5.80 (d, J = 6.7 Hz, 1H), 1.83-
                                 1.68 (m, 3H), 5.33 (t, J = 5.2 Hz, 1H), 4.38 (t, J = 13.2 Hz,
                                 4H), 3.51 (s, 1H), 1.20 (d, J = 6.2 Hz, 3H). HRMS(E) m/z
                                 510.0447 (M + H). RT = 5.95 min. Chiral RT = 3.30 min.
                                 191: Second eluted product (77.1): 1H NMR (400 MHz,
                                 CDCl3) δ 8.13 (dd, J = 109.6, 2.8 Hz, 1H), 7.78 (dd, J = 8.6,
                                 2.1 Hz, 2H), 7.57 (dd, J = 8.8, 2.3 Hz, 2H), 7.40 (s, 1H),
                                 5.78 (d, J = 6.5 Hz, 1H), 1.82-1.67 (m, 3H), 5.46-5.24
                                 (m, 1H), 4.64-4.26 (m, 2H), 4.05-3.74 (m, 1H), 3.51 (s,
                                 1H), 0.96 (s, 3H). HRMS(E) m/z 510.0445 (M + H). RT =
                                 5.91 min. Chiral RT = 5.40 min.
192 and 193:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(3,4-            chromatography (Column IC 21 × 250 mm, 45% MeOH in
dichlorophenyl)pyrimidin-2-      CO2, flow 75 g/min, 220 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)-5-               (((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-
fluoropyrimidin-4-yl)-4-((R)-1-  fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
hydroxyethyl)oxazolidin-2-one    and (R)-3-(2-(((R)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-
                                 yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 192: First eluted product (49 mg 1H NMR (400 MHz,
                                 CDCl3) δ 8.88 (s, 2H), 8.24 (d, J = 2.8 Hz, 1H), 7.76-7.51
                                 (m, 2H), 7.48-7.35 (m, 1H), 6.17 (d, J = 7.9 Hz, 1H), 5.30
                                 (tt, J = 12.5, 5.8 Hz, 1H), 4.69-4.47 (m, 2H), 4.41 (dd, J =
                                 8.9, 5.1 Hz, 1H), 4.09 (br s, 1H), 1.69-1.65 (m, 3H), 1.15
                                 (d, J = 6.2 Hz, 3H). HRMS(B) m/z 493.0948 (M + H)+.
                                 193: Second eluted product (40 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.89 (d, J = 1.6 Hz, 2H), 8.25 (d, J = 2.9 Hz, 1H),
                                 7.76-7.53 (m, 2H), 7.43 (ddd, J = 8.3, 3.9, 2.2 Hz, 1H),
                                 6.24 (d, J = 7.5 Hz, 1H), 5.26 (br s, 1H), 4.60-4.36 (m,
                                 4H), 1.64 (d, J = 4.8 Hz, 2H), 1.29-1.25 (m, 3H). HRMS(B)
                                 m/z 493.0949 (M + H)+.
194 and 195:                     Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column IA 21 × 250 mm, 35% IPA 10 mM
((1-(5-(3-methyl-4-              NH4OH in CO2, flow 75 g/min, 235 nm UV collection) to
(trifluoromethyl)phenyl)pyrimidin- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-methyl-4-
2-yl)ethyl)amino)pyrimidin-4-    (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
yl)oxazolidin-2-one              4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-
                                 (((R)-1-(5-(3-methyl-4-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
                                 194: First eluted product (15 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.95 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.77 (d, J =
                                 8.5 Hz, 1H), 7.54-7.42 (m, 4H), 6.07 (d, J = 8.2 Hz, 1H),
                                 5.45-5.36 (m, 1H), 4.89 (s, 1H), 4.52 (dd, J = 9.5, 2.6 Hz,
                                 1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H), 3.36 (br s, 1H), 2.60
                                 (dq, J = 3.7, 1.7 Hz, 3H), 1.71-1.60 (m, 3H), 1.11 (br s,
                                 3H). HRMS(D) m/z 489.1850 (M + H)+.
                                 195: Second eluted product (11 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.94 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.81-7.74
                                 (m, 1H), 7.49 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 5.7 Hz, 1H),
                                 6.02 (br s, 1H), 5.18 (br s, 1H), 4.80 (br s, 1H), 4.53 (d, J =
                                 8.8 Hz, 1H), 4.30 (br s, 2H), 3.71 (br s, 1H), 2.60 (q, J = 1.8
                                 Hz, 3H), 1.69-1.65 (m, 3H), 1.25-1.19 (m, 3H). HRMS(D)
                                 m/z 489.1862 (M + H)+.
196 and 197:                     Chiral separation was achieved by chiral SFC column
(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column IC 21 × 250 mm, 30% IPA 10 mM
((1-(4-methyl-5-(2-(1,1,1-       NH4OH in CO2, flow 75 g/min, 227 nm UV collection) to
trifluoro-2-methylpropan-2-      give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-
yl)pyridin-4-yl)thiazol-2-       (1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-
yl)ethyl)amino)pyrimidin-4-      yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
yl)oxazolidin-2-one              ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(4-methyl-5-(2-(1,1,1-
                                 trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
                                 198: First eluted product (50 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.65 (dd, J = 5.1, 0.8 Hz, 1H), 8.26 (d, J = 5.8 Hz,
                                 1H), 7.59-7.49 (m, 2H), 7.24 (dd, J = 5.2, 1.6 Hz, 1H),
                                 5.63 (d, J = 6.4 Hz, 1H), 5.38 (s, 1H), 4.80 (ddd, J = 8.3,
                                 4.5, 2.5 Hz, 1H), 4.51 (dd, J = 9.4, 2.5 Hz, 1H), 4.40 (dd, J =
                                 9.4, 8.3 Hz, 1H), 3.93 (br s, 1H), 2.79 (br s, 1H), 2.54 (s,
                                 3H), 1.73 (d, J = 7.0 Hz, 3H), 1.67 (s, 6H), 1.05 (d, J = 6.9
                                 Hz, 3H). HRMS(D) m/z 537.1898 (M + H)+.
                                 199: Second eluted product (50 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.65 (dd, J = 5.2, 0.8 Hz, 1H), 8.25 (d, J = 5.8 Hz,
                                 1H), 7.59-7.46 (m, 2H), 7.26 (dd, J = 5.1, 1.6 Hz, 1H),
                                 5.69 (s, 1H), 5.13 (br s, 1H), 4.82 (br s, 1H), 4.58 (d, J = 6.7
                                 Hz, 1H), 4.31 (t, J = 8.4 Hz, 2H), 4.15 (br s, 1H), 2.53 (s,
                                 3H), 1.76-1.65 (m, 9H), 1.25-1.18 (m, 3H). HRMS(D)
                                 m/z 537.1900(M + H)+.
198 and 199:                     Chiral separation was achieved by chiral SFC column
(4R)-3-(5-fluoro-2-((1-(4-methyl- chromatography (Column ID 21 × 250 mm, 25% IPA 10 mM
5-(2-(1,1,1-trifluoro-2-         NH4OH in CO2, flow 75 g/min, 230 nm UV collection) to
methylpropan-2-yl)pyridin-4-     give
yl)thiazol-2-                    (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-
yl)ethyl)amino)pyrimidin-4-yl)-4- methylpropan-2-yl)pyridin-4-yl)thiazol-2-
((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
one                              hydroxyethyl)oxazolidin-2-one and (4R)-3-(5-fluoro-2-(((R)-
                                 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-
                                 yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-
                                 ((R)-1-hydroxyethyl)oxazolidin-2-one.
                                 200: First eluted product (7 mg) 1H NMR (400 MHz, CDCl3)
                                 δ 8.55 (td, J = 5.4, 0.8 Hz, 1H), 8.17 (dd, J = 4.5, 2.8 Hz,
                                 1H), 7.46-7.40 (m, 1H), 7.16 (ddd, J = 8.1, 5.1, 1.6 Hz,
                                 1H), 5.56 (dd, J = 14.8, 6.8 Hz, 1H), 5.20-5.13 (m, 1H),
                                 4.49-4.37 (m, 2H), 4.30 (d, J = 6.8 Hz, 1H), 3.32 (d, J =
                                 3.7 Hz, 1H), 2.46 (s, 3H), 1.67-1.50 (m, 9H), 1.18-1.12
                                 (m, 3H). HRMS(D) m/z 555.1821 (M + H)+.
                                 201: Second eluted product (33 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.60-8.52 (m, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.42
                                 (dt, J = 1.7, 0.8 Hz, 1H), 7.21-7.12 (m, 1H), 5.56 (d, J =
                                 6.9 Hz, 1H), 5.24 (p, J = 7.0 Hz, 1H), 4.55 (dt, J = 8.6, 5.5
                                 Hz, 1H), 4.45 (t, J = 8.8 Hz, 1H), 4.31 (dd, J = 9.0, 5.2 Hz,
                                 1H), 3.95 (td, J = 13.7, 13.0, 6.9 Hz, 1H), 2.45 (s, 3H), 1.64
                                 (d, J = 6.9 Hz, 3H), 1.57 (s, 6H), 1.00 (d, J = 6.0 Hz,
                                 3H). HRMS(D) m/z 555.1839 (M + H)+.
200 and 201:                     Chiral separation was achieved by chiral SFC column
(R)-3-(2-((1-(5-(2-fluoro-3-     chromatography (Column IA 21 × 250 mm, 25% MeOH
(trifluoromethyl)phenyl)pyrimidin- 10 mM NH4OH in CO2, flow 75 g/min, 232 nm UV
2-yl)ethyl)amino)pyrimidin-4-yl)- collection) to give (R)-3-(2-(((S)-1-(5-(2-fluoro-3-
4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
2-one                            4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
                                 (((R)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 192: First eluted product (35 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.85-8.79 (m, 2H), 8.12 (dd, J = 6.1, 4.0 Hz,
                                 1H), 7.70-7.52 (m, 2H), 7.41-7.30 (m, 2H), 6.14 (s, 1H),
                                 5.36-5.27 (m, 1H), 4.85-4.76 (m, 1H), 4.43 (dd, J = 9.4,
                                 2.6 Hz, 1H), 4.38-4.24 (m, 1H), 4.13-3.93 (m, 1H), 3.15
                                 (br s, 1H), 1.60 (d, J = 7.0 Hz, 3H), 1.02 (br s,
                                 3H). HRMS(D) m/z 493.1605 (M + H)+.
                                 193: Second eluted product (36 mg) 1H NMR (400 MHz,
                                 CDCl3) δ 8.83 (d, J = 1.4 Hz, 2H), 8.12 (d, J = 5.8 Hz, 1H),
                                 7.71-7.53 (m, 2H), 7.42-7.31 (m, 2H), 6.19 (br s, 1H),
                                 5.08 (br s, 1H), 4.68 (br s, 1H), 4.46 (d, J = 8.3 Hz, 1H),
                                 4.21 (br s, 2H), 3.50 (br s, 1H), 1.60 (d, J = 7.0 Hz, 3H),
                                 1.19-1.12 (m, 3H). HRMS(D) m/z 493.1630 (M + H)+.

Examples 202 and 203

(4R)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (124 mg, 0.246 mmol) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the diastereomeric mixture. Chiral SFC chromatography on an ID column (75 g/min, 120 bar, 21×250 mm) eluting 45% IPA/CO₂ (v/v) to give (R)-3-(2-(((R)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.

202: Peak 1: 15 mg (pale orange foam): (CDCl₃) δ 8.22 (d, J=3.2 Hz, 1H), 7.63-7.50 (m, 2H), 7.45-7.38 (m, 2H), 7.28 (s, 1H), 5.65 (d, J=7.0 Hz, 1H), 5.16 (s, 1H), 4.80-4.25 (m, 3H), 3.51 (s, 1H), 1.71 (d, J=7.0 Hz, 3H), 1.38-1.15 (m, 4H). HRMS (B) m/z 447.1110. RT=2.20 min.

203: Peak 2: 87 mg (pale orange foam): (CDCl₃) δ 8.24 (d, J=2.9 Hz, 1H), 7.59-7.49 (m, 2H), 7.46-7.37 (m, 2H), 7.24-7.18 (m, 1H), 5.66 (d, J=8.1 Hz, 1H), 5.32 (dd, J=8.3, 6.6 Hz, 1H), 4.79 (s, 1H), 4.56 (t, J=8.9 Hz, 1H), 4.39 (dd, J=9.1, 5.7 Hz, 1H), 4.04 (td, J=11.0, 9.7, 4.8 Hz, 1H), 3.51 (s, 1H), 1.70 (s, 1H), 1.23 (d, J=6.2 Hz, 2H), 1.16 (d, J=6.4 Hz, 3H). HRMS (B) m/z 447.1110. RT=2.20 min.

Examples 204 and 205

(4R)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (3.50 g, 2.88 mmol) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the diastereomeric mixture. Chiral SFC chromatography on an OJ-H column (75 g/min, 120 bar, 21×250 mm) eluting 30% IPA+10 mM NH4OH/CO₂ (v/v) to give (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.

204: Peak 1: 1.40 g (white powder crystals): ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=5.8 Hz, 1H), 7.76-7.63 (m, 2H), 7.54 (d, J=5.7 Hz, 1H), 7.50-7.37 (m, 2H), 6.46 (s, 1H), 5.90-5.55 (m, 1H), 5.27-5.04 (m, 1H), 4.93-4.79 (m, 1H), 4.56 (dd, J=9.3, 2.5 Hz, 1H), 4.40 (dd, J=9.4, 8.4 Hz, 1H), 3.51 (s, 2H), 3.25 (d, J=68.4 Hz, 1H), 1.98-1.55 (m, 2H), 0.91 (s, 3H). HRMS (B) m/z 429.1204. RT=2.45 min.

205: Peak 2: 1.35 g (off-white foam): ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=6.0 Hz, 1H), 7.79-7.64 (m, 2H), 7.54 (d, J=5.8 Hz, 1H), 7.49-7.37 (m, 2H), 6.47 (s, 1H), 5.77 (s, 1H), 1.80-1.61 (m, 4H), 5.16 (s, 1H), 4.71-4.45 (m, 2H), 4.46-4.22 (m, 2H), 3.51 (s, 2H), 2.87 (s, 1H), 1.20 (d, J=6.5 Hz, 4H). HRMS (B) m/z 429.1204. RT=2.45 min.

Example 206

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (360 mg, 0.741 mg) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the desired product (120 mg, pale yellow foam). ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=6.0 Hz, 1H), 7.64-7.49 (m, 3H), 7.49-7.35 (m, 2H), 7.29 (s, 1H), 5.33 (dd, J=9.4, 5.1 Hz, 1H), 5.04-4.81 (m, 1H), 1.80-1.69 (m, 3H), 4.71-4.53 (m, 1H), 4.45 (dd, J=9.4, 8.1 Hz, 1H), 4.28-3.97 (m, 1H), 3.51 (s, 3H), 1.14 (d, J=6.4 Hz, 3H). HRMS (B) m/z 429.1204. RT=2.22 min.

Example 207

(R)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

Trifluoroacetic acid (2 mL) was added to a solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (25.0 mg, 0.039 mmol), in DCM (2 mL) and the solution was stirred at room temperature for 1 h. The reaction mixture was then concentrated and purification by reverse phase HPLC provided the trifluoroacetate salt of (R)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (10.0 mg, white solid) in 44% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 5.30 (br m, 1H), 4.80-4.77 (m, 1H), 4.55-4.52 (m, 1H), 4.41-4.36 (m, 1H), 3.77-3.62 (br m, 1H), 1.78 (d, J=7.1 Hz, 3H), 0.95 (br m, 3H); HRMS m/z 465.0847 (M+H)⁺; Rt-2.25 min.

The compounds in Table 30a were prepared using methods similar to those described for the preparation of Examples 35, 36, 37/38, or 207.

TABLE 30a
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333

TABLE 30b
Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 30a.
Example: Name	1H NMR (400 MHz, CDCl3) δ ppm	LCMS
208: (R)-3-(6-chloro-2-	7.59 (s, 1H), 7.52-7.48 (m, 1H),	HRMS
((S)-1-(2-fluoro-4-	7.44-7.42 (m, 1H), 7.37 (d, J = 9.7 Hz, 1H),	m/z
(trifluoromethyl)phenyl)ethylamino)pyrimidin-	5.31 (br m, 1H), 4.68-4.66 (m, 1H),	449.1009
4-yl)-4-	4.49-4.46 (m, 1H), 4.38-4.34 (m, 1H), 3.43 (br	(M + H)+;
((R)-1-	m, 1H), 1.59 (d, J = 7.0 Hz, 3H), 0.83 (br	Rt-2.39 min
hydroxyethyl)oxazolidin-2-	m, 3H)
one
209: (R)-3-(6-chloro-2-	7.77 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H),	HRMS
((S)-1-(2-fluoro-4-(1-	7.36-7.30 (m, 1H), 7.25-7.21 (m, 1H),	m/z
methyl-1H-pyrazol-4-	7.17 (dd, J = 11.4, 1.5 Hz, 1H), 5.26 (br m,	461.1505
yl)phenyl)ethylamino)pyrimidin-	1H), 4.70 (ddd, J = 8.1, 5.2, 2.5 Hz, 1H),	(M + H)+;
4-yl)-4-((R)-1-	4.45 (dd, J = 9.4, 2.5 Hz, 1H),	Rt-2.00
hydroxyethyl)oxazolidin-2-	4.39-4.31 (m, 1H), 3.98 (s, 3H), 3.67-3.55 (m, 1H),
one	1.57 (d, J = 6.9 Hz, 3H), 0.82 (br m, 3H)
210: (R)-3-(2-((S)-1-(3-(4-	8.00 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H),	HRMS
chlorophenyl)-1,2,4-	7.48 (d, J = 8.6 Hz, 2H), 6.45 (t, J = 56 Hz, 1H),	m/z
oxadiazol-5-	4.84 (m, 1H), 4.83 (dt, J = 5.3, 2.5 Hz, 1H),	481.1206
yl)ethylamino)-6-	4.57 (d, J = 9.0 Hz, 1H), 4.46-4.37 (m,	(M + H)+;
(difluoromethyl)pyrimidin-	1H), 3.69 (m, 1H), 1.83 (d, J = 7.0 Hz, 3H),	Rt-2.32
4-yl)-4-((R)-1-	0.96 (br m, 3H)
hydroxyethyl)oxazolidin-2-
one
211: (R)-3-(2-((S)-1-(3-(4-	8.00 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H),	HRMS
chlorophenyl)-1,2,4-	7.48 (d, J = 8.6 Hz, 2H), 5.31 (br. s., 1H),	m/z
oxadiazol-5-	4.90-4.80 (m, 1H), 4.57 (dd, J = 9.6, 1.8 Hz,	499.1106
yl)ethylamino)-6-	1H), 4.48-4.35 (m, 1H), 3.74 (br m, 1H),	(M + H)+;
(trifluoromethyl)pyrimidin-	1.81 (d, J = 7.1 Hz, 3H), 1.25-0.84 (br m,	Rt-2.50
4-yl)-4-((R)-1-	3H)
hydroxyethyl)oxazolidin-2-
one
212: (R)-3-(6-chloro-2-	7.90 (s, 1H), 7.80 (s, 1H), 7.59 (br s, 1H),	HRMS
(((S)-1-(2,5-difluoro-4-(1-	7.25-7.21 (m, 1H), 7.12 (dd, J = 11.0, 6.3 Hz,	m/z
methyl-1H-pyrazol-4-	1H), 5.25 (br m, 1H), 4.72 (m, 1H),	479.1415
yl)phenyl)ethyl)amino)pyrimidin-	4.49 (d, J = 9.4 Hz, 1H), 4.43-4.33 (m,	(M + H)+;
4-yl)-4-((R)-1-	1H), 4.02 (s, 3H), 3.72 (br m, 1H), 1.58 (d,	Rt-2.04
hydroxyethyl)oxazolidin-2-	J = 7.0 Hz, 3H), 0.88 (br s, 3H)
one
213: (R)-3-(6-chloro-2-	7.70 (d, J = 8.6 Hz, 2H), 7.60 (s, 1H),	HRMS
(((S)-1-(5-(4-	7.46 (d, J = 8.6 Hz, 2H), 6.54 (s, 1H), 5.23 (m,	m/z
chlorophenyl)isoxazol-3-	1H), 4.87 (m, 1H), 4.58 (d, J = 9.5 Hz, 1H),	464.0894
yl)ethyl)amino)pyrimidin-4-	4.47-4.39 (m, 1H), 3.89 (m, 1H), 1.67 (d,	(M + H)+;
yl)-4-((R)-1-	J = 7.1 Hz, 3H), 1.05 (d, J = 5.7 Hz, 3H)	Rt-2.38
hydroxyethyl)oxazolidin-2-
one
214: (R)-3-(6-chloro-2-	7.78-7.73 (m, 2H), 7.59 (s, 1H),	HRMS
(((S)-1-(5-phenylisoxazol-	7.50-7.44 (m, 3H), 6.54 (s, 1H), 5.23 (m, 1H),	m/z
3-yl)ethyl)amino)pyrimidin-	4.87 (m, 1H), 4.58 (d, J = 9.5 Hz, 1H),	430.1278
4-yl)-4-((R)-1-	4.42 (d, J = 9.3, 8.4 Hz, 1H), 3.89 (m, 1H),	(M + H)+;
hydroxyethyl)oxazolidin-2-	1.67 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 5.7 Hz, 3H)	Rt-2.19
one
215: (R)-3-(6-fluoro-2-	7.80 (s, 1H), 7.73 (s, 1H), 7.63-7.55 (m,	HRMS
(((S)-1-(1-(4-fluorophenyl)-	2H), 7.19-7.10 (m, 3H), 5.04 (m, 1H),	m/z
1H-pyrazol-4-	4.72 (m, 1H), 4.47 (m, 1H), 4.43-4.34 (m,	431.1644
yl)ethyl)amino)pyrimidin-4-	1H), 3.73 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H),	(M + H)+;
yl)-4-((R)-1-	0.97 (br m, 3H)	Rt-2.06
hydroxyethyl)oxazolidin-2-
one
216: (R)-3-(6-chloro-2-	7.95 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H),	HRMS
(((S)-1-(2-(4-	7.65 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 5.35 (m,	m/z
chlorophenyl)thiazol-5-	1H), 4.80 (m, 1H), 4.59 (d, J = 8.5 Hz, 1H),	480.0666
yl)ethyl)amino)pyrimidin-4-	4.40 (m, 1H), 3.72 (m, 1H), 1.74 (d, J = 6.9 Hz,	(M + H)+;
yl)-4-((R)-1-	3H), 0.97 (br s, 3H)	Rt-2.46
hydroxyethyl)oxazolidin-2-
one
217: (R)-3-(2-(((S)-1-(2-(4-	8.14 (d, J = 3.4 Hz, 1H), 7.93 (s, 1H),	HRMS
chlorophenyl)thiazol-5-	7.79 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz,	m/z
yl)ethyl)amino)-5-	2H), 5.33 (m, 1H), 4.71 (m, 1H), 4.58 (t, J = 9.0 Hz,	464.0964
fluoropyrimidin-4-yl)-4-	1H), 4.48 (dd, J = 9.3, 5.3 Hz,	(M + H)+;
((R)-1-	1H), 3.72 (m, 1H), 1.79 (d, J = 7.0 Hz, 3H),	Rt-2.08
hydroxyethyl)oxazolidin-2-	1.02 (d, J = 6.2 Hz, 3H)
one
218: (R)-3-(2-(((S)-1-(5-(4-	8.07 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 8.8 Hz,	HRMS
chlorophenyl)isoxazol-3-	2H), 7.46 (d, J = 8.8 Hz, 2H), 6.62 (s,	m/z
yl)ethyl)amino)-5-	1H), 5.31 (m, 1H), 4.95 (m, 1H), 4.62 (t, J = 9.0 Hz,	448.1186
fluoropyrimidin-4-yl)-4-	1H), 4.43 (dd, J = 9.3, 5.4 Hz,	(M + H)+;
((R)-1-	1H), 3.98-3.88 (m, 1H), 1.73 (d, J = 7.1 Hz,	Rt-2.03
hydroxyethyl)oxazolidin-2-	3H), 1.18 (d, J = 6.5 Hz, 3H)
one
219: (R)-3-(6-chloro-2-	7.85 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H),	HRMS
(((S)-1-(5-(4-	7.48 (d, J = 8.4 Hz, 2H), 5.44 (m, 1H), 4.86 (m,	m/z
chlorophenyl)-1,3,4-	1H), 4.59 (d, J = 9.5 Hz, 1H), 4.40 (t, J = 8.9 Hz,	481.0618
thiadiazol-2-	1H), 3.33 (m, 1H), 1.80 (d, J = 7.0 Hz,	(M + H)+;
yl)ethyl)amino)pyrimidin-4-	3H), 0.91 (br s, 3H)	Rt-2.25
yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-
one
220: (R)-3-(6-chloro-2-	7.86 (s, 1H), 7.79 (s, 1H), 7.60 (s, 1H),	HRMS
(((S)-1-(1-(4-	7.56 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 9.0 Hz,	m/z
chlorophenyl)-1H-pyrazol-	2H), 5.03 (m, 1H), 4.76 (m, 1H),	463.1055
4-yl)ethyl)amino)pyrimidin-	4.51 (m, 1H), 4.45-4.33 (m, 1H), 3.75 (m, 1H),	(M + H)+;
4-yl)-4-((R)-1-	1.63 (d, J = 6.9 Hz, 3H), 0.96 (br m, 3H)	Rt-2.31
hydroxyethyl)oxazolidin-2-
one
221: (R)-3-(2-(((S)-1-(1-(4-	8.24 (d, J = 2.7 Hz, 1H), 7.85 (s, 1H),	HRMS
chlorophenyl)-1H-pyrazol-	7.70 (s, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.9 Hz,	m/z
4-yl)ethyl)amino)-5-	2H), 5.34 (m, 1H), 5.04 (m, 1H),	447.1350
fluoropyrimidin-4-yl)-4-	4.57-4.48 (m, 2H), 4.43-4.34 (m, 1H),	(M + H)+;
((R)-1-	3.84 (m, 1H), 1.61 (d, J = 6.9 Hz, 3H),	Rt-1.98
hydroxyethyl)oxazolidin-2-	1.08 (d, J = 6.2 Hz, 3H)
one
222: (R)-3-(2-(((S)-1-(5-(4-	7.82 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H),	HRMS
chlorophenyl)isoxazol-3-	7.46 (d, J = 8.5 Hz, 2H), 6.65 (s, 1H), 5.46 (s,	m/z
yl)ethyl)amino)-6-	1H), 5.36-5.29 (m, 2H), 4.96 (m, 1H),	462.1347
(fluoromethyl)pyrimidin-4-	4.62 (d, J = 9.0 Hz, 1H), 4.53-4.45 (m,	(M + H)+;
yl)-4-((R)-1-	1H), 3.99 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H),	Rt-2.22
hydroxyethyl)oxazolidin-2-	1.13 (d, J = 6.6 Hz, 3H)
one
223: (R)-3-(2-(((S)-1-(2-(4-	7.88 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 8.6 Hz,	HRMS
chlorophenyl)thiazol-5-	2H), 7.46 (d, J = 8.6 Hz, 2H), 5.47 (s,	m/z
yl)ethyl)amino)-6-	1H), 5.38-5.30 (m, 2H), 4.86 (ddd, J = 8.1,	478.1116
(fluoromethyl)pyrimidin-4-	4.3, 2.2 Hz, 1H), 4.69-4.62 (m, 1H),	(M + H)+;
yl)-4-((R)-1-	4.45 (dd, J = 9.5, 8.2 Hz, 1H), 3.61 (m,	Rt-2.28
hydroxyethyl)oxazolidin-2-	1H), 1.80 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.4 Hz,
one	3H)
224: (R)-3-(2-(((S)-1-(2-(4-	7.99 (d, J = 7.1 Hz, 1H), 7.93 (s, 1H),	HRMS
chlorophenyl)thiazol-5-	7.85-7.78 (m, 3H), 7.47 (d, J = 8.7 Hz, 2H),	m/z
yl)ethyl)amino)pyrimidin-4-	5.43-5.34 (m, 1H), 4.89 (ddd, J = 8.1,	446.1065
yl)-4-((R)-1-	4.1, 2.2 Hz, 1H), 4.69 (dd, J = 9.4, 8.2 Hz,	(M + H)+;
hydroxyethyl)oxazolidin-2-	1H), 3.69 (dd, J = 6.3, 4.4 Hz, 1H), 1.83 (d,	Rt-1.90
one	J = 7.0 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H)
225: (R)-3-(2-(((S)-1-(1-(4-	10.64 (d, J = 5.9 Hz, 1H), 7.98 (s, 1H),	HRMS
chlorophenyl)-1H-pyrazol-	7.95 (d, J = 7.1 Hz, 1H), 7.78-7.74 (m,	m/z
4-yl)ethyl)amino)pyrimidin-	2H), 7.59 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 9.0 Hz,	429.1441
4-yl)-4-((R)-1-	2H), 5.06 (quin, J = 6.7 Hz, 1H),	(M + H)+;
hydroxyethyl)oxazolidin-2-	4.84 (ddd, J = 8.2, 4.4, 2.3 Hz, 1H),	Rt-1.62
one	4.62 (dd, J = 9.6 2.3 Hz, 1H), 4.45 (dd, J = 9.5,
	8.2 Hz, 1H), 3.80-3.69 (m, 1H), 1.70 (d, J = 7.0 Hz,
	3H), 0.96 (d, J = 6.5 Hz, 3H)
226: (R)-3-(6-chloro-2-	7.70 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H),	HRMS
(((S)-1-(3-(4-	7.45 (d, J = 8.6 Hz, 2H), 6.50 (s, 1H), 5.09 (m,	m/z
chlorophenyl)isoxazol-5-	1H), 4.87 (m, 1H), 4.59 (d, J = 9.1 Hz, 1H),	464.0898
yl)ethyl)amino)pyrimidin-4-	4.46-4.37 (m, 1H), 3.49 (m, 1H), 1.72 (d,	(M + H)+;
yl)-4-((R)-1-	J = 7.1 Hz, 3H), 0.89 (br s, 3H)	Rt-2.37
hydroxyethyl)oxazolidin-2-
one
227: (R)-3-(2-(((S)-1-(3-(4-	8.13 (d, J = 3.5 Hz, 1H), 7.69 (d, J = 8.5 Hz,	HRMS
chlorophenyl)isoxazol-5-	2H), 7.44 (d, J = 8.5 Hz, 2H), 6.52 (s,	m/z
yl)ethyl)amino)-5-	1H), 5.17 (m, 1H), 4.94 (m, 1H),	448.1190
fluoropyrimidin-4-yl)-4-	4.64-4.57 (m, 1H), 4.52 (dd, J = 9.4, 5.4 Hz,	(M + H)+;
((R)-1-	1H), 3.66 (m, 1H), 1.76 (d, J = 7.1 Hz, 3H),	Rt-2.07
hydroxyethyl)oxazolidin-2-	1.04 (d, J = 6.4 Hz, 3H)
one
228: (R)-3-(2-(((S)-1-(1-(4-	7.84 (br s, 1H), 7.76 (s, 1H), 7.57 (d, J = 8.9 Hz,	HRMS
chlorophenyl)-1H-pyrazol-	2H), 7.44 (d, J = 9.0 Hz, 2H),	m/z
4-yl)ethyl)amino)-6-	7.13 (s, 1H), 5.05 (m, 1H), 4.72 (m, 1H),	447.1347
fluoropyrimidin-4-yl)-4-	4.47 (m, 1H), 4.43-4.35 (m, 1H), 1.62 (d, J = 6.9 Hz,	(M + H)+;
((R)-1-	3H), 0.96 (br m, 3H)	Rt-2.23
hydroxyethyl)oxazolidin-2-
one
229: (R)-3-(6-chloro-2-	7.82-7.69 (m, 2H), 7.62 (s, 1H), 7.17 (t, J = 8.6 Hz,	HRMS
(((S)-1-(5-(4-	2H), 6.51 (s, 1H), 5.23 (d, J = 5.8 Hz,	m/z
fluorophenyl)isoxazol-3-	1H), 4.89 (m, 1H), 4.59 (m, 1H),	448.1192
yl)ethyl)amino)pyrimidin-4-	4.47-4.40 (m, 1H), 3.91 (m, 1H), 1.68 (d, J = 7.1 Hz,	(M + H)+;
yl)-4-((R)-1-	3H), 1.07 (d, J = 6.3 Hz, 3H)	Rt-2.23
hydroxyethyl)oxazolidin-2-
one
230: (R)-3-(6-chloro-2-	7.59 (s, 1H), 6.57 (s, 1H), 5.23 (m, 1H),	HRMS
(((S)-1-(5-	4.82 (m, 1H), 4.56 (m, 1H), 4.43-4.34 (m,	m/z
(morpholinomethyl)isoxazol-	2H), 4.20 (m, 1H), 3.97 (m, 4H), 3.24 (m,	453.1662
3-	4H), 1.61 (d, J = 7.2 Hz, 3H), 1.04 (br s,	(M + H)+;
yl)ethyl)amino)pyrimidin-4-	3H)	Rt-1.26
yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-
one
231: (R)-3-(6-chloro-2-	7.55 (s, 1H), 6.55 (s, 1H), 5.87 (m, 1H),	HRMS
(((R)-1-(5-	5.05 (m, 1H), 4.65 (m, 1H), 4.56 (m, 1H),	m/z
(morpholinomethyl)isoxazol-	4.34-4.31 (m, 2H), 4.20 (m, 1H),	453.1651
3-	3.97-3.95 (m, 4H), 3.18 (m, 4H), 1.62 (d, J = 7.0 Hz,	(M + H)+;
yl)ethyl)amino)pyrimidin-4-	3H), 1.18 (d, J = 6.5 Hz, 3H)	Rt-1.27
yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-
one
232: (R)-3-(2-(((S)-1-(1-(4-	10.78 (d, J = 5.8 Hz, 1H), 7.98 (s, 1H),	HRMS
chlorophenyl)-1H-pyrazol-	7.73 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H),	m/z
4-yl)ethyl)amino)-6-	7.56 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 5.00 (m,	443.1596
methylpyrimidin-4-yl)-4-	1H), 4.89-4.74 (m, 1H), 4.60 (dd, J = 9.6,	(M + H)+;
((R)-1-	2.2 Hz, 1H), 4.52-4.35 (m, 1H), 3.69 (dd,	Rt-1.62
hydroxyethyl)oxazolidin-2-	J = 6.5, 4.6 Hz, 1H), 2.52 (s, 3H), 1.69 (d,
one	J = 7.0 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H)
233: (R)-3-(6-chloro-2-	8.63 (m, 1H), 8.14 (s, 1H), 7.95-7.89 (m,	HRMS
(((S)-1-(2-(pyridin-2-	2H), 7.61 (s, 1H), 7.42 (m, 1H), 5.28 (m,	m/z
yl)thiazol-5-	1H), 4.52 (m, 1H), 4.47-4.35 (m, 3H),	447.1011
yl)ethyl)amino)pyrimidin-4-	1.77 (m, 3H), 0.96 (br s, 3H)	(M + H)+;
yl)-4-((R)-1-		Rt-1.99
hydroxyethyl)oxazolidin-2-
one
234: (R)-3-(6-chloro-2-	9.30 (m, 1H), 8.70 (m, 1H), 8.54 (m, 1H),	HRMS
(((S)-1-(2-(pyridin-3-	7.88 (s, 1H), 7.69 (m, 1H), 7.61 (s, 1H),	m/z
yl)thiazol-5-	5.30 (m, 1H), 4.52 (m, 1H), 4.42-4.36 (m,	447.1011
yl)ethyl)amino)pyrimidin-4-	3H), 1.76 (d, J = 6.9 Hz, 3H), 1.03 (br s,	(M + H)+;
yl)-4-((R)-1-	3H)	Rt-1.72
hydroxyethyl)oxazolidin-2-
one
235: (R)-3-(6-chloro-2-	8.83 (m, 2H), 8.12 (m, 2H), 7.98 (s, 1H),	HRMS
(((S)-1-(2-(pyridin-4-	7.63 (s, 1H), 5.40 (m, 1H), 4.73 (m, 1H),	m/z
yl)thiazol-5-	4.52 (m, 1H), 4.39 (m, 1H), 1.77 (m, 3H),	447.1006
yl)ethyl)amino)pyrimidin-4-	1.00 (br s, 3H)	(M + H)+;
yl)-4-((R)-1-		Rt-1.52
hydroxyethyl)oxazolidin-2-
one
236: (R)-3-(2-(((S)-1-(5-(4-	11.03 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 8.7 Hz,	HRMS
chlorophenyl)isoxazol-3-	2H), 7.56 (s, 1H), 7.46 (d, J = 8.7 Hz,	m/z
yl)ethyl)amino)-6-	2H), 6.70 (s, 1H), 5.32 (quin, J = 7.1 Hz,	444.1443
methylpyrimidin-4-yl)-4-	1H), 4.95 (ddd, J = 7.9, 4.4, 1.9 Hz, 1H),	(M + H)+;
((R)-1-	4.62 (dd, J = 9.5, 1.9 Hz, 1H),	Rt-1.81
hydroxyethyl)oxazolidin-2-	4.53-4.43 (m, 1H), 4.06-3.94 (m, 1H), 2.51 (s, 3H),
one	1.74 (d, J = 7.2 Hz, 3H), 1.13 (d, J = 6.6 Hz,
	3H)
237: (R)-3-(2-(((S)-1-(2-(4-	11.12 (d, J = 5.4 Hz, 1H), 7.88 (s, 1H),	HRMS
chlorophenyl)thiazol-5-	7.81 (d, J = 8.7 Hz, 2H), 7.62 (s, 1H),	m/z
yl)ethyl)amino)-6-	7.45 (d, J = 8.7 Hz, 2H), 5.37-5.27 (m, 1H),	460.1213
methylpyrimidin-4-yl)-4-	4.84 (ddd, J = 8.2, 4.2, 2.2 Hz, 1H),	(M + H)+;
((R)-1-	4.65 (dd, J = 9.6, 2.2 Hz, 1H), 4.44 (dd, J = 9.4,	Rt-1.88
hydroxyethyl)oxazolidin-2-	8.3 Hz, 1H), 3.61-3.52 (m, 1H), 2.52 (s,
one	3H), 1.81 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.5 Hz,
	3H)
238: (R)-3-(2-(((S)-1-(1-(4-	11.13 (d, J = 8.3 Hz, 1H), 8.43 (s, 1H),	HRMS
chlorophenyl)-1H-	7.91 (s, 1H), 7.67 (s, 1H), 7.60 (d, J = 8.8 Hz,	m/z
imidazol-4-yl)ethyl)amino)-	2H), 7.46 (d, J = 8.8 Hz, 2H),	443.1599
6-methylpyrimidin-4-yl)-4-	5.97 (quin, J = 7.0 Hz, 1H), 4.98 (ddd, J = 8.1,	(M + H)+;
((R)-1-	4.4, 2.4 Hz, 1H), 4.77 (dd, J = 9.6, 2.3 Hz,	Rt-1.35
hydroxyethyl)oxazolidin-2-	1H), 4.53-4.46 (m, 1H), 4.44-4.36 (m,
one	1H), 2.55 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H),
	1.06 (d, J = 6.6 Hz, 3H)
239: (R)-3-(2-(((S)-1-(3-(4-	11.42 (d, J = 5.0 Hz, 1H), 8.00 (d, J = 8.6 Hz,	HRMS
chlorophenyl)-1,2,4-	2H), 7.64 (s, 1H), 7.48 (d, J = 8.6 Hz,	m/z
oxadiazol-5-	2H), 5.30-5.20 (m, 1H), 4.77 (ddd, J = 7.9,	445.1393
yl)ethyl)amino)-6-	4.5, 2.0 Hz, 1H), 4.57 (dd, J = 9.5, 1.9 Hz,	(M + H)+;
methylpyrimidin-4-yl)-4-	1H), 4.40 (dd, J = 9.4, 8.2 Hz, 1H),	Rt-1.96
((R)-1-	3.65-3.55 (m, 1H), 2.56 (s, 3H), 1.90 (d, J = 7.2 Hz,
hydroxyethyl)oxazolidin-2-	3H), 0.92 (d, J = 6.5 Hz, 3H)
one
240: (R)-3-(2-(((S)-1-(1-(4-	10.80 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 2.5 Hz,	HRMS
chlorophenyl)-1H-pyrazol-	1H), 7.54-7.48 (m, 3H),	m/z
3-yl)ethyl)amino)-6-	7.46-7.41 (m, 2H), 6.58 (d, J = 2.5 Hz, 1H),	443.1601
methylpyrimidin-4-yl)-4-	5.40-5.30 (m, 1H), 4.85 (ddd, J = 7.7, 5.1, 2.3 Hz,	(M + H)+;
((R)-1-	1H), 4.50-4.38 (m, 2H),	Rt-1.66
hydroxyethyl)oxazolidin-2-	4.02-3.93 (m, 1H), 2.50 (s, 3H), 1.71 (d, J = 7.1 Hz,
one	3H), 0.94 (d, J = 6.5 Hz, 3H)
241: (R)-3-(2-(((S)-1-(1-(4-	11.00 (m, 1H), 8.15 (s, 1H), 7.69 (d, J = 8.5 Hz,	HRMS
chlorophenyl)-1H-1,2,3-	2H), 7.53 (s, 1H), 7.51 (d, J = 8.5 Hz,	m/z
triazol-4-yl)ethyl)amino)-6-	2H), 5.51 (m, 1H), 4.70 (m, 1H),	444.1548
methylpyrimidin-4-yl)-4-	4.58 (m, 1H), 4.51 (m, 1H), 3.96 (m, 1H),	(M + H)+;
((R)-1-	2.50 (s, 3H), 1.78 (d, J = 6.5 Hz, 3H), 1.17 (d, J = 6.5 Hz,	Rt-1.54
hydroxyethyl)oxazolidin-2-	3H)
one
242: (R)-3-(6-chloro-2-	7.97 (s, 1H), 7.69 (m, 2H), 7.60 (s, 1H),	HRMS
(((S)-1-(1-(4-	7.52 (d, J = 8.9 Hz, 2H), 5.41 (m, 1H),	m/z
chlorophenyl)-1H-1,2,3-	4.97 (m, 1H), 4.54 (m, 1H), 4.43 (m, 1H),	464.1003
triazol-4-	3.77 (m, 1H), 1.71 (d, J = 7.0 Hz, 3H), 1.05 (br	(M + H)+;
yl)ethyl)amino)pyrimidin-4-	s, 3H)	Rt-2.15
yl)-4-((R)-1-
hydroxyethyl)oxazolidin-2-
one
243: (R)-3-(2-(((S)-1-(1-(4-	10.91 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H),	HRMS
chlorophenyl)-1H-1,2,3-	7.89 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 7.0 Hz,	m/z
triazol-4-	1H), 7.70 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz,	430.1398
yl)ethyl)amino)pyrimidin-4-	2H), 5.53 (quin, J = 6.9 Hz, 1H),	(M + H)+;
yl)-4-((R)-1-	5.04 (m, 1H), 4.60-4.50 (m, 2H), 3.99 (m,	Rt-1.56
hydroxyethyl)oxazolidin-2-	1H), 1.79 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.5 Hz,
one	3H)
244: (R)-3-(2-(((S)-1-(4-	11.05 (d, J = 5.9 Hz, 1H), 7.56 (s, 1H),	HRMS
(1,1-difluoroethyl)-2-	7.52 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.7 Hz,	m/z
fluorophenyl)ethyl)amino)-	1H), 7.24 (s, 1H), 5.37 (quin, J = 6.7 Hz,	425.1803
6-methylpyrimidin-4-yl)-4-	1H), 4.75 (m, 1H), 4.56 (dd, J = 9.6, 2.3 Hz,	(M + H)+;
((R)-1-	1H), 4.40 (m, 1H), 3.47 (m, 1H),	Rt-1.68
hydroxyethyl)oxazolidin-2-	2.53 (s, 3H), 1.92 (t, J = 18.2, Hz, 3H), 1.66 (d,
one	J = 7.0 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H)
245: (R)-3-(2-(((S)-1-(2,5-	11.1 (d, J = 6.6 Hz, 1H), 7.58 (s, 1H),	HRMS
difluoro-4-(2,2,2-	7.25 (m, 1H), 6.83 (dd, J = 10.5, 6.6 Hz, 1H),	m/z
trifluoroethoxy)phenyl)ethyl)amino)-	5.33 (quin, J = 6.9 Hz, 1H), 4.83 (ddd, J = 8.1,	477.1574
6-	4.7, 2.3 Hz, 1H), 4.59 (dd, J = 9.6, 2.3 Hz,	(M + H)+;
methylpyrimidin-4-yl)-4-	1H), 4.48-4.37 (m, 3H), 3.83 (m, 1H),	Rt-1.78
((R)-1-	2.53 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H),
hydroxyethyl)oxazolidin-2-	0.96 (d, J = 6.5 Hz, 3H)
one
246: (R)-4-((R)-1-	11.16 (d, J = 6.9 Hz, 1H), 9.54 (d, J = 1.9 Hz,	HRMS
hydroxyethyl)-3-(6-methyl-	1H), 8.76 (dd, J = 8.3, 2.1 Hz, 1H),	m/z
2-(((S)-1-(2-(6-	8.00 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H),	441.1710
methylpyridin-3-yl)thiazol-	7.63 (s, 1H), 5.43 (quin, J = 6.9 Hz, 1H),	(M + H)+;
5-yl)ethyl)amino)pyrimidin-	5.06 (ddd, J = 7.9, 4.2, 1.8 Hz, 1H), 4.74 (dd, J = 9.6,	Rt-1.16
4-yl)oxazolidin-2-one	1.9 Hz, 1H), 4.14 (m, 1H), 2.86 (s,
	3H), 2.52 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H),
	1.13 (d, J = 6.4 Hz, 3H)
247: (R)-4-((R)-1-	11.05 (br s, 1H), 9.21 (s, 1H), 8.34 (d, J = 8.8 Hz,	HRMS
hydroxyethyl)-3-(2-(((S)-1-	1H), 7.97 (d, J = 7.0 Hz, 1H),	m/z
(2-(6-	7.92 (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 8.3 Hz,	481.1272
(trifluoromethyl)pyridin-3-	1H), 5.35 (m, 1H), 4.85 (m, 1H),	(M + H)+;
yl)thiazol-5-	4.64 (m, 1H), 4.46 (m, 1H), 3.58 (m, 1H),	Rt-1.77
yl)ethyl)amino)pyrimidin-4-	1.85 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.4 Hz,
yl)oxazolidin-2-one	3H)
248: (R)-4-((R)-1-	11.05 (br s, 1H), 8.84 (d, J = 5.1 Hz, 1H),	HRMS
hydroxyethyl)-3-(2-(((S)-1-	8.15 (s, 1H), 7.99 (d, J = 7.1 Hz, 1H),	m/z
(2-(2-	7.95 (s, 1H), 7.92 (dd, J = 5.1, 1.3 Hz, 1H),	481.1268
(trifluoromethyl)pyridin-4-	7.83 (d, J = 7.0 Hz, 1H), 5.36 (m, 1H), 4.85 (m,	(M + H)+;
yl)thiazol-5-	1H), 4.65 (dd, J = 9.7, 2.0 Hz, 1H),	Rt-1.72
yl)ethyl)amino)pyrimidin-4-	4.46 (m, 1H), 3.62 (m, 1H), 1.85 (d, J = 6.9 Hz,
yl)oxazolidin-2-one	3H), 0.97 (d, J = 6.5 Hz, 3H)
249: methyl 2-(((S)-1-(2-	8.27 (s, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.6 Hz,	HRMS
(4-chlorophenyl)thiazol-5-	2H), 7.47 (d, J = 8.6 Hz, 2H), 5.41 (m,	m/z
yl)ethyl)amino)-6-((R)-4-	1H), 4.66 (m, 1H), 4.45 (m, 1H), 4.01 (s,	504.1111
((R)-1-hydroxyethyl)-2-	3H), 3.75 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H),	(M + H)+;
oxooxazolidin-3-	0.98 (d, J = 6.1 Hz, 3H)	Rt-2.17
yl)pyrimidine-4-
carboxylate
250: (R)-3-(2-(((S)-1-(1-(4-	11.00 (d, J = 8.5 Hz, 1H), 7.95 (m, 1H),	LCMS m/z
chlorophenyl)-2-methyl-	7.87 (m, 1H), 7.61 (m, 2H), 7.43 (d, J = 1.8 Hz,	443.2 (M + H)+;
1H-imidazol-4-	1H), 7.35 (m, 2H), 5.95 (m, 1H),	Rt-
yl)ethyl)amino)pyrimidin-4-	5.02 (m, 1H), 4.80 (dd, J = 9.6, 2.4 Hz, 1H),	0.60
yl)-4-((R)-1-	4.50 (m, 1H), 4.40 (m, 1H), 2.60 (m, 3H),
hydroxyethyl)oxazolidin-2-	1.70 (m, 3H), 1.07 (m, 3H)
one
251: (R)-3-(2-(((S)-1-(2-(4-	10.92 (br s, 1H), 7.95 (m, 3H), 7.84 (s, 1H),	LCMS m/z
(difluoromethyl)phenyl)thiazol-	7.80 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 8.2 Hz,	462.2 (M + H)+;
5-	2H), 6.69 (t, J = 56 Hz, 1H), 5.27 (m,	Rt-
yl)ethyl)amino)pyrimidin-4-	1H), 4.81 (ddd, J = 8.2, 4.3, 2.1 Hz, 1H),	0.70
yl)-4-((R)-1-	4.64 (dd, J = 9.6, 2.1 Hz, 1H), 4.45 (m,
hydroxyethyl)oxazolidin-2-	1H), 3.39 (br m, 1H), 1.84 (d, J = 7.0 Hz,
one	3H), 0.89 (d, J = 6.5 Hz, 3H)
252: (R)-3-(2-((S)-1-(2-	(CD3OD) 0.77 (br. s., 3 H) 1.64 (d, J = 6.99 Hz,	HRMS (B)
fluoro-4-(trifluoromethyl)phenyl)ethylamino)	3 H) 4.40-4.47 (m, 1 H) 4.57 (dd,	m/z
pyrimidin-4-yl)-4-((R)-1-	J = 9.22, 2.52 Hz, 1 H) 5.43-5.51 (m, 1 H)	415.1402
hydroxyethyl)oxazolidin-2-	7.50 (d, J = 9.15 Hz, 2 H) 7.62 (t, J = 7.73 Hz,	(M + H)+;
one	1 H) 7.67 (d, J = 6.85 Hz, 1 H) 8.15 (d,	Rt-2.18 min
	J = 6.80 Hz, 1 H)
253: (R)-3-(2-((S)-1-(4-(1-	(CD3OD) 0.80 (br. s., 3 H) 0.95-1.00 (m, 2	HRMS (B)
ethoxycyclopropyl)-2-	H) 1.15 (t, J = 7.07 Hz, 3 H) 1.19-1.23 (m,	m/z
fluorophenyl)	2 H) 1.61 (d, J = 6.99 Hz, 3 H) 3.44 (qd,	431.2090
ethylamino)pyrimidin-4-yl)-	J = 7.05, 1.34 Hz, 2 H) 4.41-4.49 (m, 1 H)	(M + H)+;
4-((R)-1-hydroxyethyl)	4.59 (dd, J = 9.19, 2.49 Hz, 1 H) 5.40 (br. s.,	Rt-1.72 min
oxazolidin-2-one	1 H) 7.06 (d, J = 2.15 Hz, 1 H) 7.09 (s, 1 H)
	7.36 (t, J = 7.92 Hz, 1 H) 7.66 (d, J = 6.85 Hz,
	1 H) 8.12 (d, J = 7.14 Hz, 1 H)
254: 2-chloro-N-	(CD3OD) 0.86 (br. s., 3 H) 1.57 (d, J = 6.99 Hz,	HRMS (B)
cyclopentyl-4-((S)-1-(4-	3 H) 1.59-1.69 (m, 3 H) 1.74 (d,	m/z
((R)-4-((R)-1-	J = 4.99 Hz, 2 H) 1.95-2.06 (m, 2 H)	474.1908
hydroxyethyl)-2-	2.66 (s, 1 H) 4.29 (d, J = 6.46 Hz, 1 H)	(M + H)+;
oxooxazolidin-3-	4.38-4.46 (m, 1 H) 4.57 (dd, J = 9.24, 2.54 Hz, 1	Rt-1.58 min
yl)pyrimidin-2-	H) 5.13 (br. s., 1 H) 7.39 (s, 2 H) 7.47 (s, 1
ylamino)ethyl)benzamide	H) 7.61 (d, J = 6.21 Hz, 1 H) 8.13 (br. s., 1
	H) 8.40 (br. s., 1 H)
255: 1-(3-fluoro-4-((S)-1-	(CD3OD) 0.80 (br. s., 3 H) 1.47-1.51 (m, 2	HRMS (B)
(4-((R)-4-((R)-1-	H) 1.60 (d, J = 6.94 Hz, 3 H) 1.72-1.76 (m,	m/z
hydroxyethyl)-2-	2 H) 4.41-4.47 (m, 1 H) 4.58 (dd, J = 9.22,	412.1785
oxooxazolidin-3-	2.57 Hz, 1 H) 5.39 (br. s., 1 H) 7.12 (dd,	(M + H)+;
yl)pyrimidin-2-	J = 11.64, 1.91 Hz, 1 H) 7.18 (dd, J = 8.09,	Rt-1.51 min
ylamino)ethyl)phenyl)cyclopropanecarbonitrile	1.79 Hz, 1 H) 7.41 (t, J = 8.05 Hz, 1 H)
	7.64 (d, J = 6.65 Hz, 1 H) 8.13 (d, J = 6.80 Hz, 1
	H)
256: (R)-3-(2-((S)-1-(2-	(CD3OD) 0.82 (br. s., 3 H) 1.64 (d, J = 6.94 Hz,	HRMS (B)
fluoro-4-(1-methyl-1H-	3 H) 3.92 (s, 3 H) 4.07 (d, J = 16.09 Hz,	m/z
pyrazol-4-yl)phenyl)	1 H) 4.43-4.50 (m, 1 H) 4.60 (dd, J = 9.22,	427.1890
ethylamino)pyrimidin-4-yl)-	2.47 Hz, 1 H) 4.91 (ddd, J = 8.20, 3.97, 2.45 Hz,	(M + H)+;
4-((R)-1-hydroxyethyl)	2 H) 5.45 (br. s., 1 H) 7.31-7.44 (m, 3	Rt-1.37 min
oxazolidin-2-one	H) 7.73 (d, J = 7.09 Hz, 1 H) 7.82 (d, J = 0.68 Hz,
	1 H) 7.98 (s, 1 H) 8.13 (d, J = 7.04 Hz, 1
	H)
257: (R)-4-((R)-1-	(CD3OD) 0.80 (br. s., 3 H) 1.62 (d, J = 6.94 Hz,	HRMS (B)
hydroxyethyl)-3-(2-((S)-1-	3 H) 3.92 (s, 3 H) 3.99 (br. s., 1 H)	m/z
(4-(1-methyl-1H-pyrazol-4-	4.42-4.50 (m, 1 H) 4.60 (dd, J = 9.24, 2.45 Hz,	409.1982
yl)phenyl)ethylamino)	1 H) 5.21 (br. s., 1 H) 7.38 (d, J = 8.17 Hz,	(M + H)+;
pyrimidin-4-yl)oxazolidin-	2 H) 7.53-7.59 (m, 2 H) 7.73 (d,	Rt-1.27 min
2-one	J = 7.14 Hz, 1 H) 7.79 (d, J = 0.68 Hz, 1 H)
	7.93 (s, 1 H) 8.12 (d, J = 6.11 Hz, 1 H)
258: (R)-3-(2-((S)-1-(2-	(CD3OD) 0.83 (br. s., 3 H) 1.65 (d, J = 6.99 Hz,	HRMS (B)
fluoro-4-(1H-pyrazol-4-	3 H) 4.07 (br. s., 1 H) 4.43-4.52 (m, 1	m/z
yl)phenyl)ethylamino)	H) 4.61 (dd, J = 9.24, 2.45 Hz, 1 H)	413.1732
pyrimidin-4-yl)-4-((R)-1-	4.90-4.94 (m, 2 H) 5.45 (br. s., 1 H)	(M + H)+;
hydroxyethyl)oxazolidin-2-	7.36-7.42 (m, 3 H) 7.73 (d, J = 7.04 Hz, 1 H) 7.98 (s, 2	Rt-1.26 min
one	H) 8.13 (d, J = 6.90 Hz, 1 H)
259: (R)-3-(5-fluoro-2-((S)-	(CD3OD) 0.75 (br. s., 3 H) 1.54 (d, J = 7.04 Hz,	HRMS (B)
1-(2-fluoro-4-	3 H) 3.85 (br. s., 1 H) 4.42-4.55 (m, 2	m/z
(trifluoromethyl)phenyl)ethylamino)pyrimidin-	H) 5.27 (q, J = 6.99 Hz, 1 H)	433.1299
4-yl)-4-	7.42 (d, J = 8.90 Hz, 2 H) 7.58 (t, J = 7.92 Hz, 1 H)	(M + H)+;
((R)-1-hydroxyethyl)	8.21 (d, J = 2.74 Hz, 1 H)	Rt-2.03 min
oxazolidin-2-one
260: (R)-3-(2-((S)-1-(2-	(CD3OD) 0.73-0.87 (m, 7 H) 1.39 (s, 3 H)	HRMS (B)
fluoro-4-(1-	1.60 (d, J = 6.94 Hz, 3 H) 3.99 (br. s., 1 H)	m/z
methylcyclopropyl)phenyl)	4.40-4.49 (m, 1 H) 4.59 (dd, J = 9.19, 2.54 Hz,	401.1992
ethylamino)pyrimidin-4-yl)-	1 H) 5.39 (br. s., 1 H) 7.01 (dd,	(M + H)+;
4-((R)-1-hydroxyethyl)	J = 12.40, 1.74 Hz, 1 H) 7.05 (dd, J = 8.00,	Rt-1.87 min
oxazolidin-2-one	1.79 Hz, 1 H) 7.29 (t, J = 8.09 Hz, 1 H)
	7.69 (d, J = 6.99 Hz, 1 H) 8.12 (d, J = 6.94 Hz, 1
	H)
261: (R)-3-(2-((S)-1-(2-	(CD3OD) 8.12 (d, J = 6.7 Hz, 1 H), 7.69 (d,	HRMS (B)
fluoro-4-	J = 7.0 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H),	m/z
isopropylphenyl)ethylamino)pyrimidin-	6.98-7.09 (m, 2 H), 5.42 (d, J = 12.9 Hz, 1	389.1987
4-yl)-4-((R)-1-	H), 4.59 (dd, J = 9.2, 2.5 Hz, 1 H),	(M + H)+;
hydroxyethyloxazolidin-2-	4.40-4.49 (m, 1 H), 2.91 (spt, J = 6.8 Hz, 1 H),	Rt-1.83 min
one	1.61 (d, J = 6.7 Hz, 3 H), 1.23 (d, J = 7.0 Hz,
	6 H), 0.80 (br. s., 3 H)
262: (R)-3-(5-fluoro-2-((S)-	(CD3OD) 0.75 (br. s., 3 H) 1.53 (d, J = 6.94 Hz,	HRMS (B)
1-(2-fluoro-4-(1-methyl-	3 H) 3.91 (s, 3 H) 4.42-4.56 (m, 2 H)	m/z
1H-pyrazol-4-	4.65 (br. s., 1 H) 5.22 (m, J = 7.04 Hz, 1 H)	445.1800
yl)phenyl)ethylamino)pyrimidin-	7.22-7.31 (m, 2 H) 7.31-7.40 (m, 1 H)	(M + H)+;
4-yl)-4-((R)-1-	7.79 (s, 1 H) 7.94 (s, 1 H) 8.21 (br. s., 1 H)	Rt-1.64 min
hydroxyethyl)oxazolidin-2-
one
263: (R)-3-(5-fluoro-2-((S)-	(CD3OD) 0.52-0.78 (m, 5 H) 0.82 (br. s., 2	HRMS (B)
1-(2-fluoro-4-(1-	H) 1.36 (s, 3 H) 1.49 (d, J = 6.99 Hz, 3 H)	m/z
methylcyclopropyl)phenyl)	3.86 (br. s., 1 H) 4.42-4.56 (m, 2 H)	419.1895
ethylamino)pyrimidin-4-yl)-	4.62 (br. s., 1 H) 5.18 (m, J = 6.31 Hz, 1 H)	(M + H)+;
4-((R)-1-hydroxyethyl)	6.90-7.00 (m, 2 H) 7.24 (t, J = 8.17 Hz, 1 H)	Rt-2.21 min
oxazolidin-2-one	8.20 (d, J = 2.93 Hz, 1 H)
264: (R)-3-(5-fluoro-2-((S)-	(CD3OD) 0.76 (br. s., 3 H) 1.53 (d, J = 6.90 Hz,	HRMS (B)
1-(2-fluoro-4-(1H-pyrazol-	3 H) 3.91 (br. s., 1 H) 4.42-4.57 (m, 2	m/z
4-yl)phenyl)	H) 4.66 (br. s., 1 H) 5.23 (d, J = 6.41 Hz, 1	431.1640
ethylamino)pyrimidin-4-yl)-	H) 7.28-7.40 (m, 3 H) 7.97 (s, 2 H)	(M + H)+;
4-((R)-1-hydroxyethyl)	8.21 (br. s., 1 H)	Rt-1.55 min
oxazolidin-2-one
265: (R)-3-(5-fluoro-2-((S)-	(CD3OD) 0.71 (br. s., 3 H) 1.21 (d, J = 6.94 Hz,	HRMS (B)
1-(2-fluoro-4-	6 H) 1.50 (d, J = 6.99 Hz, 3 H) 2.87 (dt,	m/z
isopropylphenyl)ethylamino)pyrimidin-	J = 13.72, 6.83 Hz, 1 H) 3.89 (br.s., 1 H)	407.1890
4-yl)-4-((R)-1-	4.43-4.56 (m, 2 H) 4.63 (br. s., 1 H)	(M + H)+;
hydroxyethyl) oxazolidin-	5.20 (q, J = 6.52 Hz, 1 H) 6.90-7.00 (m, 2 H)	Rt-2.18 min
2-one	7.26 (t, J = 7.90 Hz, 1 H) 8.21 (d, J = 2.84 Hz,
	1 H)
266: (R)-3-(5-fluoro-2-((S)-	(CD3OD) 0.73 (br. s., 3 H) 1.47-1.52 (m, 9	HRMS (B)
1-(2-fluoro-4-(2-	H) 4.43-4.55 (m, 3 H) 4.59-4.67 (m, 1 H)	m/z
hydroxypropan-2-	5.15-5.27 (m, 1 H)	423.1838
yl)phenyl)ethylamino)pyrimidin-	7.15-7.23 (m, 2 H) 7.30 (t, J = 8.09 Hz, 1 H)	(M + H)+;
4-yl)-4-((R)-1-	8.20 (d, J = 3.08 Hz, 1 H)	Rt-1.59 min
hydroxyethyl)oxazolidin-2-
one
267: (R)-3-(2-(((S)-1-(2,5-	(CD3OD) 0.79 (br. s., 3 H) 1.52 (d, J = 6.99 Hz,	HRMS (B)
difluoro-4-(1-methyl-1H-	3 H) 3.92 (s, 3 H) 4.43-4.56 (m, 2 H)	m/z
pyrazol-4-	4.64 (d, J = 3.42 Hz, 1 H) 5.21 (q, J = 6.83 Hz,	463.1708
yl)phenyl)ethyl)amino)-5-	1 H) 7.14 (dd, J = 11.40, 6.31 Hz, 1 H)	(M + H)+;
fluoropyrimidin-4-yl)-4-	7.39 (dd, J = 10.93, 6.14 Hz, 1 H) 7.86 (d,	Rt-1.72 min
((R)-1-hydroxyethyl)	J = 0.59 Hz, 1 H) 8.00 (d, J = 1.86 Hz, 1 H)
oxazolidin-2-one	8.23 (d, J = 3.03 Hz, 1 H)
268: (R)-3-(2-(((S)-1-(2-(4-	(CD3CN) 0.98 (d, J = 6.65 Hz, 3 H) 1.72 (d,	HRMS (B)
chlorophenyl) thiazol-5-	J = 7.04 Hz, 3 H) 4.00 (br. s., 1 H)	m/z
yl)ethyl)amino) pyrimidin-	4.26-4.42 (m, 1 H) 4.51 (dd, J = 8.80, 2.93 Hz, 1	446.1060
4-yl)-4-((S)-1-	H) 4.62 (dd, J = 7.24, 1.37 Hz, 1 H)	(M + H)+;
hydroxyethyl)oxazolidin-2-	5.49 (quin, J = 6.85 Hz, 1 H) 7.49 (d, J = 8.61 Hz,	Rt-1.81 min
one	2 H) 7.66-7.78 (m, 2 H) 7.91 (d, J = 8.61 Hz,
	2 H) 8.05 (d, J = 7.04 Hz, 1 H)
	10.52 (br. s., 1 H)
269: (R)-3-(6-chloro-2-	(CDCl3) 0.80 (br. s., 3 H) 1.26 (s, 3 H)	HRMS (B)
(((S)-1-(2-fluoro-4-(2-	1.63-1.73 (m, 9 H) 4.28-4.36 (m, 1 H)	m/z
fluoropropan-2-	4.44 (dd, J = 9.39, 2.54 Hz, 1 H) 4.64 (br. s., 1 H)	441.1501
yl)phenyl)ethyl)amino)pyrimidin-	5.21 (br. s., 1 H) 7.07-7.18 (m, 2 H)	(M + H)+;
4-yl)-4-((R)-1-	7.28-7.33 (m, 1 H) 7.51 (s, 1 H)	Rt-2.35 min
hydroxyethyl)oxazolidin-2-
one
270: (R)-3-(5-chloro-2-	(CD3OD) δ	HRMS (B)
(((S)-1-(1-(4-	8.20 (s, 1 H), 8.03 (d, J = 1.2 Hz, 1 H),	m/z
chlorophenyl)-1H-	7.30-7.52 (m, 6 H), 5.06 (d, J = 6.7 Hz, 1 H),	399.1029
imidazol-4-	4.67 (dt, J = 8.6, 6.1 Hz, 1 H), 4.45 (t, J = 8.8 Hz,	(M + H)+
yl)ethyl)amino)pyrimidin-4-	1 H), 4.31 (dd, J = 9.0, 6.3 Hz, 1 H),	RT = 1.95 min.
yl)-4-((R)-1-	3.81 (br. s., 1 H), 1.49 (d, J = 6.7 Hz, 3 H),
hydroxyethyl)oxazolidin-2-	0.91 (br. s., 3 H)
one
271: (R)-3-(2-((S)-1-(2,5-	(CD3OD) 8.14 (br. s., 1 H), 7.64 (d, J = 6.7 Hz,	HRMS (B)
difluoro-4-	1 H), 7.07 (dd, J = 10.2, 6.3 Hz, 2 H),	m/z
isopropylphenyl)ethylamino)pyrimidin-	5.37 (d, J = 5.1 Hz, 1 H), 4.85 (s, 1H),	407.1895,
4-yl)-4-((R)-1-	4.57 (dd, J = 9.4, 2.3 Hz, 1 H), 4.38-4.49 (m, 1	(M + H)+,
hydroxyethyl)oxazolidin-2-	H), 3.96 (br. s., 1 H), 3.11-3.25 (m, 1 H),	RT = 1.95 min.
one	1.57 (d, J = 7.0 Hz, 3 H), 1.23 (dd, J = 7.0,
	2.0 Hz, 6 H), 0.80 (br. s., 3 H)
272: (R)-3-(2-(((S)-1-(4-	(CD3OD) 8.14 (d, J = 5.9 Hz, 1 H), 7.51 (d,	HRMS (B)
bromo-2,5-	J = 6.3 Hz, 1 H), 7.44 (dd, J = 9.4, 5.5 Hz, 1	m/z
difluorophenyl)ethyl)amino)pyrimidin-	H), 7.24 (dd, J = 9.0, 6.3 Hz, 1 H), 5.33 (q,	443.0527,
4-yl)-4-((R)-1-	J = 6.7 Hz, 1 H), 4.85 (s, 8 H), 4.54 (dd,	(M + H)+,
hydroxyethyl)oxazolidin-2-	J = 9.2, 2.5 Hz, 2 H), 4.34-4.47 (m, 1 H),	RT = 1.74 min.
one	1.54 (d, J = 6.7 Hz, 3 H), 0.83 (br. s., 3 H)
273: (R)-3-(2-((S)-1-(5-	(CD3OD) 8.55 (d, J = 1.2 Hz, 1 H), 8.16 (d,	HRMS (B)
chloro-6-(1,1-	J = 5.9 Hz, 1 H), 7.99 (s, 1 H), 7.64 (d,	m/z
difluoroethyl)pyridin-3-	J = 5.9 Hz, 1 H), 5.27 (br. s., 1 H), 4.85 (s, 2	428.1299,
yl)ethylamino)pyrimidin-4-	H), 4.56 (dd, J = 9.0, 2.3 Hz, 1 H),	(M + H)+,
yl)-4-((R)-1-	4.39-4.47 (m, 1 H), 2.04 (t, J = 19.0 Hz, 3 H),	RT = 1.65 min.
hydroxyethyl)oxazolidin-2-	1.63 (d, J = 7.0 Hz, 3 H), 0.82 (br. s., 3 H)
one
274: (R)-3-(2-((S)-1-(5-	(CD3OD) 8.15 (d, J = 2.0 Hz, 2 H), 7.92 (d,	HRMS (B)
chloro-6-(2,2,2-	J = 2.3 Hz, 1 H), 7.71 (d, J = 7.0 Hz, 1 H),	m/z
trifluoroethoxy)pyridin-3-	5.25 (br. s., 1 H), 4.89-4.99 (m, 3H),	462.1149,
yl)ethylamino)pyrimidin-4-	4.59 (dd, J = 9.4, 2.3 Hz, 1 H), 4.41-4.50 (m, 1	(M + H)+,
yl)-4-((R)-1-	H), 4.00 (br. s., 1 H), 1.62 (d, J = 7.0 Hz, 6	RT = 1.87 min.
hydroxyethyl)oxazolidin-2-	H)
one
275: (R)-3-(2-((S)-1-(4-	(CD3OD) 8.16 (br. s., 1 H), 7.71 (d, J = 6.7 Hz,	HRMS (B)
bromo-2,3-	1 H), 7.36-7.48 (m, 1 H),	m/z
difluorophenyl)ethylamino)	7.09-7.22 (m, 1 H), 5.42 (br. s., 1 H), 4.87 (s, 1 H),	443.0532,
pyrimidin-4-yl)-4-((R)-1-	4.57 (dd, J = 9.0, 2.3 Hz, 1 H),	(M + H)+,
hydroxyethyl)oxazolidin-2-	4.39-4.50 (m, 1 H), 3.82 (br. s., 1 H), 1.62 (d, J = 7.0 Hz,	RT = 1.81 min.
one	6 H)
276: (R)-3-(2-(((S)-1-(4-	(CD3OD) 8.22 (d, J = 2.3 Hz, 1 H), 7.41 (dd,	HRMS (B)
bromo-2,5-	J = 9.0, 5.5 Hz, 1 H), 7.21 (dd, J = 9.2, 6.5 Hz,	m/z
difluorophenyl)ethyl)amino)-	1 H), 5.13-5.23 (m, 1 H),	461.0432,
5-fluoropyrimidin-4-yl)-4-	4.86 (s, 1 H), 4.38-4.55 (m, 2 H),	(M + H)+,
((R)-1-	3.99-4.16 (m, 1 H), 1.49 (d, J = 7.0 Hz, 6 H)	RT = 2.01 min.
hydroxyethyl)oxazolidin-2-
one
277: (R)-3-(2-(((S)-1-(4-	(CD3OD) 8.20 (d, J = 2.3 Hz, 1 H),	HRMS (B)
bromo-2-	7.18-7.38 (m, 3 H), 5.18 (q, J = 7.0 Hz, 1 H),	m/z
fluorophenyl)ethyl)amino)-	4.61 (t, J = 9.0 Hz, 1 H), 4.42-4.55 (m, 2 H),	443.0534,
5-fluoropyrimidin-4-yl)-4-	3.89 (br. s., 1 H), 1.49 (d, J = 7.0 Hz, 6 H)	(M + H)+,
((R)-1-		RT = 1.99 min.
hydroxyethyl)oxazolidin-2-
one
278: (R)-3-(2-(((S)-1-(4-	(CD3OD) 8.21 (d, J = 2.7 Hz, 1 H), 7.36 (t,	HRMS (B)
chloro-2-	J = 8.4 Hz, 1 H), 7.05-7.21 (m, 2 H),	m/z
fluorophenyl)ethyl)amino)-	5.20 (q, J = 7.0 Hz, 1 H), 4.62 (d, J = 8.6 Hz, 1 H),	399.1029,
5-fluoropyrimidin-4-yl)-4-	4.42-4.56 (m, 2 H), 3.90 (br. s., 1 H),	(M + H)+,
((R)-1-	1.50 (d, J = 7.0 Hz, 6 H)	RT = 1.95 min.
hydroxyethyl)oxazolidin-2-
one
279: (R)-3-(2-((S)-1-(5-	(CD3OD) 8.45 (s, 1 H), 8.21 (d, J = 2.7 Hz,	HRMS (B)
bromo-3-fluoropyridin-2-	1 H), 7.86 (dd, J = 9.4, 2.0 Hz, 1 H), 5.35 (q,	m/z
yl)ethylamino)-5-	J = 6.7 Hz, 1 H), 4.67-4.77 (m, 1H),	444.0483,
fluoropyrimidin-4-yl)-4-	4.43-4.58 (m, 2 H), 4.08-4.20 (m, 1 H), 1.51 (d,	(M + H)+,
((R)-1-	J = 6.7 Hz, 3 H), 1.09 (d, J = 6.7 Hz, 3 H)	RT = 1.75 min.
hydroxyethyl)oxazolidin-2-
one
280: (R)-3-(2-((R)-1-(5-	(CD3OD) 8.44 (s, 1 H), 8.22 (d, J = 2.7 Hz,	HRMS (B)
bromo-3-fluoropyridin-2-	1 H), 7.86 (dd, J = 9.4, 1.6 Hz, 1 H),	m/z
yl)ethylamino)-5-	5.30-5.38 (m, 1 H), 4.61-4.71 (m, 1H),	444.0478,
fluoropyrimidin-4-yl)-4-	4.50-4.58 (m, 1 H), 4.43-4.49 (m, 1 H),	(M + H)+,
((R)-1-	3.92 (br. s., 1 H), 1.52 (d, J = 7.0 Hz, 6 H)	RT = 1.75 min.
hydroxyethyl)oxazolidin-2-
one
281: (R)-3-(2-((S)-1-(3-(4-	(CD3OD) 8.27 (br. s., 1 H), 8.01 (dd,	HRMS (B)
chlorophenyl)-1,2,4-	J = 8.6, 2.3 Hz, 2 H), 7.47-7.56 (m, 2 H),	m/z
oxadiazol-5-	5.30-5.43 (m, 1 H), 4.68 (d, J = 13.7 Hz, 1	449.1140,
yl)ethylamino)-5-	H), 4.40-4.57 (m, 2 H), 4.00 (br. s., 1 H),	(M + H)+,
fluoropyrimidin-4-yl)-4-	1.72 (d, J = 7.0 Hz, 6 H)	RT = 2.04 min.
((R)-1-
hydroxyethyl)oxazolidin-2-
one
282: (R)-3-(2-((S)-1-(5-	(CD3OD) 8.65 (d, J = 2.0 Hz, 1 H), 8.22 (d,	HRMS (B)
bromopyridin-2-	J = 2.3 Hz, 1 H), 8.07 (dd, J = 8.6, 2.3 Hz, 1	m/z
yl)ethylamino)-5-	H), 7.51 (d, J = 8.2 Hz, 1 H), 5.00-5.08 (m,	426.0574,
fluoropyrimidin-4-yl)-4-	1 H), 4.61 (br. s., 1 H), 4.42-4.55 (m, 2	(M + H)+,
((R)-1-	H), 4.06-4.17 (m, 1 H), 1.55 (d, J = 7.0 Hz,	RT = 1.61 min.
hydroxyethyl)oxazolidin-2-	3 H), 1.08 (d, J = 6.7 Hz, 3 H)
one
283: (R)-3-(2-(((S)-1-(4-	(CD3OD) 8.21 (d, J = 2.7 Hz, 1 H), 7.52 (t,	HRMS (B)
bromo-3-	J = 7.6 Hz, 1 H), 7.21 (dd, J = 9.8, 2.0 Hz, 1	m/z
fluorophenyl)ethyl)amino)-	H), 7.12 (dd, J = 8.2, 2.0 Hz, 1 H),	443.0526,
5-fluoropyrimidin-4-yl)-4-	4.88-4.97 (m, 1 H), 4.59 (d, J = 8.2 Hz, 1 H),	(M + H)+,
((R)-1-	4.42-4.55 (m, 2 H), 3.88 (br. s., 1 H), 1.49 (d,	RT = 1.96 min.
hydroxyethyl)oxazolidin-2-	J = 7.0 Hz, 3 H), 0.80 (br. s., 3 H)
one
284: (R)-3-(2-(((S)-1-(5-	(CD3OD) 8.51 (s, 1H), 8.24 (s, 1H), 7.76 (s,	HRMS (B)
chloro-6-(1,1-	1H), 5.13 (m, 1 H), 4.91 (m, 1H),	m/z
difluoroethyl)pyridin-3-	4.42-4.55 (m, 2H), 4.41 (br. s., 1 H), 2.12 (t,	446.1208,
yl)ethyl)amino)-5-	J = 7.0 Hz, 3H), 1.22 (m, 6H)	(M + H)+,
fluoropyrimidin-4-yl)-4-		RT = 1.85 min.
((R)-1-
hydroxyethyl)oxazolidin-2-
one
285: (R)-3-(2-(((S)-1-(5-	(CD3OD) 8.22 (d, J = 2.7 Hz, 1 H), 8.11 (d,	HRMS (B)
chloro-6-(2,2,2-	J = 2.0 Hz, 1 H), 7.84 (d, J = 2.0 Hz, 1 H),	m/z
trifluoroethoxy)pyridin-3-	4.89-5.02 (m, 3 H), 4.62 (d, J = 3.5 Hz, 1	480.1065,
yl)ethyl)amino)-5-	H), 4.42-4.57 (m, 2 H), 3.90 (br. s., 1 H),	(M + H)+,
fluoropyrimidin-4-yl)-4-	1.52 (d, J = 7.0 Hz, 3 H), 0.85 (br. s., 3 H)	RT = 2.10 min.
((R)-1-
hydroxyethyl)oxazolidin-2-
one
286: (R)-3-(2-(((S)-1-(2,4-	(CD3OD) 8.21 (d, J = 2.3 Hz, 1 H),	HRMS (B)
dichlorophenyl)ethyl)amino)-	7.36-7.46 (m, 2 H), 7.24 (dd, J = 8.2, 2.0 Hz, 1	m/z
5-fluoropyrimidin-4-yl)-	H), 5.25 (q, J = 6.7 Hz, 1 H), 4.59 (br.s., 1	415.0741,
4-((R)-1-	H), 4.40-4.54 (m, 2 H), 3.81 (br. s., 1 H),	(M + H)+,
hydroxyethyl)oxazolidin-2-	1.47 (d, J = 7.0 Hz, 6 H)	RT = 2.07 min.
one
287: (R)-3-(2-(((S)-1-(6-	(CD3OD) 8.40 (d, J = 2.3 Hz, 1 H), 8.12 (br.	HRMS (B)
bromopyridin-3-	s., 1 H), 7.75 (dd, J = 8.4, 2.5 Hz, 1 H),	m/z
yl)ethyl)amino)-5-	7.59 (d, J = 8.2 Hz, 1 H), 5.17 (br. s., 1 H),	426.0570,
fluoropyrimidin-4-yl)-4-	5.05 (q, J = 7.0 Hz, 1 H), 4.43 (t, J = 8.6 Hz, 1 H),	(M + H)+,
((R)-1-	4.00-4.14 (m, 2 H), 1.59 (d, J = 7.0 Hz, 3	RT = 1.51 min.
hydroxyethyl)oxazolidin-2-	H), 1.40 (d, J = 6.7 Hz, 3 H)
one
288: (R)-3-(2-(((S)-1-(4-	(CD3OD) 8.21 (d, J = 3.1 Hz, 1 H), 7.38 (t,	HRMS (B)
chloro-3-	J = 8.0 Hz, 1 H), 7.12-7.28 (m, 2 H),	m/z
fluorophenyl)ethyl)amino)-	4.88-5.00 (m, 1 H), 4.59 (br. s., 1 H),	399.1031,
5-fluoropyrimidin-4-yl)-4-	4.42-4.55 (m, 2 H), 3.89 (br. s., 1 H), 1.49 (d, J = 7.0 Hz,	(M + H)+,
((R)-1-	3 H), 0.81 (br. s., 3 H)	RT = 1.91 min.
hydroxyethyl)oxazolidin-2-
one
289: (R)-3-(2-(((R)-1-(5-	(CD3OD) 8.57 (d, J = 2.3 Hz, 1 H),	HRMS (B)
bromopyridin-2-	7.88-7.97 (m, 2 H), 7.37 (d, J = 8.6 Hz, 1 H),	m/z
yl)ethyl)amino)-5-	5.09 (br. s., 1 H), 4.94 (d, J = 7.0 Hz, 1H), 4.38 (t,	426.0574,
fluoropyrimidin-4-yl)-4-	J = 8.8 Hz, 1 H), 3.93-4.12 (m, 2 H),	(M + H)+,
((R)-1-	1.51 (d, J = 7.0 Hz, 3 H), 1.31 (d, J = 6.3 Hz, 3 H)	RT = 1.55 min.
hydroxyethyl)oxazolidin-2-
one
290: (R)-3-(2-(((S)-1-(3,4-	(CD3OD) 8.20 (d, J = 2.7 Hz, 1 H), 7.51 (d,	HRMS (B)
dichlorophenyl)ethyl)amino)-	J = 2.0 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H),	m/z
5-fluoropyrimidin-4-yl)-	7.29 (dd, J = 8.4, 1.8 Hz, 1 H),	415.0738,
4-((R)-1-	4.87-4.97 (m, 1 H), 4.59 (br. s., 1 H), 4.40-4.55 (m,	(M + H)+,
hydroxyethyl)oxazolidin-2-	2 H), 3.89 (br. s., 1 H), 1.49 (d, J = 7.0 Hz, 6	RT = 2.02 min.
one	H)
291: (R)-3-(2-(((S)-1-(6-	(CDCl3) 8.25 (s, 1H), 8.22 (m, 1H),	HRMS (B)
chloro-5-fluoropyridin-3-	7.51 (m, 1H), 5.51 (s, 1H), 4.91 (m, 1 H),	m/z
yl)ethyl)amino)-5-	4.51 (m, 2H), 4.41 (m, 1 H), 3.62 (m, 1H),	400.0981,
fluoropyrimidin-4-yl)-4-	1.45 (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3H)	(M + H)+,
((R)-1-		RT = 1.61 min.
hydroxyethyl)oxazolidin-2-
one
292: (R)-3-(2-(((S)-1-(5,6-	(CDCl3) 8.37 (s, 1H), 8.15 (m, 1H),	HRMS (B)
dichloropyridin-3-	7.76 (m, 1H), 5.68 (s, 1H), 4.94 (m, 1 H),	m/z
yl)ethyl)amino)-5-	4.51 (m, 2H), 4.45 (m, 1 H), 3.68 (m, 1H),	416.0690,
fluoropyrimidin-4-yl)-4-	1.58 (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3H)	(M + H)+,
((R)-1-		RT = 1.73 min.
hydroxyethyl)oxazolidin-2-
one
293: (R)-3-(2-(((R)-1-(3,5-	(cdcl3) 8.43 (d, J = 2.0 Hz, 1 H), 8.23 (d,	HRMS (B)
dichloropyridin-2-	J = 2.3 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H),	m/z
yl)ethyl)amino)-5-	6.29 (d, J = 7.8 Hz, 1 H), 5.50 (br. s., 1 H),	416.0685,
fluoropyrimidin-4-yl)-4-	4.48-4.59 (m, 2 H), 4.37-4.47 (m, 1 H),	(M + H)+,
((R)-1-	4.24 (br. s., 1 H), 1.48 (d, J = 6.7 Hz, 3 H),	RT = 1.83 min.
hydroxyethyl)oxazolidin-2-	1.22 (d, J = 6.7 Hz, 3 H)
one
294: (R)-3-(2-(((S)-1-(3,5-	(CDCl3) 8.42 (d, J = 2.0 Hz, 1 H), 8.22 (d,	HRMS (B)
dichloropyridin-2-	J = 2.7 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H),	m/z
yl)ethyl)amino)-5-	6.22 (d, J = 8.2 Hz, 1 H), 5.51 (br. s.,1 H),	416.0687,
fluoropyrimidin-4-yl)-4-	4.47-4.67 (m, 2 H), 4.34-4.45 (m, 1 H),	(M + H)+,
((R)-1-	1.49 (d, J = 7.0 Hz, 3 H), 1.14 (br. s., 3 H)	RT = 1.82 min.
hydroxyethyl)oxazolidin-2-
one
295: (R)-3-(6-chloro-2-	(CDCl3) 8.43 (d, J = 2.0 Hz, 1 H), 7.73 (d,	HRMS (B)
(((S)-1-(3,5-	J = 2.0 Hz, 1 H), 7.50 (s, 1 H), 6.39 (d,	m/z
dichloropyridin-2-	J = 7.4 Hz, 1 H), 5.52 (br. s., 1 H),	432.0391,
yl)ethyl)amino)pyrimidin-4-	4.72-4.93 (m, 1 H), 4.32-4.62 (m, 2 H),	(M + H)+,
yl)-4-((R)-1-	4.13 (br. s., 1 H), 1.50 (d, J = 6.7 Hz, 3 H),	RT = 2.27 min.
hydroxyethyl)oxazolidin-2-	1.07 (br. s., 3 H)
one
296: (R)-3-(6-chloro-2-	(CDCl3) 8.13 (br. s., 1 H), 7.49 (s, 1 H),	HRMS (B)
(((S)-1-(3-fluoro-5-(2,2,2-	7.07 (dd, J = 10.8, 2.2 Hz, 1 H), 6.17 (br. s.,	m/z
trifluoroethoxy)pyridin-2-	1 H), 5.40 (br. s., 1 H), 4.70-5.04 (m, 1 H),	480.1066,
yl)ethyl)amino)pyrimidin-4-	4.52 (br. s., 1 H), 4.41 (q, J = 7.8 Hz, 3 H),	(M + H)+,
yl)-4-((R)-1-	4.18 (br. s., 1 H), 1.53 (br. s., 3 H),	RT = 2.21 min.
hydroxyethyl)oxazolidin-2-	1.01-1.18 (m, 3 H)
one
297: (R)-3-(2-(((R)-1-(1-(4-	(CDCl3) 8.19 (d, J = 2.7 Hz, 1 H), 7.81 (d,	HRMS (B)
chlorophenyl)-1H-pyrazol-	J = 2.3 Hz, 1 H), 7.59 (d, J = 9.0 Hz, 2 H),	m/z
3-yl)ethyl)amino)-5-	7.41 (d, J = 9.0 Hz, 2 H), 6.39 (d, J = 2.3 Hz, 1	447.1348,
fluoropyrimidin-4-yl)-4-	H), 5.12 (br. s., 1 H), 4.25-4.58 (m, 4 H),	(M + H)+,
((R)-1-	3.03 (br. s., 1 H), 1.61 (d, J = 7.0 Hz, 3 H),	RT = 2.00 min.
hydroxyethyl)oxazolidin-2-	1.20 (d, J = 6.3 Hz, 3 H)
one
298: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 8.19 (d, J = 2.0 Hz, 1 H), 7.80 (d,	HRMS (B)
chlorophenyl)-1H-pyrazol-	J = 2.0 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 2 H),	m/z
3-yl)ethyl)amino)-5-	7.41 (d, J = 9.0 Hz, 2 H), 6.39 (d, J = 2.3 Hz, 1	447.1345,
fluoropyrimidin-4-yl)-4-	H), 5.18 (br. s., 1 H), 4.60 (t, J = 5.5 Hz, 1	(M + H)+,
((R)-1-	H), 4.51 (t, J = 8.6 Hz, 1 H), 4.34 (dd, J = 8.8,	RT = 1.98 min.
hydroxyethyl)oxazolidin-2-	5.3 Hz, 1 H), 4.00 (br. s., 1 H), 1.62 (d,
one	J = 7.0 Hz, 3 H), 1.03 (br. s., 3 H)
299: (R)-3-(2-(((R)-1-(1-(4-	(CDCl3) 8.20 (d, J = 2.7 Hz, 1 H), 7.76 (s, 1	HRMS (B)
chlorophenyl)-1H-	H), 7.45 (d, J = 8.6 Hz, 2 H), 7.31 (d, J = 8.6 Hz,	m/z
imidazol-4-yl)ethyl)amino)-	2 H), 7.14 (s, 1 H), 5.61 (d, J = 7.4 Hz, 1	447.1346,
5-fluoropyrimidin-4-yl)-4-	H), 5.07 (d, J = 5.9 Hz, 1 H), 4.32-4.57 (m,	(M + H)+,
((R)-1-	4 H), 1.59 (d, J = 6.7 Hz, 3 H), 1.21 (d,	RT = 1.32 min.
hydroxyethyl)oxazolidin-2-	J = 6.3 Hz, 3 H)
one
300: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 8.19 (d, J = 2.7 Hz, 1 H), 7.71 (s, 1	HRMS (B)
chlorophenyl)-1H-	H), 7.45 (d, J = 8.6 Hz, 2 H), 7.30 (d, J = 8.6 Hz,	m/z
imidazol-4-yl)ethyl)amino)-	2 H), 7.12 (s, 1 H), 5.42 (d, J = 7.8 Hz, 1	447.1350,
5-fluoropyrimidin-4-yl)-4-	H), 5.20 (quin, J = 7.1 Hz, 1 H), 4.74 (br. s.,	(M + H)+,
((R)-1-	1 H), 4.54 (t, J = 8.8 Hz, 1 H), 4.29 (dd,	RT = 1.34 min.
hydroxyethyl)oxazolidin-2-	J = 8.6, 5.9 Hz, 1 H), 3.99 (br. s., 1 H),
one	1.62 (d, J = 7.0 Hz, 3 H), 1.15 (d, J = 6.3 Hz, 3 H)
301: (R)-3-(2-(((S)-1-(2,5-	(CDCl3) 8.20 (d, J = 2.7 Hz, 1 H), 7.09 (dd,	HRMS (B)
difluoro-4-(2,2,2-	J = 11.3, 7.0 Hz, 1 H), 6.79 (dd, J = 10.4, 6.8 Hz,	m/z
trifluoroethoxy)phenyl)ethyl)amino)-	1 H), 5.52 (br. s., 1 H), 5.11 (quin,	481.1315,
5-	J = 6.7 Hz, 1 H), 4.45-4.59 (m, 2 H),	(M + H)+,
fluoropyrimidin-4-yl)-4-	4.31-4.44 (m, 3 H), 3.87 (br. s., 1 H), 1.53 (d,	RT = 2.04 min.
((R)-1-	J = 7.0 Hz, 3 H), 1.03 (d, J = 4.3 Hz, 3 H)
hydroxyethyl)oxazolidin-2-
one
302: (R)-3-(5-fluoro-2-	(CDCl3) 8.19 (d, J = 2.3 Hz, 1 H),	HRMS (B)
(((S)-1-(2-fluoro-4-(2,2,2-	6.62-6.75 (m, 3 H), 5.48 (br. s., 1 H), 5.14 (t,	m/z
trifluoroethoxy)phenyl)ethyl)amino)pyrimidin-	J = 6.8 Hz, 1 H), 4.43-4.54 (m, 2 H),	463.1403,
4-yl)-4-	4.24-4.40 (m, 3 H), 3.82 (br. s., 1 H), 1.53 (d,	(M + H)+,
((R)-1-	J = 6.7 Hz, 3 H), 0.99 (br. s., 3 H)	RT = 2.03 min.
hydroxyethyl)oxazolidin-2-
one
303: (R)-3-(5-fluoro-2-	(CDCl3) 8.20 (d, J = 2.3 Hz, 1 H), 7.12 (dd,	HRMS (B)
(((S)-1-(3-fluoro-4-(2,2,2-	J = 11.7, 2.0 Hz, 1 H), 7.04-7.09 (m, 1 H),	m/z
trifluoroethoxy)phenyl)ethyl)amino)pyrimidin-	6.93-7.03 (m, 1 H), 5.44 (br. s., 1 H),	463.1403,
4-yl)-4-	4.86 (d, J = 6.3 Hz, 1 H), 4.45-4.55 (m, 1 H),	(M + H)+,
((R)-1-	4.27-4.45 (m, 3 H), 3.76 (br. s., 1 H),	RT = 1.99 min.
hydroxyethyl)oxazolidin-2-	1.51 (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3 H)
one
304: (R)-3-(5-fluoro-2-	(CDCl3) 8.22 (d, J = 2.7 Hz, 1 H), 7.77 (d,	HRMS (B)
(((S)-1-(1-(4-fluorophenyl)-	J = 2.3 Hz, 1 H), 7.54-7.67 (m, 2 H),	m/z
1H-pyrazol-3-	7.14 (t, J = 8.4 Hz, 2 H), 6.36 (d, J = 2.3 Hz, 1 H),	431.1643,
yl)ethyl)amino)pyrimidin-4-	5.66 (d, J = 7.8 Hz, 1 H), 5.10-5.25 (m, 1	(M + H)+,
yl)-4-((R)-1-	H), 4.55-4.64 (m, 1 H), 4.47-4.54 (m, 1	RT = 1.80 min.
hydroxyethyl)oxazolidin-2-	H), 4.34 (dd, J = 8.6, 5.1 Hz, 1 H), 4.02 (br.
one	s., 1 H), 1.61 (d, J = 7.0 Hz, 6 H)
305: (R)-3-(5-fluoro-2-	(CDCl3) 8.30 (d, J = 2.7 Hz, 1 H), 8.20 (d,	HRMS (B)
(((S)-1-(5-(2,2,2-	J = 2.7 Hz, 1 H), 7.23-7.37 (m, 2 H),	m/z
trifluoroethoxy)pyridin-2-	5.96-6.10 (m, 1 H), 4.97-5.14 (m, 1H),	446.1449,
yl)ethyl)amino)pyrimidin-4-	4.44-4.57 (m, 2 H), 4.28-4.44 (m, 3 H),	(M + H)+,
yl)-4-((R)-1-	3.96 (br. s., 1 H), 1.54 (d, J = 6.7 Hz, 6 H)	RT = 1.58 min.
hydroxyethyl)oxazolidin-2-
one
306: (R)-3-(5-fluoro-2-	(CDCl3) 8.28 (d, J = 2.3 Hz, 1 H), 8.20 (d,	HRMS (B)
(((R)-1-(5-(2,2,2-	J = 3.1 Hz, 1 H), 7.21-7.36 (m, 2 H),	m/z
trifluoroethoxy)pyridin-2-	6.02 (d, J = 6.7 Hz, 1 H), 5.00 (br. s., 1H),	446.1447,
yl)ethyl)amino)pyrimidin-4-	4.25-4.57 (m, 5 H), 1.52 (d, J = 6.7 Hz, 3 H),	(M + H)+,
yl)-4-((R)-1-	1.20 (d, J = 6.3 Hz, 3 H)	RT = 1.59 min.
hydroxyethyl)oxazolidin-2-
one
307: (R)-3-(2-(((S)-1-(1-(4-	(CD3OD) 9.02 (br. s., 1 H), 8.20 (d, J = 6.7 Hz,	HRMS (B)
chlorophenyl)-1H-	1 H), 7.89 (s, 1 H), 7.64-7.72 (m, 3	m/z
imidazol-4-	H), 7.56-7.64 (m, 2 H), 5.37 (d, J = 6.3 Hz,	429.1438,
yl)ethyl)amino)pyrimidin-4-	1 H), 4.75-5.01 (m, 2 H), 4.56 (dd, J = 9.4,	(M + H)+,
yl)-4-((R)-1-	2.3 Hz, 1 H), 4.40-4.50 (m, 1 H), 1.72 (d,	RT = 1.30 min.
hydroxyethyl)oxazolidin-2-	J = 7.0 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H)
one
308: (R)-3-(2-(((S)-1-(1-(4-	(CD3OD) 8.19 (d, J = 2.3 Hz, 1 H), 8.15 (d,	HRMS (B)
chlorophenyl)-1H-pyrazol-	J = 7.0 Hz, 1 H), 7.74 (dd, J = 7.8, 6.7 Hz, 3	m/z
3-yl)ethyl)amino)pyrimidin-	H), 7.45 (d, J = 9.0 Hz, 2 H), 6.53 (d, J = 2.3 Hz,	429.1441,
4-yl)-4-((R)-1-	1 H), 5.46 (br. s., 1 H), 4.81-4.97 (m,	(M + H)+,
hydroxyethyl)oxazolidin-2-	2 H), 4.60 (dd, J = 9.4, 2.3 Hz, 1 H),	RT = 1.65 min.
one	4.42-4.53 (m, 1 H), 4.32 (br. s., 1 H), 1.69 (d,
	J = 7.0 Hz, 3H), 0.91 (br. s., 3 H)
309: (R)-3-(6-chloro-2-	(CD3OD) 9.34 (s, 1 H), 7.95 (s, 1 H),	HRMS (B)
(((S)-1-(1-(4-	7.67-7.75 (m, 2 H), 7.60-7.67 (m, 2 H),	m/z
chlorophenyl)-1H-	7.44 (s, 1 H), 5.34 (br. s., 1 H), 4.75-4.88 (m, 2	463.1056,
imidazol-4-	H), 4.52 (d, J = 9.8 Hz, 1 H), 4.36-4.45 (m,	(M + H)+,
yl)ethyl)amino)pyrimidin-4-	1 H), 1.68 (d, J = 7.0 Hz, 3 H), 0.99 (br. s., 3	RT = 1.68 min.
yl)-4-((R)-1-	H)
hydroxyethyl)oxazolidin-2-
one
310: (R)-3-(6-chloro-2-	(cd3od) 8.04 (d, J = 2.3 Hz, 1 H), 7.71 (dd,	HRMS (B)
(((S)-1-(1-(4-fluorophenyl)-	J = 9.0, 4.7 Hz, 2 H), 7.35 (s, 1 H), 7.19 (t,	m/z
1H-pyrazol-3-	J = 8.8 Hz, 2 H), 6.43 (d, J = 2.7 Hz, 1 H),	447.1346,
yl)ethyl)amino)pyrimidin-4-	5.29 (q, J = 7.0 Hz, 1 H), 4.79-4.87 (m, 2	(M + H)+,
yl)-4-((R)-1-	H), 4.52 (dd, J = 9.2, 2.5 Hz, 1 H),	RT = 2.18 min.
hydroxyethyl)oxazolidin-2-	4.35-4.44 (m, 1 H), 1.59 (d, J = 7.0 Hz, 3 H),
one	0.85 (br. s., 3 H)
311: (R)-3-(2-(((S)-1-(2,4-	(CD3OD) 8.15 (d, J = 6.7 Hz, 1 H), 7.70 (d,	HRMS (B)
dichlorophenyl)ethyl)amino)pyrimidin-	J = 7.0 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H),	m/z
4-yl)-4-((R)-1-	7.46 (d, J = 8.6 Hz, 1 H), 7.34 (dd, J = 8.6, 2.0 Hz,	397.0834,
hydroxyethyl)oxazolidin-2-	1 H), 5.47 (d, J = 5.1 Hz, 1 H), 4.57 (dd,	(M + H)+,
one	J = 9.0, 2.3 Hz, 2 H), 4.33-4.50 (m, 2 H),	RT = 1.77 min.
	3.80 (br. s., 2 H), 1.58 (d, J = 7.0 Hz, 6 H)
312: (R)-3-(2-(((S)-1-(3,4-	(CD3OD) 8.13 (d, J = 6.7 Hz, 1 H), 7.70 (d,	HRMS (B)
dichlorophenyl)ethyl)amino)pyrimidin-	J = 7.0 Hz, 1 H), 7.57 (d, J = 2.0 Hz, 1 H),	m/z
4-yl)-4-((R)-1-	7.51 (d, J = 8.2 Hz, 1 H), 7.33 (dd, J = 8.4, 2.2 Hz,	397.0831,
hydroxyethyl)oxazolidin-2-	1 H), 5.19 (br. s., 1 H), 4.75-5.00 (m,	(M + H)+,
one	2 H), 4.58 (dd, J = 9.4, 2.3 Hz, 1 H),	RT = 1.72 min.
	4.34-4.51 (m, 1 H), 3.92 (br. s., 1 H), 1.59 (d,
	J = 6.7 Hz,
	6 H)
313: (R)-3-(6-chloro-2-	(CDCl3) 7.80 (d, J = 2.3 Hz, 1 H), 7.56 (d,	HRMS (B)
(((S)-1-(1-(4-	J = 8.6 Hz, 2 H), 7.51 (s, 1 H), 7.42 (d,	m/z
chlorophenyl)-1H-pyrazol-	J = 8.6 Hz, 3 H), 6.39 (d, J = 2.3 Hz, 1H),	463.1056,
3-yl)ethyl)amino)pyrimidin-	6.08 (br. s., 1 H), 5.22 (br. s., 1 H),	(M + H)+,
4-yl)-4-((R)-1-	4.76 (ddd, J = 7.9, 5.0, 2.3 Hz, 1 H),	RT = 2.34 min.
hydroxyethyl)oxazolidin-2-	4.40-4.49 (m, 1 H), 4.31-4.39 (m, 1 H), 3.99 (br. s.,
one	1 H), 1.61 (dd, J = 7.0 Hz, 6 H)
314: (R)-3-(2-(((S)-1-(2,5-	(CDCl3) 10.88 (br. s., 1 H), 7.93 (d, J = 7.0 Hz,	HRMS (B)
difluoro-4-(2,2,2-	1 H), 7.75 (d, J = 7.0 Hz, 1 H),	m/z
trifluoroethoxy)phenyl)ethyl)amino)pyrimidin-	7.20-7.30 (m, 1 H), 6.83 (dd, J = 10.6, 6.7 Hz, 1	463.1410,
4-yl)-4-	H), 5.34 (t, J = 6.8 Hz, 1 H), 4.85 (ddd,	(M + H)+,
((R)-1-	J = 7.4, 4.7, 2.0 Hz, 1 H), 4.61 (dd, J = 9.4,	RT = 1.79 min.
hydroxyethyl)oxazolidin-2-	2.0 Hz, 1 H), 4.34-4.52 (m, 3 H),
one	3.78-3.96 (m, 1 H), 1.61 (d, J = 7.0 Hz, 3 H),
	0.96 (d, J = 6.3 Hz, 3 H)
315: (R)-3-(2-(((S)-1-(2-	(CDCl3) 10.61 (d, J = 4.7 Hz, 1 H), 7.98 (d,	HRMS (B)
fluoro-4-(2,2,2-	J = 5.5 Hz, 1 H), 7.75 (d, J = 5.9 Hz, 1 H),	m/z
trifluoroethoxy)phenyl)ethyl)amino)pyrimidin-	7.41 (t, J = 8.8 Hz, 1 H), 6.64-6.85 (m, 2 H),	445.1492,
4-yl)-4-	5.39 (t, J = 6.5 Hz, 1 H), 4.85 (ddd, J = 7.6,	(M + H)+,
((R)-1-	4.9, 2.0 Hz, 1 H), 4.60 (dd, J = 9.8, 2.0 Hz, 1	RT = 1.74 min.
hydroxyethyl)oxazolidin-2-	H), 4.40-4.50 (m, 1 H), 4.35 (q, J = 8.2 Hz,
one	2 H), 3.79-3.96 (m, 1 H), 1.61 (d, J = 7.0 Hz,
	3 H), 0.94 (d, J = 6.3 Hz, 3 H)
316: (R)-3-(2-(((S)-1-(3-	(cdcl3) 10.84 (d, J = 3.9 Hz, 1 H), 7.92 (d,	HRMS (B)
fluoro-4-(2,2,2-	J = 7.0 Hz, 1 H), 7.73 (d, J = 7.0 Hz, 1 H),	m/z
trifluoroethoxy)phenyl)ethyl)amino)pyrimidin-	7.09-7.20 (m, 2 H), 6.97-7.10 (m, 1 H),	445.1491,
4-yl)-4-	4.93 (t, J = 6.7 Hz, 1 H), 4.78 (td, J = 5.1, 2.3 Hz,	(M + H)+,
((R)-1-	1 H), 4.56 (dd, J = 9.4, 2.0 Hz, 1 H),	RT = 1.69 min.
hydroxyethyl)oxazolidin-2-	4.35-4.47 (m, 3 H), 3.64-3.75 (m, 1 H),
one	1.62 (d, J = 7.0 Hz, 3 H), 0.94 (d, J = 6.3 Hz, 3
	H)
317: (R)-3-(2-(((S)-1-(5-	(CDCl3) 11.02 (d, J = 6.7 Hz, 1 H), 8.59 (d,	HRMS (B)
bromopyridin-2-	J = 1.6 Hz, 1 H), 8.03 (dd, J = 8.4, 1.8 Hz, 1	m/z
yl)ethyl)amino)pyrimidin-4-	H), 7.94 (d, J = 6.7 Hz, 1 H), 7.76 (d, J = 6.7 Hz,	408.0668,
yl)-4-((R)-1-	1 H), 7.58 (d, J = 8.6 Hz, 1 H), 5.40 (t,	(M + H)+,
hydroxyethyl)oxazolidin-2-	J = 7.0 Hz, 1 H), 4.83-4.95 (m, 1 H),	RT = 1.29 min.
one	4.62 (dd, J = 9.4, 1.6 Hz, 1 H), 4.40-4.51 (m, 1
	H), 3.70-3.84 (m, 1 H), 1.70 (d, J = 7.0 Hz,
	3 H), 1.02 (d, J = 6.3 Hz, 3 H)
318: (R)-3-(2-(((R)-1-(5-	(CDCl3) 10.97 (d, J = 4.3 Hz, 1 H), 8.62 (d,	HRMS (B)
bromopyridin-2-	J = 1.6 Hz, 1 H), 8.09 (dd, J = 8.2, 1.6 Hz, 1	m/z
yl)ethyl)amino)pyrimidin-4-	H), 7.99 (d, J = 6.7 Hz, 1 H), 7.77 (d, J = 6.7 Hz,	408.0670,
yl)-4-((R)-1-	1 H), 7.63 (d, J = 8.2 Hz, 1 H), 5.37 (t,	(M + H)+,
hydroxyethyl)oxazolidin-2-	J = 6.5 Hz, 1 H), 4.59-4.74 (m, 2 H),	RT = 1.33 min.
one	4.29-4.46 (m, 2 H), 1.70 (d, J = 6.7 Hz, 3 H),
	1.17 (d, J = 6.3 Hz, 3 H)
319: (R)-3-(2-(((S)-1-(4,5-	(CD3OD) 8.15 (d, J = 7.0 Hz, 1 H), 7.70 (d,	HRMS (B)
dichloro-2-	J = 6.3 Hz, 1 H), 7.58 (d, J = 7.0 Hz, 1 H),	m/z
fluorophenyl)ethyl)amino)	7.41 (d, J = 9.8 Hz, 1 H), 5.42 (d, J = 3.5 Hz, 1	415.0733,
pyrimidin-4-yl)-4-((R)-1-	H), 4.87 (d, J = 5.5 Hz, 2 H), 4.58 (dd,	(M + H)+,
hydroxyethyl)oxazolidin-2-	J = 9.0, 2.3 Hz, 1 H), 4.38-4.50 (m, 1 H),	RT = 1.84 min.
one	3.91 (br. s., 1 H), 1.60 (d, J = 7.0 Hz, 3 H),
	0.84 (br. s., 3H)
320: (R)-3-(2-(((S)-1-(2,5-	(CD3OD) 9.26 (s, 1 H), 8.19 (d, J = 7.0 Hz,	HRMS (B)
difluoro-4-(4-methyl-1H-	1 H), 7.77 (d, J = 6.7 Hz, 1 H),	m/z
imidazol-1-	7.54-7.71 m, 3 H), 5.51 (d, J = 5.9 Hz, 1 H),	445.1794,
yl)phenyl)ethyl)amino)pyrimidin-	4.81-4.90 (m, 1 H), 4.58 (dd, J = 9.2, 2.2 Hz, 1	(M + H)+,
4-yl)-4-((R)-1-	H), 4.41-4.51 (m, 1 H), 3.75 (br. s., 1 H),	RT = 1.02 min.
hydroxyethyl)oxazolidin-2-	2.44 (s, 3 H), 1.66 (d, J = 6.7 Hz, 3 H),
one	0.87 (br. s., 3 H)
321: (R)-3-(5-chloro-2-	(CD3OD) 8.20 (s, 1 H), 7.43 (d, J = 7.0 Hz,	HRMS (B)
(((S)-1-(4,5-dichloro-2-	1 H), 7.26 (d, J = 9.4 Hz, 1 H), 5.11 (br. s., 1	m/z
fluorophenyl)ethyl)amino)	H), 4.68-4.90 (m, 1 H), 4.43 (t, J = 8.2 Hz, 1	449.0347,
pyrimidin-4-yl)-4-((R)-1-	H), 4.25-4.37 (m, 1 H), 3.44-3.86 (m, 1	(M + H)+,
hydroxyethyl)oxazolidin-2-	H), 1.42 (d, J = 7.0 Hz, 3 H), 0.73 (br. s., 3	RT = 2.14 min.
one	H)
322: (R)-3-(2-(((S)-1-(2,5-	(CD3OD) 8.74 (d, J = 6.3 Hz, 1 H),	HRMS (B)
difluoro-4-(2-	8.11-8.22 (m, 2 H), 8.07 (d, J = 6.3 Hz, 1 H),	m/z
methylpyridin-4-	7.59-7.77 (m, 2 H), 7.40-7.53 (m, 1H),	456.1840,
yl)phenyl)ethyl)amino)pyrimidin-	5.48 (d, J = 5.5 Hz, 1 H), 4.77-5.01 (m, 2 H),	(M + H)+,
4-yl)-4-((R)-1-	4.57 (dd, J = 9.0, 2.3 Hz, 1 H),	RT = 1.10 min.
hydroxyethyl)oxazolidin-2-	4.38-4.51 (m, 1 H), 2.83 (s, 3 H), 1.66 (d, J = 7.0 Hz, 2
one	H), 0.82 (br.s., 3 H)
323: (R)-3-(2-(((S)-1-(2,5-	(CD3OD) 8.91 (s, 1 H), 8.60 (d, J = 8.2 Hz,	HRMS (B)
difluoro-4-(6-	1 H), 8.18 (d, J = 6.3 Hz, 1 H), 7.95 (d,	m/z
methylpyridin-3-	J = 8.2 Hz, 1 H), 7.73 (d, J = 6.3 Hz, 1H),	456.1847,
yl)phenyl)ethyl)amino)pyrimidin-	7.54 (dd, J = 10.2, 6.7 Hz, 1 H), 7.42 (dd,	(M + H)+,
4-yl)-4-((R)-1-	J = 10.8, 6.1 Hz, 1 H), 5.49 (d, J = 4.7 Hz, 1	RT = 1.18 min.
hydroxyethyl)oxazolidin-2-	H), 4.88 (s, 1 H), 4.58 (dd, J = 9.2, 2.2 Hz, 1
one	H), 4.39-4.51 (m, 1 H), 3.83 (br. s., 1 H),
	2.82 (s, 3 H), 1.66 (d, J = 7.0 Hz, 3 H),
	0.83 (br. s., 3 H)
324: (R)-3-(2-(((S)-1-(2,5-	(CD3OD) 8.80 (d, J = 5.1 Hz, 1 H), 8.18 (d,	HRMS (B)
difluoro-4-(2-	J = 6.7 Hz, 1 H), 7.97-8.07 (m, 1 H),	m/z
(trifluoromethyl)pyridin-4-	7.77-7.90 (m, 2 H), 7.54 (dd, J = 10.6, 6.3 Hz, 1	510.1560,
yl)phenyl)ethyl)amino)pyrimidin-	H), 7.40 (dd, J = 11.0, 6.3 Hz, 1 H), 5.49 (br.	(M + H)+,
4-yl)-4-((R)-1-	s., 1 H), 4.79-5.02 (m, 1 H),	RT = 1.94 min.
hydroxyethyl)oxazolidin-2-	4.53-4.68 (m, 1 H), 4.39-4.52 (m, 1 H), 3.80 (br. s.,
one	1 H), 1.61-1.73 (m, 6 H)
325: (R)-3-(2-(((S)-1-(2,5-	(CD3OD) 8.90 (s, 1 H), 8.12-8.29 (m, 2	HRMS (B)
difluoro-4-(6-	H), 7.92 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 6.7 Hz,	m/z
(trifluoromethyl)pyridin-3-	1 H), 7.43-7.55 (m, 1 H), 7.37 (dd,	510.1565,
yl)phenyl)ethyl)amino)pyrimidin-	J = 10.8, 6.1 Hz, 1 H), 5.47 (br. s., 1 H),	(M + H)+,
4-yl)-4-((R)-1-	4.81-4.97 (m, 1 H), 4.58 (dd, J = 9.0, 2.3 Hz,	RT = 1.98 min.
hydroxyethyl)oxazolidin-2-	1 H), 4.39-4.51 (m, 1 H), 3.82 (br. s.,
one	1 H), 1.66 (d,
	J = 7.0 Hz, 3 H), 0.82 (br. s., 3 H)
326: (R)-4-((R)-1-		HRMS (B)
hydroxyethyl)-3-(2-(((S)-1-		m/z
(4-		401.2188
isobutoxyphenyl)ethyl)amino)pyrimidin-		(M + H)+;
4-		Rt 1.80 min
yl)oxazolidin-2-one
327: (R)-3-(5-fluoro-2-	(CD3OD) 8.22 (d, J = 3.13 Hz, 1H),	HRMS (B)
(((S)-1-(2-fluoro-4-	7.14-7.41 (m, 1H), 6.55-6.79 (m, 2H), 5.19 (q,	m/z
methoxyphenyl)-	J = 7.04 Hz, 1H), 4.68 (d, J = 3.91 Hz, 1 H),	395.1525
ethyl)amino)pyrimidin-4-	4.43-4.60 (m, 2H), 3.92 (d, J = 17.22 Hz,	(M + H)+;
yl)-4-((R)-1-hydroxy-	1H), 3.78 (s, 3H), 1.50 (d, J = 6.65 Hz, 3H)	Rt 1.78 min
ethyl)oxazolidin-2-one
328: (R)-3-(2-(((S)-1-(2,3-	1H NMR (400 MHz, <cd3od>) 0.83 (br. s.,	HRMS (B)
difluorophenyl)ethyl)amino)pyrimidin-	3 H) 1.60 (d, J = 6.65 Hz, 3 H)	m/z
4-yl)-4-((R)-1-	4.40-4.45 (m, 1 H) 4.56 (d, J = 7.43 Hz, 1 H) 4.85 (m,	365.1414,
hydroxyethyl)oxazolidin-2-	2H) 5.39-5.47 (m, 1 H) 7.11-7.21 (m, 3	(M + H)+,
one	H) 7.61-7.68 (m, 1 H) 8.12 (d, J = 6.65 Hz,	RT = 1.49 min.
	1 H)
329: (R)-3-(2-(((S)-1-(2,3-	1H NMR (400 MHz, <cd3od>) 0.81 (br. s.,	HRMS (B)
difluorophenyl)ethyl)amino)-	3 H) 1.52 (d, J = 7.04 Hz, 3 H)	m/z
5-fluoropyrimidin-4-yl)-4-	3.81-3.96 (m, 1 H) 4.44-4.56 (m, 2 H)	383.1327,
((R)-1-	4.57-4.68 (m, 1 H) 5.21-5.32 (m, 1 H)	(M + H)+,
hydroxyethyl)oxazolidin-2-	7.01-7.22 (m, 3H) 8.21 (d, J = 3.08 Hz, 1 H)	RT = 1.81 min.
one
330: (R)-3-(2-(((S)-1-(3,4-	1H NMR (400 MHz, <cd3od>) 0.83 (br. s.,	HRMS (B)
difluorophenyl)ethyl)amino)-	3 H) 1.48 (d, J = 7.04 Hz, 3 H)	m/z
5-fluoropyrimidin-4-yl)-4-	3.81-3.97 (m, 1 H) 4.39-4.57 (m, 2 H)	383.1328,
((R)-1-	4.59-4.68 (m, 1 H)	(M + H)+,
hydroxyethyl)oxazolidin-2-	4.89-5.01 (m, 2 H) 7.11-7.32 (m, 3 H) 8.21 (d,	RT = 1.81 min.
one	J = 3.13 Hz, 1 H)
331: (R)-3-(2-(((S)-1-(2,4-	1H NMR (400 MHz, <cd3od>) 0.73 (br. s.,	HRMS (B)
difluorophenyl)ethyl)amino)-	3 H) 1.41 (d, J = 6.99 Hz, 3 H) 3.81 (br. s., 1	m/z
5-fluoropyrimidin-4-yl)-4-	H) 4.32-4.47 (m, 2 H) 4.54 (d, J = 3.03 Hz,	383.1323,
((R)-1-	1 H)	(M + H)+,
hydroxyethyl)oxazolidin-2-	5.11 (d, J = 6.94 Hz, 1 H) 6.73-6.89 (m, 2 H)	RT = 1.80 min.
one	7.29 (td, J = 8.57, 6.53 Hz, 1 H) 8.11 (d,
	J = 2.98 Hz, 1 H)
332: (R)-3-(2-(((S)-1-(3,5-		HRMS (B)
difluorophenyl)ethyl)amino)-		m/z
5-fluoropyrimidin-4-yl)-4-		383.1328,
((R)-1-		(M + H)+,
hydroxyethyl)oxazolidin-2-		RT = 1.81 min.
one
333: (R)-3-(5-chloro-2-	1H NMR (400 MHz, <cd3od>)	LCMS
(((S)-1-(5-(2-	1.26-1.39 (m, 3 H) 1.61 (d, J = 7.04 Hz, 3 H)	m/z 509.2,
(trifluoromethyl)pyridin-4-	4.74-4.79 (m, 3 H) 4.96 (br. s., 1 H) 5.13 (d,	(M + H)+,
yl)pyrimidin-2-	J = 7.04 Hz, 1 H) 7.69 (d, J = 7.83 Hz, 1 H)	RT = 0.69 min.
yl)ethyl)amino)pyrimidin-4-	7.99 (d, J = 4.30 Hz, 1 H) 8.17 (s, 1 H)
yl)-4-((R)-1-	8.29 (d, J = 8.22 Hz, 1 H) 8.80 (d, J = 5.09 Hz, 1
hydroxyethyl)oxazolidin-2-	H) 8.96 (s, 1 H)
one

Example 334

(R)-3-(5-fluoro-2-(((S)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

To (R)-3-(2-(((S)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (20 mg, 0.042 mmol) in MeOH (10 mL) was added Pd(OH)₂ (10 mg, 0.014 mmol). The reaction was purged with N₂ and H₂ three times each. A hydrogen balloon was applied to the reaction. The reaction mixture was stirred for one hour and concentrated. The residue was applied directly to HPLC separation to give product (15 mg). 1HNMR (CD3OD) δ ppm 8.21 (d, J=3.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12-7.28 (m, 2H), 4.88-5.00 (m, 1H), 4.59 (br. s., 1H),4.42-4.55 (m, 2H), 3.89 (br. s., 1H), 1.49 (d, J=7.0 Hz, 3H), 0.81 (br. s., 3H). HRMS (B) m/z 446.1448 (M+H)⁺, RT=1.90 min.

Example 335

(R)-3-(2-((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A mixture of (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-5-fluoropyrimidin-4-yl)oxazolidin-2-one (40 mg, 0.126 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine (36.9 mg, 0.164 mmol) and Huenig's base (0.11 mL, 0.629 mmol) in DMSO (0.25 mL) under argon atmosphere was heated at ˜120° C. for ˜16 hr in a sealed vial. The mixture was allowed to cool to room temperature and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine and dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was dissolved in DCM (0.8 mL) and cooled to 0° C. To the mixture was added trifluoroacetic acid (0.3 mL), the ice-bath was removed and the mixture was stirred for ˜1 hr at room temperature. The mixture was diluted with methanol (2 mL) and concentrated under reduced pressure. The residue was dissolved in DMSO/water (˜9/1), filtered through a syringe filter, and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (R)-3-(2-((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one as its trifluoroacetic acid salt (19 mg) as a white solid.

¹H NMR (400 Mhz, CD₃OD) δ ppm 9.77 (d, J=2.7 Hz, 1H), 9.06 (t, J=7.8 Hz, 1H), 8.80-8.87 (m, 2H), 8.12-8.44 (m, 1H), 6.82 (q, J=6.7 Hz, 1H), 6.12-6.21 (m, 1H), 5.99-6.11 (m, 2H), 5.30-5.52 (m, 1H), 3.09 (d, J=7.0 Hz, 3H), 2.14-2.51 (m, 3H). HRMS m/z 415.1390 (M+H)+; Rt-1.84 min.

The following Example was prepared using a method similar to that described for the preparation of Example 335

Example 336

(R)-3-(2-(((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

¹H NMR (400 Mhz, CCl₃D) δ ppm 8.19 (d, J=2.7 Hz, 1H), 7.33-7.44 (m, 1H), 7.18-7.30 (m, 2H), 5.49 (m, J=5.9 Hz, 1H), 5.19 (m, J=6.7, 6.7 Hz, 1H), 4.41-4.52 (m, 2H), 4.34 (m, J=7.2, 3.7 Hz, 1H), 1.90 (t, J=18.2 Hz, 3H), 1.51-1.60 (m, 3H), 0.80-1.00 (m, 3H). HRMS m/z 429.1553 (M+H)+; Rt-1.98 min.

Example 337

(R)-3-(6-chloro-2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A mixture of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (55 mg, 0.165 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (35 mg, 0.155 mmol) and Huenig's base (0.072 mL, 0.411 mmol) in DMSO (0.6 mL) under argon atmosphere was heated at ˜85° C. for ˜3 hr in a sealed vial. The mixture was allowed to cool to room temperature and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine and dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was dissolved in DCM (0.8 mL) and cooled to 0° C. To the mixture was added trifluoroacetic acid (0.4 mL), the ice-bath was removed and the mixture was stirred for ˜1 hr at room temperature. The mixture was diluted with methanol (2 mL) and concentrated under reduced pressure. The residue was dissolved in DMSO/water (˜9/1), filtered through a syringe filter, and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (R)-3-(6-chloro-2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one as its trifluoroacetic acid salt (8.2 mg) as a white solid.

¹H NMR (400 Mhz, CD₃OD) δ ppm 7.50 (m, J=7.60, 7.6 Hz, 1H), 7.25-7.38 (m, 3H), 6.76 (t, J=1.0 Hz, 1H), 5.31-5.43 (m, 1H), 4.72-4.81 (m, 1H), 4.52 (m, J=7.0 Hz, 1H), 4.34-4.44 (m, 1H), 1.55 (d, J=7.0 Hz, 3H), 0.54-0.75 (m, CH₃). HRMS m/z 431.1097 (M+H)⁺; Rt-2.21 min.

The following Example was prepared using a method similar to that described for the preparation of Example 337

Example 338

(R)-3-(6-chloro-2-(((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

¹H NMR (400 Mhz, CD₃OD) δ ppm 7.45 (m, J=7.6, 7.6 Hz, 1H), 7.21-7.36 (m, 3H), 5.34 (m, J=7.0 Hz, 1H), 4.71-4.79 (m, 1H), 4.45-4.55 (m, 1H), 4.32-4.41 (m, 1H), 1.89 (t, J=18.2 Hz, 3H), 1.52 (d, J=7.0 Hz, 3H), 0.55-0.71 (m, CH₃). HRMS m/z 445.1257 (M+H)⁺; Rt-2.32 min.

Example 339

(R)-3-(6-chloro-2-(((S)-1-(5-phenylthiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A solution of (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (0.040 g, 0.144 mmol), (S)-1-(5-(pyridin-2-yl)thiophen-2-yl)ethanamine hydrochloride (0.083 g, 0.346 mmol, 2.4 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.075 mL, 0.432 mmol, 3.0 equiv) in DMSO (0.72 mL) was heated at 100° C. for 1 h. Purification by reverse phase HPLC separated the regioisomeric products and provided the trifluoroacetate salt of (R)-3-(6-chloro-2-(((S)-1-(5-phenylthiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (7.0 mg, white solid) in 8% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.56-7.52 (m, 2H), 7.40-7.34 (m, 2H), 7.29 (d, J=7.4 Hz, 1H), 7.15 (d, J=3.6 hz, 1H), 6.93 (br s, 1H), 5.21 (m, 1H), 4.78-4.68 (m, 1H), 4.50-4.31 (m, 2H), 3.85 (m, 1H), 1.69 (d, J=6.9 Hz, 3H), 0.93 (br s, 3H); HRMS m/z 445.1109 (M+H)⁺; Rt-2.49 min.

The following Example was prepared using a method similar to that described for the preparation of Example 339

Example 340

(R)-3-(6-chloro-2-(((S)-1-(5-(pyridin-2-yl)thiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ ppm 8.84 (d, J=5.0 Hz, 1H), 8.05 (t, J=7.8 Hz, 1H), 7.77-7.70 (m, 2H), 7.60 (s, 1H), 7.47 (t, J=6.5 Hz, 1H), 7.13 (d, J=3.9 Hz, 1H), 5.19 (m, 1H), 4.87 (m, 1H), 4.62 (m, 1H), 4.37 (t, J=9.0 Hz, 1H), 3.61 (m, 1H), 1.70 (d, J=7.0 Hz, 3H), 0.89 (br s, 3H). HRMS m/z 446.1054 (M+H)⁺; Rt-2.04

Example 341

1:1 TFA:DCM

A solution of (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (56.5 mg, 0.12 mmol) in DCM (0.6 ml) was treated with TFA (0.6 ml) at room temperature. The resulting solution was let sit for 2 hours, then concentrated. The crude material was purified by reverse phase HPLC. Product fractions were combined and lyophilized to afford (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (15.2 mg, 0.036 mmol, 30% yield) as a TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ 0.65 (br. s., 3H) 1.41 (d, J=6.99 Hz, 3H) 1.84-1.94 (m, 1H) 2.10-2.22 (m, 1H) 3.67-3.89 (m, 4H) 4.33-4.47 (m, 2H) 4.70-4.77 (m, 1H) 4.96 (dd, J=6.06, 4.60 Hz, 1H) 5.01-5.11 (m, 1H) 6.73 (dd, J=8.07, 2.05 Hz, 1H) 6.89-6.97 (m, 2H) 7.19 (t, J=7.85 Hz, 1H) 7.24 (d, J=6.06 Hz, 1H) 8.14 (br. s., 1H). LCMS m/z 415.3 (M+H)⁺, Rt 0.55 min. HRMS (A) m/z 415.1981 (M+H)⁺, Rt 1.33 min.

The compounds in Table 31a were prepared using methods similar to those described for the preparation of Example 341.

TABLE 31a
342
343
344
345
346
347
348
349
350
351
352
353
354
355

TABLE 31b
Chemical name, NMR chemical shifts and LCMS signal for each compound listed
in Table 31a.
Example: Name	1H NMR (400 MHz) d ppm	LCMS
342: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-	(DMSO-d6) δ 0.93 (s, 3 H)	HRMS m/z
isobutoxyphenyl)ethylamino)pyrimidin-4-	0.95 (s, 3 H) 1.41 (d, J = 6.99 Hz,	401.2189
yl)oxazolidin-2-one	3 H) 1.96 (dquin, J = 13.30,	(M + H)+;
	6.64, 6.64, 6.64, 6.64 Hz, 1 H)	Rt-1.86 min
	3.55-3.89 (m, 4 H)
	4.34-4.41 (m, 1 H) 4.42-4.48 (m, 1 H)
	4.71-4.78 (m, 1 H) 5.06 (br.
	s., 1 H) 6.73 (dd, J = 8.14,
	1.93 Hz, 1 H) 6.87-6.99 (m, 2 H)
	7.17 (t, J = 7.87 Hz, 1 H)
	7.23 (d, J = 6.02 Hz, 1 H) 8.13 (br.
	s., 1 H)
343: (R)-3-(6-chloro-2-(((S)-1-(4-	(DMSO-d6) δ 0.55 (d, J = 6.31 Hz,	HRMS m/z
(isobutylsulfonyl)phenyl)ethyl)amino)pyrimidin-	3 H) 0.94 (dd, J = 6.70, 1.91 Hz,	483.1472
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	6 H) 1.43 (d, J = 6.85 Hz, 3	(M + H)+;
	H) 1.97 (dt, J = 13.11, 6.70 Hz,	Rt-2.10 min
	1 H) 3.14 (d, J = 6.36 Hz, 2 H)
	4.31-4.49 (m, 3 H) 4.71 (br.
	s., 1 H) 5.09 (t, J = 7.19 Hz, 1
	H) 7.17 (s, 1 H) 7.61 (d,
	J = 8.22 Hz, 2 H) 7.83 (d,
	J = 8.31 Hz, 2 H) 8.49 (d,
	J = 7.78 Hz, 1 H)
344: (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-	(DMSO-d6) δ 0.59 (br. s., 3 H)	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-	1.44 (d, J = 6.99 Hz, 3 H)	413.1435
4-yl)oxazolidin-2-one	3.83 (br. s., 1 H) 4.34-4.41 (m, 1	(M + H)+;
	H) 4.41-4.47 (m, 1 H)	Rt-1.72 min
	4.70-4.76 (m, 2 H) 5.09 (quin,
	J = 7.24 Hz, 1 H) 7.24 (d,
	J = 6.02 Hz, 1 H) 7.28 (d,
	J = 7.97 Hz, 2 H) 7.49 (d,
	J = 8.61 Hz, 2 H) 8.16 (br. s., 1
	H) 8.24 (br. s., 1 H)
345: (R)-3-(2-(((S)-1-(3-fluoro-4-	(DMSO-d6) δ 0.57 (br. s., 3 H)	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-	1.43 (d, J = 7.04 Hz, 3 H)	431.1345
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.31-4.47 (m, 3 H) 4.71 (br. s., 1 H)	(M + H)+;
	5.08 (t, J = 7.16 Hz, 1 H)	Rt-1.83 min
	7.23 (d, J = 5.87 Hz, 1 H) 7.29 (d,
	J = 8.66 Hz, 1 H)
	7.42-7.52 (m, 2 H) 8.09 (br. s., 1 H)
	8.16 (br. s., 1 H)
346: (R)-3-(2-(((S)-1-(2-fluoro-4-	(DMSO-d6) δ 0.37-0.66 (m, 3	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-	H) 1.43 (d, J = 7.04 Hz, 3 H)	431.1341
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.32-4.46 (m, 2 H) 4.71 (br.	(M + H)+;
	s., 1 H) 5.26 (br. s., 1 H)	Rt-1.85 min
	7.18 (d, J = 8.51 Hz, 1 H) 7.22 (d,
	J = 5.82 Hz, 1 H) 7.29 (d,
	J = 10.86 Hz, 1 H) 7.49 (t,
	J = 8.49 Hz, 1 H) 8.03 (br. s., 1
	H) 8.16 (br. s., 1 H)
347: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-3-	(DMSO-d6) δ 0.64 (br. s., 3 H)	HRMS m/z
fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-	1.42 (d, J = 6.99 Hz, 3 H)	413.1436
1-hydroxyethyl)oxazolidin-2-one	4.34-4.47 (m, 3 H) 4.67-4.78 (m, 1	(M + H)+;
	H) 5.06 (quin, J = 7.27 Hz, 1 H)	Rt-1.60 min
	6.93-7.18 (m, 1 H)
	7.19-7.32 (m, 3 H) 7.38 (d, J = 11.84 Hz,
	1 H) 8.03-8.11 (m, 1 H)
	8.15 (br. s., 1 H)
348: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-3-	(DMSO-d6) δ 0.60 (br. s., 3 H)	HRMS m/z
fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-	1.41 (d, J = 7.04 Hz, 3 H)	431.1333
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.35-4.43 (m, 1 H) 4.45-4.57 (m, 2	(M + H)+;
	H) 4.89 (br. s., 1 H)	Rt-1.89 min
	6.91-7.17 (m, 1 H) 7.17-7.31 (m, 2 H)
	7.31-7.41 (m, 1 H)
	7.82-8.03 (m, 1 H) 8.34 (br. s., 1 H)
349: (R)-3-(2-(((S)-1-(4-	(DMSO-d6) δ 0.61 (br. s., 3 H)	HRMS m/z
(difluoromethoxy)phenyl)ethyl)amino)pyrimidin-	1.37 (d, J = 7.04 Hz, 3 H)	395.1523
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.29-4.42 (m, 3 H) 4.65-4.73 (m, 1	(M + H)+;
	H) 5.01 (quin, J = 7.20 Hz, 1 H)	Rt-1.49 min
	7.04 (d, J = 8.51 Hz, 2 H)
	7.09 (s, 1 H) 7.17 (d, J = 5.92 Hz, 1
	H) 7.37 (d, J = 8.51 Hz, 2 H)
	8.08 (br. s., 1 H)
350: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-2-	(DMSO-d6) δ 0.61 (br. s., 3 H)	HRMS m/z
fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-	0.93 (br. s., 1 H) 1.44 (d,	413.1431
1-hydroxyethyl)oxazolidin-2-one	J = 6.94 Hz, 3 H) 3.76 (br. s., 1	(M + H)+;
	H) 4.34-4.47 (m, 2 H) 4.73 (d,	Rt-1.60 min
	J = 3.57 Hz, 1 H) 5.26 (quin,
	J = 6.90 Hz, 1 H) 6.98 (dd,
	J = 8.46, 2.20 Hz, 1 H) 7.06 (dd,
	J = 11.20, 2.30 Hz, 1 H) 7.26 (d,
	J = 5.77 Hz, 1 H) 7.43 (t, J = 8.66 Hz,
	1 H) 8.17 (br. s., 1 H)
351: (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-	(DMSO-d6) δ 0.60 (br. s., 3 H)	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-	1.44 (d, J = 7.04 Hz, 3 H)	413.1432
4-yl)oxazolidin-2-one	3.87 (br. s., 1 H) 4.34-4.47 (m, 2	(M + H)+;
	H) 4.71-4.76 (m, 2 H)	Rt-1.73 min
	5.14 (quin, J = 7.23 Hz, 1 H)
	7.13-7.21 (m, 1 H) 7.25 (d, J = 5.97 Hz,
	1 H) 7.34 (s, 1 H)
	7.38-7.46 (m, 2 H) 8.16 (br. s., 1 H)
352: (R)-3-(2-(((S)-1-(3-	(DMSO-d6) δ 0.63 (br. s., 3 H)	HRMS m/z
(difluoromethoxy)phenyl)ethyl)amino)pyrimidin-	1.43 (d, J = 7.04 Hz, 3 H)	395.1534
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	3.85 (br. s., 4 H) 4.35-4.47 (m, 2	(M + H)+;
	H) 4.71-4.76 (m, 1 H)	Rt-1.52 min
	5.09 (quin, J = 7.30 Hz, 1 H)
	6.96-7.02 (m, 1 H) 7.17 (d, J = 7.48 Hz,
	1 H) 7.21-7.27 (m, 2 H)
	7.31-7.37 (m, 1 H) 8.15 (br.
	s., 1 H)
353: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-2-	(DMSO-d6) δ 0.33-1.02 (m, 3	HRMS m/z
fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-	H) 1.40 (d, J = 6.99 Hz, 3 H)	431.1334
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.32-4.55 (m, 3 H) 5.13 (br.	(M + H)+;
	s., 1 H) 6.96 (dd, J = 8.53, 2.37 Hz,	Rt-1.92 min
	1 H) 7.04 (dd, J = 11.10,
	2.40 Hz, 1 H) 7.17-7.38 (m, 1
	H) 7.41 (t, J = 8.58 Hz, 1 H)
	7.97 (br. s., 1 H) 8.34 (br. s., 1
	H)
354: (R)-3-(5-fluoro-2-(((S)-1-(3-	(DMSO-d6) δ 0.15-0.91 (m, 3	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-	H) 1.41 (d, J = 7.04 Hz, 3 H)	431.1337
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.27-4.56 (m, 3 H) 4.94 (br.	(M + H)+;
	s., 2 H) 7.15 (d, J = 7.34 Hz, 1	Rt-2.04 min
	H) 7.30 (s, 1 H) 7.34-7.45 (m,
	2 H) 7.97 (br. s., 1 H) 8.33 (br.
	s., 1 H)
355: (R)-3-(2-(((S)-1-(3-	(DMSO-d6) δ 0.58 (br. s., 3 H)	HRMS m/z
(difluoromethoxy)phenyl)ethyl)amino)-5-	1.41 (d, J = 7.04 Hz, 3 H)	413.1435
fluoropyrimidin-4-yl)-4-((R)-1-	3.89 (br. s., 2 H) 4.33-4.57 (m, 3	(M + H)+;
hydroxyethyl)oxazolidin-2-one	H) 4.90 (br. s., 1 H)	Rt-1.83 min
	6.93-7.00 (m, 1 H) 7.11-7.18 (m, 1 H)
	7.21 (d, J = 7.78 Hz, 1 H)
	7.32 (t, J = 8.00 Hz, 1 H) 7.93 (br. s.,
	1 H) 8.32 (br. s., 1 H)

Example 356

1:3 TFA:DCM

A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (70.1 mg, 0.147 mmol) in DCM (1.1 ml) was treated with TFA (368 ul) at room temperature. The resulting solution was let sit for 30 min, then concentrated. The crude material was purified by reverse phase HPLC. Product fractions were combined and lyophilized to afford (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (41.3 mg, 0.097 mmol, 66% yield) as a TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ 0.64 (br. s., 3H) 1.42 (d, J=6.90 Hz, 3H) 3.70 (br. s., 1H) 4.32-4.48 (m, 3H) 4.67-4.75 (m, 1H) 5.08 (br. s., 1H) 6.78 (d, J=7.87 Hz, 1H) 6.91 (d, J=7.87 Hz, 2H) 7.00-7.18 (m, 3H) 7.22-7.37 (m, 4H) 8.14 (br. s., 1H). LCMS m/z 421.3 (M+H)⁺, Rt 0.72 min. HRMS (A) m/z 421.1873 (M+H)⁺, Rt 1.84 min.

The compounds in Table 32a were prepared using methods similar to those described for the preparation of Example 356

TABLE 32a
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372

TABLE 32b
Chemical name, NMR chemical shifts and LCMS signal for each compound listed
in Table 32a.
Example: Name	1H NMR (400 MHz) δ ppm	LCMS
357: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(4-	(DMSO-d6) δ 0.69 (br. s., 3	HRMS m/z
isopropoxyphenyl)ethylamino)pyrimidin-4-	H) 1.20 (d, J = 6.02 Hz, 6 H)	387.2032
yl)oxazolidin-2-one	1.39 (d, J = 6.90 Hz, 3 H)	(M + H)+;
	4.33-4.46 (m, 2 H)	Rt-1.54 min
	4.51 (dt, J = 11.93, 5.87 Hz, 1 H)
	4.74 (br. s., 1 H)
	4.94-5.05 (m, 1 H) 6.80 (d,
	J = 8.41 Hz, 2 H)
	7.17-7.29 (m, 3 H) 8.12 (d, J = 5.67 Hz,
	1 H)
358: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(4-	The NMR not taken (not	HRMS m/z
isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4-	enough material made).	415.2340
yl)oxazolidin-2-one		(M + H)+;
		Rt-1.98 min
359: (R)-3-(6-chloro-2-(((S)-1-(4-	(DMSO-d6) δ 0.56 (d,	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	J = 6.11 Hz, 3 H)	477.1054
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	0.78-1.00 (m, 1 H) 1.41 (d, J = 6.85 Hz,	(M + H)+;
	3 H) 3.78 (br. s., 1 H)	Rt-2.39 min
	4.66-4.74 (m, 1 H)
	4.97-5.10 (m, 1 H) 7.16 (s, 1 H)
	7.28 (d, J = 8.22 Hz, 2 H)
	7.47 (d, J = 8.66 Hz, 2 H)
	8.40 (d, J = 7.63 Hz, 1 H)
360: (R)-3-(5-fluoro-2-(((S)-1-(4-	(DMSO-d6) δ 0.49 (br. s., 3	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	H) 1.43 (d, J = 7.04 Hz, 3 H)	431.1345
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	4.39 (dd, J = 8.31, 4.30 Hz,	(M + H)+;
	1 H) 4.46-4.60 (m, 2 H)	Rt-2.05 min
	4.92 (br. s., 2 H)
	7.23-7.31 (m, 2 H) 7.47 (d,
	J = 8.61 Hz, 2 H) 7.98 (br.
	s., 1 H) 8.34 (d, J = 2.20 Hz,
	1 H)
361: (R)-3-(6-chloro-2-(((S)-1-(2-fluoro-4-	(DMSO-d6) δ 0.50 (d,	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	J = 6.02 Hz, 3 H) 0.93 (dd,	465.0958
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	J = 12.30, 6.33 Hz, 1 H)	(M + H)+;
	1.42 (d, J = 6.99 Hz, 3 H)	Rt-2.45 min
	4.25-4.57 (m, 3 H) 4.66 (br. s., 1
	H) 5.14-5.27 (m, 1 H)
	7.13-7.25 (m, 2 H) 7.29 (d,
	J = 10.07 Hz, 1 H)
	7.40-7.59 (m, 1 H)
	8.36-8.49 (m, 1 H)
362: (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-	(DMSO-d6) δ 0.48 (br. s., 3	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	H) 0.91-1.34 (m, 1 H)	449.1243
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	1.45 (d, J = 7.04 Hz, 3 H)	(M + H)+;
	4.34-4.59 (m, 3 H) 5.16 (br. s., 1	Rt-2.09 min
	H) 7.20 (d, J = 8.51 Hz, 1 H)
	7.32 (d, J = 10.51 Hz, 1 H)
	7.52 (t, J = 8.56 Hz, 1 H)
	8.06 (br. s., 1 H) 8.37 (br.
	s., 1 H)
363: (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-	(DMSO-d6) δ	HRMS m/z
isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-	0.40-0.82 (m, 3 H) 0.95 (d, J = 6.65 Hz,	437.2005
1-hydroxyethyl)oxazolidin-2-one	6 H) 1.40 (d, J = 6.99 Hz,	(M + H)+;
	3 H) 1.98 (dquin,	Rt-2.28 min
	J = 13.29, 6.64, 6.64, 6.64,
	6.64 Hz, 1 H) 3.71 (d,
	J = 6.50 Hz, 2 H)
	4.38-4.70 (m, 4 H) 5.12 (br. s., 1 H)
	6.65-6.78 (m, 2 H) 7.29 (t,
	J = 9.00 Hz, 1 H) 7.89 (br.
	s., 1 H) 8.35 (br. s., 1 H)
364: (R)-3-(2-(((S)-1-(4-	(DMSO-d6) δ 0.62 (br. s., 3	HRMS m/z
(difluoromethoxy)phenyl)ethyl)amino)-5-	H) 1.42 (d, J = 6.99 Hz, 3 H)	413.1433
fluoropyrimidin-4-yl)-4-((R)-1-	4.35-4.44 (m, 1 H)	(M + H)+;
hydroxyethyl)oxazolidin-2-one	4.47-4.54 (m, 1 H) 4.56 (br. s., 1	Rt-1.83 min
	H) 4.91 (br. s., 1 H) 7.10 (d,
	J = 8.51 Hz, 2 H)
	6.95-7.35 (m, 1 H) 7.41 (d, J = 8.61 Hz,
	2 H) 7.94 (br. s., 1 H)
	8.34 (d, J = 2.64 Hz, 1 H)
365: (R)-3-(5-fluoro-2-(((S)-1-(3-fluoro-4-	(DMSO-d6) δ	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	0.26-1.06 (m, 3 H) 1.44 (d, J = 6.99 Hz,	449.1244
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	3 H) 4.35-4.61 (m, 2	(M + H)+;
	H) 5.21 (br. s., 3 H)	Rt-2.09 min
	7.25-7.38 (m, 1 H)
	7.42-7.55 (m, 2 H) 8.00 (br. s., 1 H)
	8.37 (br. s., 1 H)
366: (R)-3-(6-chloro-2-(((S)-1-(4-	(DMSO-d6) δ 0.65 (d,	HRMS m/z
(difluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	J = 6.06 Hz, 3 H)	429.1139
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	0.87-1.02 (m, 1 H) 1.42 (d, J = 6.70 Hz,	(M + H)+;
	3 H) 4.36-4.54 (m, 2	Rt-2.20 min
	H) 4.69-4.79 (m, 1 H)
	4.99-5.11 (m, 1 H)
	6.96-7.39 (m, 1 H) 7.12 (d, J = 8.51 Hz,
	2 H) 7.17 (d, J = 7.24 Hz,
	1 H) 7.43 (d, J = 8.51 Hz,
	2 H) 8.39 (d, J = 8.02 Hz,
	1 H)
367: (R)-3-(6-chloro-2-(((S)-1-(3-fluoro-4-	(DMSO-d6) δ 0.57 (d,	HRMS m/z
(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-	J = 6.21 Hz, 3 H) 1.43 (d,	465.0959
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	J = 6.75 Hz, 3 H)	(M + H)+;
	4.31-4.55 (m, 3 H) 4.71 (br. s., 1 H)	Rt-2.43 min
	4.99-5.13 (m, 1 H)
	7.20 (s, 1 H) 7.30 (d, J = 8.56 Hz,
	1 H) 7.40-7.58 (m, 2 H)
	8.41 (d, J = 7.19 Hz, 1 H)
368: (R)-3-(5-fluoro-2-(((S)-1-(4-	(DMSO-d6) δ 0.48 (br. s., 3	HRMS m/z
(isobutylsulfonyl)phenyl)ethyl)amino)pyrimidin-4-	H) 0.96 (dd, J = 6.70, 1.12 Hz,	467.1758
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	6 H) 1.46 (d, J = 7.04 Hz,	(M + H)+;
	3 H) 2.00 (dquin,	Rt-1.78 min
	J = 13.27, 6.60, 6.60, 6.60,
	6.60 Hz, 1 H) 3.15 (d,
	J = 6.46 Hz, 2 H)
	4.34-4.61 (m, 4 H) 4.98 (br. s., 1 H)
	7.62 (d, J = 8.31 Hz, 2 H)
	7.83 (d, J = 8.31 Hz, 2 H)
	8.07 (br. s., 1 H) 8.35 (br.
	s., 1 H)
369: (R)-3-(5-fluoro-2-(((S)-1-(4-	(DMSO-d6) δ 0.45 (br. s., 3	HRMS m/z
(isopropylsulfonyl)phenyl)ethyl)amino)pyrimidin-4-	H) 1.11 (d, J = 6.80 Hz, 6 H)	453.1604
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	1.43 (d, J = 7.04 Hz, 3 H)	(M + H)+;
	3.33 (dt, J = 13.58, 6.78 Hz,	Rt-1.57 min
	1 H) 4.37 (dd, J = 8.05, 4.13 Hz,
	1 H) 4.43-4.58 (m, 2
	H) 4.97 (br. s., 1 H) 7.61 (d,
	J = 8.36 Hz, 2 H) 7.76 (d,
	J = 8.36 Hz, 2 H) 8.06 (br.
	s., 1 H) 8.33 (br. s., 1 H)
370: (R)-3-(6-chloro-2-(((S)-1-(4-	(DMSO-d6) δ 0.53 (d,	HRMS m/z
(isopropylsulfonyl)phenyl)ethyl)amino)pyrimidin-4-	J = 6.21 Hz, 3 H) 1.11 (dd,	469.1314
yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	J = 6.77, 3.74 Hz, 6 H)	(M + H)+;
	1.43 (d, J = 6.75 Hz, 3 H)	Rt-1.92 min
	3.34 (dt, J = 13.17, 6.50 Hz, 1 H)
	3.68 (br. s., 1 H) 4.38 (dd,
	J = 16.43, 7.97 Hz, 2 H)
	4.64-4.76 (m, 1 H)
	4.98-5.17 (m, 1 H) 7.18 (s, 1 H)
	7.62 (d, J = 8.31 Hz, 2 H) 7.78 (d,
	J = 8.27 Hz, 2 H) 8.50 (d,
	J = 7.34 Hz, 1 H)
371: (R)-3-(2-(((S)-1-(4-	(DMSO-d6) δ	HRMS m/z
(cyclopropylmethoxy)phenyl)ethyl)amino)pyrimidin-	0.24-0.35 (m, 2 H) 0.54 (dd, J = 8.09,	399.2034
4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one	1.74 Hz, 2 H) 0.74 (br. s., 3	(M + H)+;
	H) 1.12-1.24 (m, 1 H)	Rt-1.59 min
	1.42 (d, J = 6.99 Hz, 3 H) 3.76 (d,
	J = 6.99 Hz, 2 H)
	4.36-4.50 (m, 3 H) 4.78 (d, J = 2.89 Hz,
	1 H) 4.98-5.10 (m, 1
	H) 6.84 (d, J = 8.61 Hz, 2 H)
	7.18-7.36 (m, 3 H)
	8.15 (d, J = 5.62 Hz, 1 H)
372: (R)-3-(2-(((S)-1-(2-fluoro-4-	(DMSO-d6) δ	HRMS m/z
isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-	0.51-0.82 (m, 3 H) 0.94 (d, J = 6.70 Hz,	419.2102
1-hydroxyethyl)oxazolidin-2-one	6 H) 1.42 (d, J = 6.85 Hz,	(M + H)+;
	3 H) 1.97 (dquin,	Rt-1.95 min
	J = 13.32, 6.70, 6.70, 6.70,
	6.70 Hz, 1 H) 3.70 (d,
	J = 6.55 Hz, 2 H)
	4.35-4.48 (m, 2 H) 4.71-4.79 (m, 1
	H) 5.24 (quin, J = 7.10 Hz, 1
	H) 6.65-6.79 (m, 2 H)
	7.19-7.34 (m, 2 H) 8.15 (br. s.,
	1 H)

Example 373

(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one

To a microwave vial with stir bar was added (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (28 mg, 0.12 mmol) and DMSO (1 mL). To this reaction mixture was added (S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine (48 mg, 0.17 mmol) and DIEA (61 ul, 0.35 mmol). Vial was capped and the reaction mixture was heated in a preheated sand bath at 80° C. for 18 hr. Reaction mixture was purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford a TFA salt of (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (28 mg, 0.04 mmol, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.01 (d, J=6.65 Hz, 3H) 1.82 (d, J=7.04 Hz, 3H) 3.24 (s, 3H) 3.72-3.86 (m, 1H) 4.36-4.47 (m, 1H) 4.60 (dd, J=9.39, 2.35 Hz, 1H) 4.92-5.01 (m, 1H) 5.48 (t, J=7.04 Hz, 1H) 7.43 (d, J=8.61 Hz, 2H) 7.72 (s, 1H) 7.77-7.85 (m, 4H) 8.02 (d, J=7.04 Hz, 1H) 10.95 (d, J=6.65 Hz, 1H).). LCMS m/z 460.2 (M+H)⁺, Rt 0.82 min. HRMS (B) m/z 460.1213 (M+H)⁺, Rt 2.28 min.

The compounds in Table 33a were prepared using methods similar to those described for the preparation of Example 373.

TABLE 33a
374
375
376
377
378
379

TABLE 33b
Chemical name, NMR chemical shifts and LCMS signal for each compound listed
in Table 33a.
Example: Name	1H NMR (400 MHz, CDCl3) δ ppm	HRMS
374: (R)-3-(6-chloro-2-	0.89 (br. s., 3 H) 1.56 (br. s., 3 H) 3.20 (br.	HRMS (B)
(((S)-1-(2,5-difluoro-4-(1-	s., 3 H) 3.96 (s, 3 H) 4.28-4.37 (m, 1 H)	m/z
methyl-1H-pyrazol-4-	4.50 (dd, J = 9.39, 2.89 Hz, 1 H) 4.88 (ddd,	493.1567
yl)phenyl)ethyl)	J = 8.50, 4.32, 2.98 Hz, 1 H) 5.30 (quin,	(M + H)+;
amino)pyrimidin-4-yl)-4-	J = 6.97 Hz, 1 H) 5.50 (br. s., 1 H) 7.07 (dd,	Rt-2.35 min
((R)-1-methoxyethyl)	J = 10.91, 6.36 Hz, 1 H) 7.21 (dd, J = 10.88,
oxazolidin-2-one	6.04 Hz, 1 H) 7.55 (s, 1 H) 7.76 (d, J = 2.45 Hz,
	1 H) 7.79 (s, 1 H)
375: (R)-3-(6-chloro-2-	0.69-0.95 (m, 3 H) 1.57-1.61 (m, 3 H)	HRMS (B)
(((S)-1-(2-fluoro-4-	3.16 (br. s., 3 H) 4.26-4.37 (m, 1 H)	m/z
(trifluoromethyl)	4.49 (dd, J = 9.39, 2.74 Hz, 1 H) 4.78-4.90 (m, 1	463.1170
phenyl)ethyl)amino)pyrimidin-	H) 5.37 (quin, J = 6.93 Hz, 1 H) 5.51 (br. s.,	(M + H)+;
4-yl)-4-((R)-1-	1 H) 7.33 (d, J = 9.44 Hz, 1 H)	Rt-2.74 min
methoxyethyl)oxazolidin-	7.38-7.43 (m, 1 H) 7.44-7.51 (m, 1 H) 7.56 (s, 1 H)
2-one
376: (R)-3-(6-chloro-2-	1.01 (d, J = 4.21 Hz, 3 H) 1.72-1.77 (m, 3	HRMS (B)
(((S)-1-(2-(4-	H) 3.21 (br. s., 3 H) 4.31-4.42 (m, 1 H)	m/z
chlorophenyl)thiazol-5-	4.53 (dd, J = 9.46, 2.76 Hz, 1 H) 4.89 (ddd,	494.0823
yl)ethyl)amino)pyrimidin-4-	J = 8.36, 4.21, 2.79 Hz, 1 H) 5.46 (br. s., 1	(M + H)+;
yl)-4-((R)-1-	H) 7.42-7.48 (m, 2 H) 7.65 (s, 1 H)	Rt-2.80 min
methoxyethyl)oxazolidin-	7.80 (d, J = 8.56 Hz, 3 H)
2-one
377: (R)-3-(2-(((S)-1-(5-	1.00 (d, J = 6.26 Hz, 3 H) 1.74 (d, J = 7.04 Hz,	HRMS (B)
(4-chlorophenyl) isoxazol-	3 H) 3.46 (s, 3 H) 4.03-4.19 (m, 1 H)	m/z
3-yl)ethyl)amino)	4.43 (t, J = 8.80 Hz, 1 H) 4.65 (dd, J = 9.59,	444.1433
pyrimidin-4-yl)-4-((R)-1-	2.54 Hz, 1 H) 5.03 (ddd, J = 7.92, 4.60, 2.74 Hz,	(M + H)+;
methoxyethyl)oxazolidin-	1 H) 5.44 (quin, J = 7.14 Hz, 1 H)	Rt-2.21 min
2-one	6.69 (s, 1 H) 7.45 (d, J = 8.61 Hz, 2 H) 7.71 (d,
	J = 8.61 Hz, 2 H) 7.80 (d, J = 7.04 Hz, 1 H)
	7.94 (d, J = 7.04 Hz, 1 H) 10.98 (d, J = 7.43 Hz,
	1 H)
378: (R)-3-(2-(((S)-1-(1-	1.04 (d, J = 5.87 Hz, 3 H) 1.75 (d, J = 6.26 Hz,	HRMS (B)
(4-chlorophenyl)-1H-	3 H) 3.31 (s, 3 H) 3.95 (br. s., 1 H)	m/z
imidazol-4-yl)ethyl)	4.46 (t, J = 8.61 Hz, 1 H) 4.60 (dd, J = 9.39,	443.1598
amino)pyrimidin-4-yl)-4-	2.35 Hz, 1 H) 5.07 (d, J = 3.13 Hz, 1 H)	(M + H)+;
((R)-1-methoxyethyl)	5.57 (br. s., 1 H) 7.44 (d, J = 8.61 Hz, 2 H)	Rt-1.57 min
oxazolidin-2-one	7.57 (d, J = 8.22 Hz, 2 H) 7.61 (br. s., 1 H)
	7.85 (d, J = 7.04 Hz, 1 H) 7.96 (d, J = 6.65 Hz, 1
	H) 8.53 (br. s., 1 H) 10.90 (d, J = 6.65 Hz, 1
	H)
379: (R)-3-(2-(((S)-1-(2,5-	0.97 (d, J = 6.65 Hz, 3 H) 1.67 (d, J = 7.04 Hz,	HRMS (B)
difluoro-4-(6-	3 H) 2.88 (s, 3 H) 3.30 (s, 3 H)	m/z
methylpyridin-3-	3.67-3.89 (m, 1 H) 4.37-4.49 (m, 1 H) 4.61 (dd,	470.2007
yl)phenyl)ethyl)amino)pyrimidin-	J = 9.39, 2.35 Hz, 1 H) 4.94-5.07 (m, 1 H)	(M + H)+;
4-yl)-4-((R)-1-	5.62 (quin, J = 6.95 Hz, 1 H) 7.22-7.26 (m,	Rt-1.53 min
methoxyethyl)oxazolidin-	1 H) 7.48 (dd, J = 10.37, 6.06 Hz, 1 H)
2-one	7.66 (d, J = 8.22 Hz, 1 H) 7.82 (d, J = 7.04 Hz, 1
	H) 7.97 (d, J = 7.04 Hz, 1 H) 8.34 (d, J = 8.22 Hz,
	1 H) 9.00 (s, 1 H) 11.04 (d, J = 7.83 Hz,
	1 H)

Example 380

(S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Step 1

To a microwave vial with stir bar was added (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (147 mg, 0.49 mmol) and DMSO (4 mL). To this reaction mixture was added (S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine HCl (148 mg, 0.54 mmol) and DIEA (0.26 mL, 1.47 mmol). Vial capped and the reaction mixture was heated in a preheated sand bath at 110° C. for 42 hr. The reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol, 33% yield). ¹H NMR (400 MHz, CDCl₃) δ 0.82 (br. s., 9H) 0.90-0.98 (m, 3H) 1.71 (d, J=6.90 Hz, 3H) 4.13 (q, J=7.16 Hz, 1H) 4.21-4.32 (m, 1H) 4.42-4.51 (m, 1H) 4.56 (dd, J=8.31, 2.79 Hz, 1H) 5.39 (br. s., 1H) 7.34-7.45 (m, 2H) 7.57 (d, J=5.77 Hz, 1H) 7.64 (s, 1H) 7.76-7.86 (m, 2H) 8.22 (d, J=5.82 Hz, 1H). LCMS m/z 502.3 (M+H)⁺, Rt 0.92 min.

Step 2

To a round bottom flask containing a stir bar and (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol) was added DCM (1 mL) followed by the addition of TFA (1 mL). Resulting reaction mixture allowed to stir 30 min at RT. The volatiles were then removed and the residue neutralized by the addition of a saturated solution of NaHCO₃. The aqueous mixture was then extracted with DCM. Organic phases combined, washed with water, brine, dried (Na₂SO₄), filtered and concentrated to a brown foam of (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (61 mg, 0.14 mmol, 84% yield) which was used without further purification. LCMS m/z 446.2 (M+H)⁺, Rt 0.71 min.

Step 3

To a round bottom flask with stir bar was added (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (19 mg, 0.04 mmol) followed by the addition of DCM (1 mL) under nitrogen. Mixture was cooled to 0° C. in a ice/water bath. To this cold solution was added DIEA (0.03 mL, 0.17 mmol) followed by the addition of methanesulfonyl chloride (10 μL, 0.13 mmol). Reaction mixture stirred for 1 hr at 0° C. The reaction mixture was then quenched with water and diluted with DCM. Phases partitioned and the aqueous phase extracted with DCM. Organic layers combined and washed with brine, dried (Na₂SO₄), filtered and concentrated to afford a orange residue of (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol, 94% yield). LCMS m/z 524.2 (M+H)⁺, Rt 0.75 min.

Step 4

To a microwave vial containing (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol) in DMF (1 mL) was added sodium azide (13 mg, 0.20 mmol). Resulting reaction mixture heated to 50° C. for 1 hr in a sand bath then to 80° C. for 42 hr. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with brine, dried (Na₂SO₄), filtered and concentrated to a yellow residue of (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.030 mmol, 74.2% yield). LCMS m/z 471.2 (M+H)⁺, Rt 0.92 min.

Step 5

To a round bottom flask containing (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.03 mmol) and stir bar was added THF (1 mL) and trimethylphosphine (0.06 mL, 0.06 mmol, 1.0 M in THF). The resulting reaction mixture allowed to stir 2 hr at RT. A second addition of trimethylphosphine (0.06 mL, 0.06 mmol) occurred and the mixture allowed to stir 1.5 hr at RT. Reaction was quenched by the addition of a saturated solution of NH₄Cl and EtOAc. The phases were partitioned and aqueous phase extracted with EtOAc. Organic phases combined and washed with brine, dried (Na₂SO₄), filtered and concentrated to a yellow residue. Residue dissolved in DMSO and purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (2.6 mg, 4.60 μmol, 15% yield) as a TFA salt. ¹H NMR (400 MHz, CD₃CN) δ 1.26-1.44 (m, 3H) 1.68 (d, J=6.65 Hz, 3H) 3.83 (quin, J=6.26 Hz, 1H) 4.43-4.53 (m, 1H) 7.46 (d, J=8.61 Hz, 2H) 7.76 (s, 1H) 7.89 (d, J=8.61 Hz, 2H) 8.20 (br. s., 1H). LCMS m/z 445.2 (M+H)⁺, Rt 0.65 min. HRMS (B) m/z 445.1211 (M+H)⁺, Rt 1.58 min.

The compounds in Table 34a were prepared using methods similar to those described for the preparation of Example 380

TABLE 34a
381
382
383

TABLE 34b
Chemical name, NMR chemical shifts and LCMS
signal for each compound listed in Table 34a.
Example: Name	1H NMR (400 MHz) δ ppm	HRMS
381: (S)-4-((R)-1-	(DMSO) 1.03-1.32 (m, 3 H) 1.55 (d,	HRMS (B)
aminoethyl)-3-(2-(((S)-1-	J = 6.65 Hz, 3 H) 3.86 (br. s., 1 H) 4.51 (d,	m/z
(1-(4-chlorophenyl)-1H-	J = 7.04 Hz, 1 H) 5.23 (br. s., 1 H) 7.28 (d,	428.1598
imidazol-4-yl)ethyl)	J = 5.87 Hz, 1 H) 7.60-7.68 (m, 2 H) 7.73	(M + H)+;
amino)pyrimidin-4-	(d, J = 8.61 Hz, 2 H) 7.83 (br. s., 1 H) 8.25	Rt-1.12
yl)oxazolidin-2-one	(d, J = 5.87 Hz, 1 H)	min
382: (S)-4-((R)-1-	(DMSO) 1.09 (br. s., 3 H) 1.56 (d, J = 7.04	HRMS (B)
aminoethyl)-3-(2-(((S)-1-	Hz, 3 H) 4.45-4.54 (m, 1 H) 5.37 (br. s., 1	m/z
(5-(4-chlorophenyl)	H) 7.00 (s, 1 H) 7.26 (d, J = 5.87 Hz, 1 H)	429.1438
isoxazol-3-yl)ethyl)amino)	7.60 (d, J = 8.61 Hz, 2 H) 7.87 (d, J = 8.61	(M + H)+;
pyrimidin-4-yl)oxazolidin-	Hz, 2 H) 8.07 (br. s., 1 H) 8.24 (d, J = 5.87	Rt-1.49
2-one	Hz, 1 H)	min
383: (S)-4-((R)-1-	(CDCl3) 1.24 (br. s., 1 H) 1.53 (d, J = 5.87	HRMS (B)
aminoethyl)-3-(2-(((S)-1-	Hz, 3 H) 2.64 (br. s., 3 H) 3.31 (br. s., 3 H)	m/z
(2,5-difluoro-4-(6-	4.42 (br. s., 1 H) 7.23-7.26 (m, 3 H) 7.40	455.2005
methylpyridin-3-	(br. s., 1 H) 7.95-8.12 (m, 2 H) 8.67 (br.	(M + H)+;
yl)phenyl)ethyl)amino)pyrimidin-	s., 1 H)	Rt-1.06
4-yl)oxazolidin-2-		min
one

Example 384

(S)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(methylamino)ethyl)oxazolidin-2-one

To a microwave vial containing (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (20 mg, 0.04 mmol) in DMF (1 mL) was added methyl amine (30 mg, 0.38 mmol, 40% wt in H₂O). Resulting reaction mixture allowed to stir at 80° C. for 18 hr whereupon a second addition of methylamine (0.1 mL, 40% wt in H₂O) occurred. The reaction mixture was stirred at 80° C. for 18 hr. The reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined and washed with brine, dried (Na₂SO₄),filtered and concentrated. Residue dissolved in DMSO and purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford a TFA salt of (S)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(methylamino)ethyl)oxazolidin-2-one (3.4 mg, 5.87 μmol, 15% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.47 (d, J=5.87 Hz, 3H) 1.78 (d, J=7.04 Hz, 3H) 2.70 (s, 3H) 4.02 (br. s., 1H) 4.14 (br. s., 2H) 5.33 (br. s., 1H) 5.73 (d, J=6.26 Hz, 1H) 6.23 (d, J=5.48 Hz, 1H) 7.41 (d, J=8.61 Hz, 2H) 7.78 (s, 1H) 7.83 (d, J=8.22 Hz, 2H) 8.05 (d, J=5.48 Hz, 1H). LCMS m/z 459.2 (M+H)⁺, Rt 0.73 min. HRMS (B) m/z 459.1373 (M+H)⁺, Rt 1.68 min.

Example 385

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one

To a microwave vial with stir bar was added (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (20 mg, 0.09 mmol) and DMSO (1 mL). To this reaction mixture was added (S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethanamine (34 mg, 0.13 mmol) and DIEA (46 uL, 0.26 mmol). Vial was then capped and heated in a preheated sand bath at 80° C. for 2 hr. Reaction mixture was then purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford a TFA salt of (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one (4.2 mg, 7.63 μmol, 8.74% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.21 (dd, J=24.26, 6.26 Hz, 3H) 1.74 (d, J=6.65 Hz, 3H) 4.52-4.58 (m, 2H) 4.79-5.06 (m, 1H) 5.29 (br. s., 1H) 5.65 (t, J=6.85 Hz, 1H) 7.41 (d, J=8.61 Hz, 2H) 7.52 (s, 1H) 7.57 (d, J=9.00 Hz, 2H) 7.82 (d, J=6.65 Hz, 1H) 7.98 (d, J=7.04 Hz, 1H) 8.48 (s, 1H) 10.97 (d, J=6.65 Hz, 1H).). LCMS m/z 431.1 (M+H)⁺, Rt 0.61 min. HRMS (B) m/z 431.1392 (M+H)⁺, Rt 1.54 min.

The compounds in Table 35a were prepared using methods similar to those described for the preparation of Example 385.

TABLE 35a
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402

TABLE 35b
Chemical name, NMR chemical shifts and LCMS
signal for each compound listed in Table 35a.
Example: Name	1H NMR (400 MHz, CDCl3) δ ppm	HRMS
386: (R)-3-(2-(((S)-1-(5-	10.84 (d, J = 6.7 Hz, 1 H), 8.02 (d, J = 7.0 Hz,	HRMS (B)
(4-chlorophenyl) isoxazol-	1 H), 7.79 (d, J = 7.0 Hz, 1 H), 7.71 (d,	m/z
3-yl)ethyl)amino)	J = 8.6 Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2 H),	432.1242
pyrimidin-4-yl)-4-((R)-1-	6.63 (s, 1 H), 5.33 (quin, J = 6.9 Hz, 1 H),	(M + H)+;
fluoroethyl)oxazolidin-2-	4.95-5.21 (m, 2 H), 4.58-4.71 (m, 1 H),	Rt-2.18
one	4.43-4.56 (m, 1 H), 1.75 (d, J = 7.0 Hz, 3	min
	H), 1.17 (dd, J = 23.9, 5.9 Hz, 3 H)
387: (R)-3-(2-(((S)-1-(2-	1.18 (dd, J = 24.26, 6.65 Hz, 3 H) 1.82 (d,	HRMS (B)
(4-chlorophenyl) thiazol-5-	J = 7.04 Hz, 3 H) 4.44-4.55 (m, 1 H) 4.57-	m/z
yl)ethyl)amino) pyrimidin-	4.66 (m, 1 H) 4.69-4.94 (m, 1 H) 5.00-	448.1014
4-yl)-4-((R)-1-	5.13 (m, 1 H) 5.40 (quin, J = 6.65 Hz, 1 H)	(M + H)+;
fluoroethyl)oxazolidin-2-	7.43 (d, J = 8.22 Hz, 2 H) 7.75 (s, 1 H) 7.77-	Rt-2.27
one	7.88 (m, 3 H) 8.04 (d, J = 6.65 Hz, 1 H)	min
	11.00 (d, J = 5.48 Hz, 1 H)
388: (R)-3-(2-(((S)-1-(1-	1.36 (dd, J = 23.87, 6.26 Hz, 3 H) 1.71 (d,	HRMS (B)
(4-chlorophenyl)-1H-	J = 6.26 Hz, 3 H) 4.46-4.58 (m, 1 H) 4.59-	m/z
imidazol-4-yl)ethyl)	4.69 (m, 1 H) 4.86-5.12 (m, 2 H) 5.59 (br.	431.1400
amino)pyrimidin-4-yl)-4-	s., 1 H) 7.42 (d, J = 8.61 Hz, 2 H) 7.57 (d,	(M + H)+;
((S)-1-fluoroethyl)	J = 9.00 Hz, 3 H) 7.90 (d, J = 6.65 Hz, 1 H)	Rt-1.55
oxazolidin-2-one	7.99 (d, J = 7.04 Hz, 1 H) 8.41 (br. s., 1 H)	min
	11.02 (d, J = 7.04 Hz, 1 H)
389: (R)-3-(2-(((S)-1-(2-	1.26 (dd, J = 21.91, 6.65 Hz, 3 H) 1.81 (d,	HRMS (B)
(4-chlorophenyl) thiazol-5-	J = 7.04 Hz, 3 H) 4.43-4.55 (m, 1 H) 4.57-	m/z
yl)ethyl)amino) pyrimidin-	4.65 (m, 1 H) 4.65-4.93 (m, 2 H) 5.33	448.1007
4-yl)-4-((S)-1-	(quin, J = 6.65 Hz, 1 H) 7.45 (d, J = 8.22 Hz,	(M + H)+;
fluoroethyl)oxazolidin-2-	2 H) 7.71 (s, 1 H) 7.81 (d, J = 8.61 Hz, 2 H)	Rt-2.22
one	7.91 (d, J = 7.04 Hz, 1 H) 8.08 (d, J = 7.04	min
	Hz, 1 H) 10.94 (d, J = 5.87 Hz, 1 H)
390: (R)-3-(2-(((S)-1-(5-	1.48 (dd, J = 23.48, 6.26 Hz, 3 H) 1.73 (d,	HRMS (B)
(4-chlorophenyl) isoxazol-	J = 7.04 Hz, 3 H) 4.41-4.56 (m, 1 H) 4.67	m/z
3-yl)ethyl)amino)	(dd, J = 9.20, 2.54 Hz, 1 H) 4.74-5.05 (m, 2	432.1233
pyrimidin-4-yl)-4-((S)-1-	H) 5.22 (t, J = 6.65 Hz, 1 H) 6.62 (s, 1 H)	(M + H)+;
fluoroethyl)oxazolidin-2-	7.46 (d, J = 8.22 Hz, 2 H) 7.70 (d, J = 8.22	Rt-2.16
one	Hz, 2 H) 7.86 (d, J = 7.04 Hz, 1 H) 7.99 (d,	min
	J = 7.04 Hz, 1 H) 10.88 (d, J = 6.26 Hz, 1 H)
391: (R)-3-(2-(((S)-1-(3-	1.11 (dd, J = 24.26, 7.04 Hz, 3 H) 1.90 (d,	HRMS (B)
(4-chlorophenyl)-1,2,4-	J = 7.04 Hz, 3 H) 4.40-4.48 (m, 1 H) 4.50-	m/z
oxadiazol-5-	4.57 (m, 1 H) 4.66-4.89 (m, 1 H) 4.93-	433.1190
yl)ethyl)amino)pyrimidin-4-	5.02 (m, 1 H) 5.30-5.41 (m, 1 H) 7.47 (d,	(M + H)+;
yl)-4-((R)-1-fluoroethyl)	J = 8.61 Hz, 2 H) 7.84 (d, J = 7.04 Hz, 1 H)	Rt-2.30
oxazolidin-2-one	8.00 (d, J = 8.61 Hz, 2 H) 8.10 (d, J = 6.65	min
	Hz, 1 H) 11.06 (d, J = 4.30 Hz, 1 H)
392: (R)-4-((R)-1-	1.20 (dd, J = 23.87, 6.26 Hz, 3 H) 1.84 (d,	HRMS (B)
fluoroethyl)-3-(2-(((S)-1-	J = 7.04 Hz, 3 H) 4.46-4.55 (m, 1 H) 4.57-	m/z
(2-(2-(trifluoromethyl)	4.65 (m, 1 H) 4.68-4.93 (m, 1 H) 5.07 (d,	483.1232
pyridin-4-yl)thiazol-5-	J = 5.87 Hz, 1 H) 5.46 (t, J = 6.85 Hz, 1 H)	(M + H)+;
yl)ethyl)amino)pyrimidin-4-	7.80 (d, J = 7.04 Hz, 1 H) 7.86 (s, 1 H) 7.94	Rt-2.06
yl)oxazolidin-2-one	(d, J = 5.09 Hz, 1 H) 8.04 (d, J = 7.04 Hz, 1	min
	H) 8.17 (s, 1 H) 8.83 (d, J = 5.09 Hz, 1 H)
	11.14 (br. s., 1 H)
393: (R)-4-((R)-1-	1.20 (dd, J = 23.87, 6.26 Hz, 3 H) 1.84 (d,	HRMS (B)
fluoroethyl)-3-(2-(((S)-1-	J = 7.04 Hz, 3 H) 4.44-4.56 (m, 1 H) 4.57-	m/z
(2-(6-(trifluoromethyl)	4.65 (m, 1 H) 4.68-4.94 (m, 1 H) 5.07 (d,	483.1233
pyridin-3-yl)thiazol-5-	J = 5.48 Hz, 1 H) 5.45 (t, J = 6.65 Hz, 1 H)	(M + H)+;
yl)ethyl)amino)pyrimidin-4-	7.72-7.88 (m, 3 H) 8.03 (d, J = 7.04 Hz, 1	Rt-2.07
yl)oxazolidin-2-one	H) 8.36 (d, J = 7.83 Hz, 1 H) 9.21 (s, 1 H)	min
	11.12 (br. s., 1 H)
394: (R)-3-(2-(((S)-1-(1-	1.21 (dd, J = 23.48, 6.65 Hz, 3 H) 1.69 (d,	HRMS (B)
(4-chlorophenyl)-1H-	J = 6.65 Hz, 3 H) 4.48-4.56 (m, 1 H) 4.59-	m/z
pyrazol-4-yl)ethyl)amino)	4.64 (m, 1 H) 4.87-5.25 (m, 3 H) 7.43 (d,	431.1407
pyrimidin-4-yl)-4-((R)-1-	J = 8.61 Hz, 2 H) 7.62 (d, J = 8.61 Hz, 2 H)	(M + H)+;
fluoroethyl)oxazolidin-2-	7.67 (s, 1 H) 7.74 (d, J = 6.65 Hz, 1 H) 7.95-	Rt-1.95
one	8.02 (m, 2 H) 10.74 (d, J = 5.48 Hz, 1 H)	min
395: (R)-3-(2-(((S)-1-(2-	1.17 (dd, J = 23.48, 4.70 Hz, 3 H) 1.76 (d,	HRMS (B)
(4-chlorophenyl) thiazol-5-	J = 6.65 Hz, 3 H) 4.39 (dd, J = 9.39, 4.30 Hz,	m/z
yl)ethyl)amino)-5-	1 H) 4.60 (t, J = 9.00 Hz, 1 H) 4.68-4.90	466.0916
fluoropyrimidin-4-yl)-4-	(m, 2 H) 5.32 (d, J = 5.09 Hz, 1 H) 7.44 (d,	(M + H)+;
((R)-1-fluoroethyl)	J = 8.61 Hz, 2 H) 7.79 (d, J = 8.61 Hz, 2 H)	Rt-2.32
oxazolidin-2-one	7.85 (s, 1 H) 8.19 (d, J = 3.13 Hz, 1 H)	min
396: (R)-3-(2-(((S)-1-(1-	1.28 (dd, J = 23.09, 6.65 Hz, 3 H) 1.68 (d,	HRMS (B)
(4-chlorophenyl)-1H-	J = 6.65 Hz, 3 H) 4.44-4.55 (m, 1 H) 4.57-	m/z
pyrazol-4-yl)ethyl)amino)	4.65 (m, 1 H) 4.67-4.78 (m, 1 H) 4.81-	431.1407
pyrimidin-4-yl)-4-((S)-1-	5.04 (m, 1 H) 5.09 (t, J = 6.65 Hz, 1 H) 7.43	(M + H)+;
fluoroethyl)oxazolidin-2-	(d, J = 8.61 Hz, 2 H) 7.56-7.67 (m, 3 H)	Rt-1.88
one	7.84 (d, J = 6.65 Hz, 1 H) 7.93 (s, 1 H) 8.00	min
	(d, J = 7.04 Hz, 1 H) 10.73 (d, J = 5.87 Hz, 1
	H)
397: (R)-3-(2-(((S)-1-(1-	1.24 (dd, J = 23.87, 5.87 Hz, 3 H) 1.68 (d,	HRMS (B)
(4-chlorophenyl)-1H-	J = 6.65 Hz, 3 H) 4.39 (dd, J = 9.39, 3.91 Hz,	m/z
pyrazol-4-yl)ethyl)amino)-	1 H) 4.62 (t, J = 9.00 Hz, 1 H) 4.76-4.99	449.1303
5-fluoropyrimidin-4-yl)-4-	(m, 2 H) 5.14 (q, J = 7.04 Hz, 1 H) 7.43 (d,	(M + H)+;
((R)-1-fluoroethyl)	J = 8.61 Hz, 2 H) 7.57 (d, J = 8.61 Hz, 2 H)	Rt-2.20
oxazolidin-2-one	7.76 (s, 1 H) 7.96 (s, 1 H) 8.15 (d, J = 3.91	min
	Hz, 1H)
398: (R)-3-(2-(((S)-1-(5-	1.15 (dd, J = 24.26, 6.26 Hz, 3 H) 1.72 (d,	HRMS (B)
(4-chlorophenyl) isoxazol-	J = 7.04 Hz, 3 H) 4.42 (dd, J = 9.39, 4.30 Hz,	m/z
3-yl)ethyl)amino)-5-	1 H) 4.62 (t, J = 9.00 Hz, 1 H) 4.73-5.07	450.1145
fluoropyrimidin-4-yl)-4-	(m, 2 H) 5.17-5.23 (m, 1 H) 6.54 (s, 1 H)	(M + H)+;
((R)-1-fluoroethyl)	7.45 (d, J = 8.61 Hz, 2 H) 7.68 (d, J = 8.22	Rt-2.26
oxazolidin-2-one	Hz, 2 H) 8.15 (d, J = 3.52 Hz, 1 H)	min
399: (R)-3-(2-(((S)-1-(1-	1.29 (dd, J = 23.87, 5.09 Hz, 3 H) 1.75 (d,	HRMS (B)
(4-chlorophenyl)-1H-	J = 6.65 Hz, 3 H) 4.38 (d, J = 6.26 Hz, 1 H)	m/z
imidazol-4-yl)ethyl)	4.58 (t, J = 8.80 Hz, 1 H) 4.93 (br. s., 1 H)	449.1313
amino)-5-fluoropyrimidin-	5.32 (br. s., 1 H) 7.42 (d, J = 7.83 Hz, 3 H)	(M + H)+;
4-yl)-4-((R)-1-fluoroethyl)	7.56 (d, J = 7.83 Hz, 2 H) 8.19 (br. s., 1 H)	Rt-1.52
oxazolidin-2-one	8.62 (br. s., 1 H)	min
400: (R)-3-(2-(((S)-1-(1-	1.33-1.53 (m, 3 H) 1.71 (br. s., 3 H) 2.60	HRMS (B)
(4-chlorophenyl)-2-methyl-	(s, 3 H) 4.54 (br. s., 1 H) 4.62 (d, J = 7.04	m/z
1H-imidazol-4-	Hz, 1 H) 4.94-5.20 (m, 1 H) 5.69 (br. s., 1	445.1556
yl)ethyl)amino)pyrimidin-4-	H) 7.30 (d, J = 8.22 Hz, 2 H) 7.59 (d, J = 8.61	(M + H)+;
yl)-4-((S)-1-fluoroethyl)	Hz, 2 H) 7.82-8.02 (m, 1 H)	Rt-1.42
oxazolidin-2-one		min
401: (R)-4-((S)-1-	1.36 (dd, J = 24.26, 5.87 Hz, 3 H) 1.72 (d,	HRMS (B)
fluoroethyl)-3-(2-(((S)-1-	J = 5.87 Hz, 3 H) 4.44-4.58 (m, 1 H) 4.63	m/z
(1-(4-fluorophenyl)-1H-	(dd, J = 9.19, 2.93 Hz, 1 H) 4.87-5.18 (m, 2	415.1695
imidazol-4-yl)ethyl)	H) 5.54 (br. s., 1 H) 7.39-7.58 (m, 3 H)	(M + H)+;
amino)pyrimidin-4-	7.87 (d, J = 6.65 Hz, 1 H) 7.97 (d, J = 5.87	Rt-1.34
yl)oxazolidin-2-one	Hz, 1 H) 8.26 (br. s., 1 H) 10.95 (br. s., 1	min
	H)
402: (R)-3-(2-(((S)-1-(2,5-	1.32 (dd, J = 23.09, 6.26 Hz, 3 H) 1.66 (d,	HRMS (B)
difluoro-4-(4-methyl-1H-	J = 7.04 Hz, 3 H) 2.45 (s, 3 H) 4.45-4.56	m/z
imidazol-1-	(m, 1 H) 4.63 (dd, J = 9.00, 2.74 Hz, 1 H)	447.1761
yl)phenyl)ethyl)amino)pyrimidin-	4.70-4.97 (m, 2 H) 5.48 (quin, J = 6.95 Hz,	(M + H)+;
4-yl)-4-((S)-1-	1 H) 7.11 (s, 1 H) 7.56 (dd, J = 10.17, 6.65	Rt-1.20
fluoroethyl)oxazolidin-2-	Hz, 1 H) 7.86 (d, J = 7.04 Hz, 1 H) 8.00 (d,	min
one	J = 7.04 Hz, 1 H) 8.59 (s, 1 H) 11.07 (br. s.,
	1 H)

Example 403

(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (10 mg, 0.044 mmol), (S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethanamine (19 mg, 0.065 mmol, 1.5 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.031 mL, 0.175 mmol, 4 equiv) in DMSO (0.5 mL) was heated at 90° C. for 3 hours. The reaction was then cooled to room temperature. Purification by reverse phase HPLC provided the trifluoroacetate salt of (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, white solid) in 55% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.83 (d, J=7.1 Hz, 1H), 9.06 (d, J=2.3 Hz, 1H), 8.15 (dd, J=8.5, 2.4 Hz, 1H), 7.93-8.04 (m, 2H), 7.81 (dd, J=7.7, 6.3 Hz, 2H), 6.61 (d, J=2.6 Hz, 1H), 5.28 (quin, J=7.1 Hz, 1H), 4.96-5.17 (m, 1H), 4.68-4.81 (m, 1H), 4.62 (dd, J=9.1, 3.2 Hz, 1H), 4.45-4.54 (m, 1H), 1.72 (d, J=7.1 Hz, 3H), 1.14-1.29 (m, 3H); HRMS m/z 466.1625 (M+H)⁺; Rt-1.83 min.

The compounds in Table 36a were prepared using methods similar to those described for the preparation of Example 403.

TABLE 36a
404
405
406

TABLE 36b
Chemical name, NMR chemical shifts and LCMS
signal for each compound listed in Table 36a.
Example: Name	1H NMR (400 MHz, CDCl3) δ ppm	LCMS
404: (R)-3-(2-(((S)-1-(1-(4-	8.22 (d, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.45	LCMS m/z
chlorophenyl)-1H-	(m, 3H), 7.30 (d, J = 8.7 Hz, 2H), 7.11 (s,	417.1 (M +
imidazol-4-	1H), 5.14 (m, 1H), 4.93 (m, 1H), 4.48 (m,	H)+; Rt-0.59
yl)ethyl)amino)pyrimidin-4-	4H), 1.63 (d, J = 6.8 Hz, 3H)	min.
yl)-4-
(fluoromethyl)oxazolidin-
2-one
405: (R)-3-(2-(((S)-1-(5-(4-	8.25 (m, 1H), 7.68 (m, 2H), 7.53 (m, 1H),	LCMS m/z
chlorophenyl)isoxazol-3-	7.44 (m, 2H), 6.48 (s, 1H), 5.47 (m, 1H),	418.2 (M +
yl)ethyl)amino)pyrimidin-4-	4.95 (m, 1H), 4.50 (m, 4H), 1.66 (d, J = 6.8	H)+; Rt-0.82
yl)-4-	Hz, 3H)	min.
(fluoromethyl)oxazolidin-
2-one
406: (R)-3-(2-(((S)-1-(1-(4-	7.96 (m, 1H), 7.82 (m, 1H), 7.60 (d, J = 8.4	LCMS m/z
chlorophenyl)-2-methyl-	Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.22 (s,	445.2 (M +
1H-imidazol-4-	1H), 5.73 (m, 1H), 5.42 (m, 1H), 5.05-	H)+; Rt-0.67
yl)ethyl)amino)pyrimidin-4-	4.90 (m, 1H), 4.54 (m, 2H), 2.60 (s, 3H),	min.
yl)-4-((R)-1-	1.72 (d, J = 6.7 Hz, 3H), 1.34-1.20 (m,
fluoroethyl)oxazolidin-2-	3H)
one

Example 407

(R)-4-((S)-1-hydroxyethyl)-3-(2-MS)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)pipendin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Example 407 was prepared using a method similar to that described for the preparation of Example 28. Product was purified by reverse phase HPLC. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.23 (d, J=4.18 Hz, 1H), 8.19 (d, J=4.88 Hz, 1H), 7.37 (d, J=4.88 Hz, 1H), 6.68 (br, s, 1H), 6.68-6.63 (m, 1H), 5.03 (br, s, 1H), 4.80 (br, s, 1H), 4.50-4.36 (m, 3H), 4.09-3.91 (m, 3H), 2.90-2.79 (m, 2H), 1.99-1.79 (m, 2H), 1.78-1.65 (m, 2H), 1.59 (s, 6H), 1.52-1.32 (m, 2H), 1.23 (d, J=6.97 Hz, 3H), 1.18 (d, J=6.27 Hz, 3H), HRMS (C) tR=3.62 min; MS m/z 523.2649 (M+H)+

Example 408

(R)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

Example 408 was prepared using a method similar to that described for the preparation of Example 28. TFA salt form of product was converted to free base form by using a PL-HCO3 MP SPE cartrage, eluting with MeOH. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.07 (d, J=5.33 Hz, 1H), 7.25 (d, J=4.33 Hz, 1H), 7.19 (d, J=9.48 Hz, 1H), 6.76-6.68 (m, 2H), 4.98 (br, s, 1H), 4.69 (br, s, 1H), 4.39-4.25 (m, 3H), 3.90 (br, s, 1H), 3.65-3.56 (m, 2H), 2.68-2.56 (m, 2H), 1.86-1.15 (m, 6H), 1.12 (d, J=6.52 Hz, 3H), 1.07 (d, J=4.74 Hz, 3H), HRMS (C) tR=4.44 min; MS m/z 530.1782 (M+H)+

Example 409

(S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

A mixture of (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (40 mg, 0.135 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (61.1 mg, 0.271 mmol), Huenig's base (0.095 mL, 0.541 mmol) in DMSO (0.7 mL) under argon atmosphere was heated at 107° C. for ˜16 hr. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one as its trifluoroacetic acid salt (35.4 mg).

¹H NMR (400 Mhz, CD₃OD) δ ppm 8.26 (br. s., 1H), 7.42-7.54 (m, 1H), 7.23-7.33 (m, 2H), 6.55-6.91 (m, 1H), 5.26 (q, J=6.9 Hz, 1H), 4.52 (t, J=9.0 Hz, 1H), 4.36-4.45 (m, 1H), 1.53 (d, J=7.0 Hz, 4H), 0.78 (br. s., 3H). HRMS m/z 449.1412 (M+H)⁺; Rt-2.27 min.

Examples 410 and 411

(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one/(S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (40 mg, 0.153 mmol), (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine/(R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (mixture of diastereomers ˜3/1, 37.7 mg, 0.168 mmol) and Huenig's base (0.059 mL, 0.337 mmol) in DMSO (0.7 mmol) under argon atmosphere was heated/radiated in the microwave at 140° C. for 15 min. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (31.8 mg; first eluted product) and (S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (11.5 mg; second eluted product) as their trifluoroacetic acid salts.

410: First eluted product: ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.22 (s, 1H), 8.03-7.93 (m, 2H), 7.54-7.46 (m, 3H), 5.84 (m, 1H), 5.49 (q, J=7.2 Hz, 1H), 5.13 (dt, J=8.4, 3.1 Hz, 1H), 4.60-4.21 (m, 2H), 2.74 (m, 1H), 1.75 (d, J=7.2 Hz, 3H), 0.90 (br. s, 3H). HRMS m/z 465.1260 (M+H)+; Rt-2.41 min.

411: Second eluted product: ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.19 (dd, J=7.5, 6.0 Hz, 1H), 8.10-7.91 (m, 2H), 7.55-7.50 (m, 2H), 7.47 (d, J=5.8 Hz, 1H), 6.08 (td, J=55.6, 3.5 Hz, 1H), 5.40 (t, J=7.1 Hz, 1H), 4.59-4.42 (m, 1H), 4.39 (s, 1H), 3.03 (s, 1H), 1.72 (d, J=7.2 Hz, 3H), 1.03 (d, J=7.2 Hz, 3H). HRMS m/z 465.1250 (M+H)⁺; Rt-2.42 min.

The following Examples were prepared using a method similar to that described for the preparation of Examples 410/411

Example 412

(S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

¹H NMR (400 Mhz, CD₃OD) δ ppm 8.19 (d, J=6.7 Hz, 1H), 7.70 (d, J=6.7 Hz, 1H), 7.47-7.56 (m, 1H), 7.28-7.40 (m, 2H), 6.60-6.95 (m, 1H), 5.57-5.95 (m, 1H), 5.47 (m, J=5.1 Hz, 1H), 5.12 (dt, J=7.8, 3.13 Hz, 1H), 4.46-4.60 (m, 2H), 1.63 (d, J=7.0 Hz, 3H), 0.77-0.95 (m, 3H). HRMS m/z 431.1506 (M+H)⁺; Rt-2.09 min.

Example 413 and 414

(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one/(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one 30 mg, 0.115 mmol), 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (53.1 mg, 0.230 mmol), Huenig's Base 0.05 mL, 0.287 mmol) in DMSO (0.7 mL) under argon atmosphere was heated at 120° C. for ˜16 hr. Additional amine (2 eq) was added and heating was continued for 3 hrs. More amine (2 eq) was added and heating was continued for 3 hr. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one/(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as their trifluoroacetic acid salts as off-white solids.

413: First eluted product (2.8 mg): ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.98 (s, 2H), 8.16 (s, 1H), 7.59 (dd, J=7.3, 2.3 Hz, 1H), 7.56-7.45 (m, 2H), 7.18 (t, J=9.0 Hz, 1H), 6.40-5.96 (m, 1H), 5.25 (q, J=6.9 Hz, 1H), 4.52 (dd, J=9.4, 2.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 1H), 3.08 (s, 1H), 2.34 (d, J=2.0 Hz, 3H), 1.62 (d, J=7.0 Hz, 3H), 1.05 (d, J=7.2 Hz, 3H). HRMS m/z 473.1916 (M+H)⁺; Rt-2.12 min.

414: Second eluted product (2.9 mg): ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.96 (s, 2H), 8.16 (s, 1H), 7.57 (dd, J=7.5, 2.4 Hz, 1H), 7.53-7.43 (m, 2H), 7.17 (t, J=9.0 Hz, 1H), 5.92 (t, J=56.9 Hz, 1H), 5.30 (q, J=7.0 Hz, 1H), 5.13 (dt, J=6.9, 3.3 Hz, 1H), 4.57-4.40 (m, 2H), 2.53 (s, 1H), 2.34 (d, J=2.0 Hz, 3H), 1.64 (d, J=7.0 Hz, 3H), 0.87 (s, 3H). HRMS m/z 473.1919 (M+H)+; Rt-2.17 min.

The compounds in Table 37a were prepared using methods similar to those described for the preparation of Examples 35, 36, or 37/38.

TABLE 37a
415
416
417
418
419
420
421
422 and 423

TABLE 37b
Chemical name, NMR chemical shifts, chiral separation
conditions and LCMS signal for compounds listed in Table 37a.
                                 Chiral separation conditions, peak identification and
Example: Name                    analytical data
415: (R)-4-((R)-1-hydroxyethyl)- Chiral separation was achieved by chiral SFC column
3-(2-(((S)-1-(3-(1-methyl-1H-    chromatography (Column OD-H 21 × 250 mm 30% MeOH +
indol-6-yl)-1,2,4-oxadiazol-5-   20 mM NH4OH in CO2, flow 80 g/min, 238 nm UV
yl)ethyl)amino)pyrimidin-4-      collection) to give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-
yl)oxazolidin-2-one              (1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
                                 ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(1-methyl-1H-indol-6-
                                 yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
                                 yl)oxazolidin-2-one
                                 415: Peak 2: (11 mg): (CDCl3) δ 8.25 (d, J = 5.7 Hz, 1H),
                                 8.08 (d, J = 1.1 Hz, 1H), 7.80 (dd, J = 8.3, 1.4 Hz, 1H), 7.70
                                 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 3.1
                                 Hz, 1H), 6.54 (dd, J = 3.0, 0.9 Hz, 1H), 5.96 (s, 1H), 5.35 (s,
                                 1H), 4.96-4.81 (m, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H),
                                 4.38 (dd, J = 9.3, 8.4 Hz, 1H), 3.88 (s, 4H), 3.19 (s, 1H),
                                 2.63 (s, 8H), 1.80 (d, J = 6.7 Hz, 1H), 0.96 (d, J = 6.4 Hz,
                                 3H). HRMS(B) m/z 449.1812RT = 2.18 min.
416: (R)-4-((R)-1-hydroxyethyl)- Chiral separation was achieved by chiral SFC column
3-(2-(((S)-1-(3-(3-              chromatography (Column IA-H 21 × 250 mm 15% MeOH in
(trifluoromethoxy)phenyl)-1,2,4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-4-
oxadiazol-5-                     ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-
yl)ethyl)amino)pyrimidin-4-      (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
yl)oxazolidin-2-one              yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
                                 ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-
                                 (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
                                 416: Peak 2 (62 mg): (CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H),
                                 8.02 (dt, J = 7.7, 1.3 Hz, 1H), 7.95 (dt, J = 2.3, 1.3 Hz, 1H),
                                 7.67-7.46 (m, 2H), 7.40 (ddt, J = 8.3, 2.5, 1.1 Hz, 1H),
                                 5.90 (s, 1H), 5.40 (s, 1H), 4.86 (ddd, J = 8.4, 4.7, 2.5 Hz,
                                 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (t, J = 8.9 Hz, 1H),
                                 3.90 (s, 1H), 3.52 (s, 1H), 2.77 (s, 1H), 1.86-1.77 (m, 3H),
                                 1.34-1.19 (m, 1H), 1.03 (s, 3H). HRMS(B) m/z 480.1369.
                                 RT = 2.67 min. Chiral RT = 4.80 min
417: (R)-3-(2-(((S)-1-(3-(1,2-   Chiral separation was achieved by chiral SFC column
dimethyl-1H-indol-4-yl)-1,2,4-   chromatography (Column IA 21 × 250 mm 40% MeOH in
oxadiazol-5-                     CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-  yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(1,2-
                                 dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one.
                                 417: Peak 2 (120 mg): (CDCl3) δ 8.16 (d, J = 6.2 Hz, 1H),
                                 7.89 (dd, J = 7.5, 0.9 Hz, 1H), 7.63 (d, J = 6.2 Hz, 1H), 7.45
                                 (dt, J = 8.1, 1.0 Hz, 1H), 7.34-7.21 (m, 1H), 6.95-6.85
                                 (m, 1H), 5.47-5.19 (m, 1H), 1.91-1.79 (m, 3H), 4.81
                                 (ddd, J = 8.3, 4.3, 2.4 Hz, 1H), 4.52 (dd, J = 9.5, 2.4 Hz,
                                 1H), 4.35 (dd, J = 9.5, 8.3 Hz, 1H), 3.75 (s, 4H), 3.52 (s,
                                 2H), 2.51 (d, J = 1.0 Hz, 3H), 0.86 (d, J = 5.5 Hz, 3H).
                                 HRMS(B) m/z 463.1968. RT = 2.23 min. Chiral RT = 3.35
                                 min
418: (R)-3-(2-(((S)-1-(3-(4-     Chiral separation was achieved by chiral SFC column
chloro-3-                        chromatography (Column AD-H 21 × 250 mm 15% MeOH +
(trifluoromethoxy)phenyl)-1,2,4- 10 mM NH4OH in CO2, flow 75 g/min, 238 nm UV
oxadiazol-5-                     collection) to give (R)-3-(2-(((R)-1-(3-(4-chloro-3-
yl)ethyl)amino)pyrimidin-4-yl)-4- (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-  yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 418: Peak 2 (120 mg): CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H),
                                 8.05 (p, J = 1.4 Hz, 1H), 7.98 (dd, J = 8.4, 1.9 Hz, 1H), 7.70-
                                 7.49 (m, 2H), 5.74 (s, 1H), 5.51-5.35 (m, 1H), 4.85 (ddd,
                                 J = 8.3, 4.8, 2.5 Hz, 1H), 4.54 (dd, J = 9.3, 2.5 Hz, 1H), 4.41
                                 (dd, J = 9.4, 8.3 Hz, 1H), 2.72 (s, 1H), 1.79 (d, J = 7.1 Hz,
                                 3H), 1.63 (d, J = 7.1 Hz, 2H), 1.05 (s, 3H). HRMS(B) m/z
                                 515.1243. Chiral RT = 4.20 min
419: (R)-3-(2-(((S)-1-(3-(4-     Chiral separation was achieved by chiral SFC column
chloro-3-methylphenyl)-1,2,4-    chromatography (Column IA 21 × 250 mm 30% MeOH in
oxadiazol-5-                     CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-  yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 chloro-3-methylphenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 419: Peak 2 (92 mg) (CDCl3) δ 8.20 (d, J = 6.0 Hz, 1H),
                                 7.95 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 8.3, 2.2 Hz, 1H), 7.61
                                 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 5.33 (d, J = 7.1
                                 Hz, 1H), 4.84 (ddd, J = 8.4, 4.7, 2.4 Hz, 1H), 1.89-1.74
                                 (m, 3H), 4.56 (dd, J = 9.4, 2.5 Hz, 1H), 4.41 (dd, J = 9.4, 8.3
                                 Hz, 1H), 3.74 (d, J = 41.0 Hz, 1H), 3.52 (s, 1H), 2.46 (s,
                                 3H), 1.12-0.85 (m, 3H). HRMS(B) m/z 411.1365. Chiral
                                 RT = 2.85 min
420: (R)-3-(2-(((S)-1-(3-(4-     Chiral separation was achieved by chiral SFC column
bromo-3-methoxyphenyl)-1,2,4-    chromatography (Column IA 21 × 250 mm 30% MeOH in
oxadiazol-5-                     CO2, flow 90 g/min, 238 nm UV collection) to give (R)-3-(2-
yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-
((R)-1-hydroxyethyl)oxazolidin-  yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
                                 bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 420: Peak 2 (96 mg) (CDCl3) δ 8.22 (d, J = 6.0 Hz, 1H),
                                 7.67 (d, J = 8.1 Hz, 1H), 7.63-7.52 (m, 3H), 5.37 (s, 1H),
                                 4.84 (ddd, J = 8.3, 4.7, 2.4 Hz, 1H), 1.91-1.72 (m, 3H),
                                 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (t, J = 8.9 Hz, 1H), 4.00
                                 (s, 3H), 3.52 (s, 1H), 1.02 (s, 3H). HRMS(B) m/z 504.0757.
                                 Chiral RT = 3.50 min
421: (R)-3-(2-(((S)-1-(3-(3-(tert- Chiral separation was achieved by chiral SFC column
butyl)phenyl)-1,2,4-oxadiazol-5- chromatography (Column IA-H 21 × 250 mm 15% MeOH in
yl)ethyl)amino)pyrimidin-4-yl)-4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
((R)-1-hydroxyethyl)oxazolidin-  (((R)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-
2-one                            yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-
                                 (tert-butyl)phenyl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 421: Peak 2 (62 mg): (CDCl3) δ 8.25 (d, J = 5.7 Hz, 1H),
                                 8.08 (t, J = 1.8 Hz, 1H), 7.87 (dt, J = 7.6, 1.4 Hz, 1H), 7.66-
                                 7.51 (m, 1H), 7.43 (t, J = 7.8 Hz, 1H), 5.92-5.68 (m, 1H),
                                 5.35 (d, J = 9.3 Hz, 1H), 4.86 (ddd, J = 8.4, 4.4, 2.4 Hz,
                                 1H), 1.74-1.64 (m, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H),
                                 4.39 (dd, J = 9.4, 8.3 Hz, 1H), 3.51 (d, J = 5.3 Hz, 3H), 3.00
                                 (d, J = 4.9 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H),
                                 1.08 (q, J = 5.5 Hz, 1H), 1.00 (s, 3H). HRMS(B) m/z
                                 452.2172. RT = 2.88 min. Chiral RT = 5.20 min
422 and 423: (R)-3-(2-(((R)-1-   Chiral separation was achieved by chiral SFC column
(3-(2,3-dihydro-1H-inden-5-yl)-  chromatography (Column ID 21 × 250 mm 40% IPA + 10 mM
1,2,4-oxadiazol-5-               NH4OH in CO2, flow 75 g/min, 222 nm UV collection) to
yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-
((R)-1-hydroxyethyl)oxazolidin-  oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
2-one                            hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(2,3-
                                 dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5-
                                 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
                                 hydroxyethyl)oxazolidin-2-one
                                 422: First eluted product (15 mg): 1H NMR (400 MHz,
                                 CDCl3) δ 8.24 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H),
                                 7.81 (dd, J = 7.8, 1.7 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.34
                                 (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 5.27 (d, J = 43.6 Hz, 1H),
                                 4.70 (d, J = 7.9 Hz, 1H), 4.49 (dd, J = 9.3, 2.4 Hz, 1H), 4.42-
                                 4.09 (m, 2H), 3.51 (d, J = 3.1 Hz, 3H), 3.23 (s, 1H), 2.98
                                 (t, J = 7.4 Hz, 4H), 2.14 (p, J = 7.5 Hz, 2H), 1.78 (d, J = 7.0
                                 Hz, 3H), 1.75-1.62 (m, 0H), 1.21 (dd, J = 14.9, 6.3 Hz,
                                 4H), 1.14 (d, J = 5.5 Hz, 1H). HRMS(D) m/z 437.1944
                                 (M + H). RT = 3.57 min. Chiral RT = 2.35 min.
                                 423: Second eluted product (63 mg): 1H NMR (400 MHz,
                                 CDCl3) δ 8.25 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H),
                                 7.83 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.33
                                 (d, J = 7.8 Hz, 1H), 5.79 (s, 1H), 5.32 (s, 1H), 4.85 (ddd, J =
                                 8.4, 4.5, 2.5 Hz, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.39 (t,
                                 J = 8.9 Hz, 1H), 3.75 (d, J = 49.5 Hz, 1H), 3.51 (s, 1H), 2.97
                                 (t, J = 7.4 Hz, 5H), 2.13 (p, J = 7.5 Hz, 2H), 1.78 (d, J = 7.2
                                 Hz, 3H), 1.63 (s, 1H), 1.23 (d, J = 6.1 Hz, 1H), 0.98 (d, J =
                                 7.1 Hz, 4H). HRMS(D) m/z 437.1942 (M + H). RT = 3.58 min.
                                 Chiral RT = 3.50 min.

Example 424 and 425

(4R)-3-(2-((1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (150 mg, 0.529 mmol), 1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamine (118 mg, 0.529 mmol, 1.0 equiv), and DIEA (0.185 mL, 1.059 mmol, 2.0 equiv) in DMSO (2 mL) was heated at 110° C. for 120 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL), 4% brine (10 mL), concentrated in vacuo. The crude material, (R)-5-((R)-1-tert-Butoxy-ethyl)-1-(2-{1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-imidazolidin-2-one, was carried to the next step without further purification.

(R)-5-((R)-1-tert-Butoxy-ethyl)-1-(2-{1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-imidazolidin-2-one (200 mg, 0.411 mmol) was treated with 10:1 TFA/water (10 ml) for 2 hours. The reaction was conc. in vacuo and neutralized by passing through a column of MP-carbonate eluting with MeOH/DCM/MeOH and Flash column (silica, 15μ, 40 g) eluting w/5-60% EtOAc/heptane over 2.5 hours to give (R)-3-(2-(((R)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

424: first eluted product (45 mg, 50.8%). HRMS m/z 430.1156.

425: Second eluted product (46 mg, 52.0%). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.09 (dq, J=8.4, 2.0, 1.6 Hz, 3H), 7.64 (d, J=6.4 Hz, 1H), 7.58-7.48 (m, 2H), 5.48-5.27 (m, 1H), 4.94 (t, J=6.6 Hz, 1H), 4.63-4.40 (m, 2H), 1.13 (d, J=6.5 Hz, 3H), 0.89 (d, J=7.1 Hz, 0H), 1.83-1.72 (m, 3H).HRMS m/z 430.1156.

Example 426

(S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23.35 mg, 0.089 mmol), (S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride (30 mg, 0.116 mmol) and Huenig's base (0.047 mL, 0.268 mmol) in DMSO (0.6 mL) under argon atmosphere was heated at 80° C. for ˜16 hr. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one as its trifluoroacetic acid salt (30.2 mg) as a white solid.

¹H NMR (400 Mhz, CD₃OD) δ ppm 9.07 (br. s., 1H), 8.24 (d, J=6.3 Hz, 1H), 7.85 (s, 1H), 7.53-7.72 (m, 5H), 5.64-6.06 (m, 1H), 5.36 (q, J=6.9 Hz, 1H), 5.07-5.23 (m, 1H), 4.41-4.62 (m, 2H), 2.62-2.90 (m, 1H), 1.71 (d, J=6.7 Hz, 3H), 0.97 (d, J=7.0 Hz, 3H);

LCMS m/z 463.2 (M+H)⁺, Rt 0.64 min.

The following Example was prepared using a method similar to that described for the preparation of Example 415

Example 427

(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 Mhz, CD₃OD) δ ppm 9.13 (s, 1H), 8.25 (d, J=6.7 Hz, 1H), 7.86 (s, 1H), 7.61-7.73 (m, 3H), 7.36 (m, J=8.6, 8.6 Hz, 2H), 5.69-6.06 (m, 1H), 5.37 (q, J=6.7 Hz, 1H), 5.10-5.18 (m, 1H), 4.46-4.59 (m, 2H), 2.67-2.82 (m, 1H), 1.72 (d, J=7.0 Hz, 3H), 0.98 (d, J=7.4 Hz, 3H)

LCMS m/z 447.2 (M+H)⁺, Rt 0.57 min.

The Examples in Table 38a were prepared using methods similar to those described for the preparation of Examples 385 and 403.

TABLE 38a
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465

TABLE 38b
Chemical name, NMR chemical shifts, chiral separation
conditions and LCMS signal for compounds listed in Table 38a.
Example: Name	1H NMR (400 MHz) δ ppm	LCMS
428: (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-	(CDCl3) 11.13 (d, J = 5.9 Hz, 1 H),	LCMS (B)
(2-(2-(trifluoromethyl)pyridin-4-yl)thiazol-5-	8.84 (d, J = 5.0 Hz, 1 H), 8.17 (s, 1	m/z 483.1;
yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-	H), 8.06 (d, J = 7.0 Hz, 1 H), 7.89-	Rt = 0.79
one	7.96 (m, 2 H), 7.80 (s, 1 H), 5.34-	min.
	5.44 (m, 1 H), 4.81-4.90 (m, 1 H),
	4.66-4.78 (m, 2 H), 4.59-4.65
	(m, 1 H), 4.47-4.55 (m, 1 H), 1.83
	(d, J = 7.0 Hz, 3 H), 1.21-1.32 (m,
	3 H)
429: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-	(CDCl3) 8.22 (d, J = 2.9 Hz, 1 H),	LCMS (B)
1H-imidazol-4-yl)ethyl)amino)-5-	7.75 (d, J = 1.2 Hz, 1 H), 7.44 (d,	m/z 435.1;
fluoropyrimidin-4-yl)-4-	J = 8.9 Hz, 2 H), 7.30 (d, J = 8.9 Hz,	Rt = 0.62
(fluoromethyl)oxazolidin-2-one	2 H), 7.11 (s, 1H), 5.57 (d, J = 7.7	min.
	Hz, 1 H), 5.02-5.14 (m, 1 H), 4.75-
	4.89 (m, 1 H), 4.56-4.64 (m, 2
	H), 4.43-4.53 (m, 2 H), 1.61 (d,
	J = 6.8 Hz, 3 H)
430: (R)-3-(5-fluoro-2-(((S)-1-(1-(4-	(CDCl3) 8.62 (d, J = 3.9 Hz, 1 H),	LCMS (B)
fluorophenyl)-1H-imidazol-4-	8.14-8.21 (m, 1 H), 7.48 (dd,	m/z 419.2;
yl)ethyl)amino)pyrimidin-4-yl)-4-	J = 8.9, 4.4 Hz, 3 H), 7.24-7.34 (m,	Rt = 0.57
(fluoromethyl)oxazolidin-2-one	2 H), 5.38 (br. s., 1	min.
	H), 4.88-5.03 (m, 1 H), 4.42-
	4.73 (m, 4 H), 1.75 (t, J = 6.3 Hz, 3
	H)
431: (R)-3-(2-(((S)-1-(1-(3,4-	(CDCl3) 8.63 (br. s., 1 H), 8.17 (d,	LCMS (B)
difluorophenyl)-1H-imidazol-4-	J = 3.3 Hz, 1 H), 7.36-7.52 (m, 4	m/z 437.2;
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	H), 5.36 (br. s., 1 H), 4.94 (d,	Rt = 0.59
(fluoromethyl)oxazolidin-2-one	J = 18.7 Hz, 1 H),	min.
	4.43-4.74 (m, 4 H), 1.74 (d, J = 7.1
	Hz, 3 H)
432: (R)-3-(2-(((S)-1-(1-(4-chloro-3-	(CDCl3) 8.57 (s, 1 H), 8.18 (d,	LCMS (B)
fluorophenyl)-1H-imidazol-4-	J = 1.9 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1	m/z 453.1;
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	H), 7.48 (br. s., 1 H), 7.35 (d, J = 8.5	Rt = 0.64
(fluoromethyl)oxazolidin-2-one	Hz, 1 H), 7.24-7.29 (m, 1 H), 5.33	min.
	(d, J = 5.3 Hz, 1 H), 4.84-4.98 (m,
	1 H), 4.54-4.74 (m, 3 H), 4.48 (t,
	J = 7.5 Hz, 1 H), 1.73 (d, J = 6.5 Hz,
	3 H)
433: (R)-3-(2-(((S)-1-(1-(3-chloro-4-	(CDCl3) 8.56 (s, 1 H), 8.18 (d,	LCMS (B)
fluorophenyl)-1H-imidazol-4-	J = 1.9 Hz, 1H), 7.57-7.63 (m, 1	m/z 453.1;
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	H), 7.33-7.48 (m, 3 H), 5.34 (br.	Rt = 0.64
(fluoromethyl)oxazolidin-2-one	s., 1 H), 4.85-5.00 (m, 1 H), 4.41-	min.
	4.75 (m, 4 H), 1.73 (d, J = 7.0 Hz, 3
	H)
434: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 8.67 (s, 1 H), 8.17 (d,	LCMS (B)
(difluoromethyl)phenyl)-1H-imidazol-4-	J = 3.3 Hz, 1 H), 7.76 (d, J = 8.3 Hz,	m/z 451.2;
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.51-	Rt = 0.61
(fluoromethyl)oxazolidin-2-one	7.57 (m, 1H),	min.
	6.58-6.90 (m, 1 H), 5.38 (d, J = 6.5
	Hz, 1 H), 4.86-5.01 (m, 1 H), 4.41-
	4.75 (m, 4 H), 1.75 (d, J = 7.1 Hz,
	3 H)
435: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 8.60 (d, J = 1.1 Hz, 1 H),	LCMS (B)
(difluoromethyl)-3-fluorophenyl)-1H-	8.17 (d, J = 3.3 Hz, 1 H), 7.84 (t,	m/z 469.2;
imidazol-4-yl)ethyl)amino)-5-	J = 7.8 Hz, 1 H), 7.53 (d, J = 4.0 Hz,	Rt = 0.63
fluoropyrimidin-4-yl)-4-	1 H), 7.41 (d,	min.
(fluoromethyl)oxazolidin-2-one	J = 8.3 Hz, 1 H), 7.35 (d, J = 9.7 Hz,
	1 H), 6.78-7.10 (m, 1 H), 5.33 (d,
	J = 6.4 Hz, 1 H), 4.85-4.99 (m, 1
	H), 4.42-4.73 (m, 4 H), 1.73 (d,
	J = 7.1 Hz, 3 H)
436: (R)-3-(2-(((S)-1-(1-(3,5-	(CDCl3) 8.63 (s, 1 H), 8.16 (dd,	LCMS (B)
difluorophenyl)-1H-imidazol-4-	J = 3.3, 2.0 Hz, 1 H), 7.51 (br. s., 1	m/z 437.1;
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	H), 7.09 (d, J = 6.6 Hz, 2 H), 6.97-	Rt = 0.59
(fluoromethyl)oxazolidin-2-one	7.05 (m, 1 H), 5.35 (d, J = 6.4 Hz, 1	min.
	H), 4.40-4.93 (m, 5 H), 1.73 (d,
	J = 7.0 Hz, 3 H)
437: (R)-3-(2-(((S)-1-(5-(4-	(CDCl3) 8.13 (d, J = 3.9 Hz, 1 H),	LCMS (B)
chlorophenyl)isoxazol-3-yl)ethyl)amino)-5-	7.69 (d, J = 8.4 Hz, 2 H), 7.46 (d,	m/z 436.1;
fluoropyrimidin-4-yl)-4-	J = 8.4 Hz, 2 H), 6.57 (s, 1 H), 5.18	Rt = 0.91
(fluoromethyl)oxazolidin-2-one	(d, J = 7.1 Hz, 1 H), 4.93-5.08 (m,	min.
	1 H), 4.64-4.72 (m, 1 H), 4.55
	(dd, J = 8.7, 7.2 Hz, 1 H), 4.27-
	4.52 (m, 2 H), 1.71 (d, J = 7.1 Hz, 3
	H)
438: (R)-3-(2-(((S)-1-(2-(4-	(CDCl3) 8.18 (d, J = 3.5 Hz, 1 H),	LCMS (B)
chlorophenyl)thiazol-5-yl)ethyl)amino)-5-	7.89 (s, 1 H), 7.75-7.80 (m, 2 H),	m/z 452.1;
fluoropyrimidin-4-yl)-4-	7.44-7.50 (m, 2 H), 5.28 (d, J = 6.6	Rt = 0.93
(fluoromethyl)oxazolidin-2-one	Hz, 1 H), 4.80-4.93 (m, 1 H), 4.68	min.
	(t, J = 8.9 Hz, 1 H), 4.42-4.49 (m, 1
	H), 4.16-4.41 (m, 2 H), 1.77 (d,
	J = 7.0 Hz, 3 H)
439: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-	(CDCl3) 8.13 (d, J = 3.1 Hz, 1 H),	LCMS (B)
2-methyl-1H-imidazol-4-yl)ethyl)amino)-5-	7.58-7.63 (m, 2 H), 7.31-7.37	m/z 449.2;
fluoropyrimidin-4-yl)-4-	(m, 2 H), 7.14-7.18 (m, 1 H), 5.41	Rt = 0.65
(fluoromethyl)oxazolidin-2-one	(br. s., 1 H), 4.77-4.96 (m, 1 H),	min.
	4.46-4.72 (m, 4 H), 2.60 (s, 3 H),
	1.70 (d, J = 6.9 Hz, 3 H)
440: (R)-3-(5-fluoro-2-(((S)-1-(2-(2-	(CDCl3) 8.85 (d, J = 5.1 Hz, 1 H),	LCMS (B)
(trifluoromethyl)pyridin-4-yl)thiazol-5-	8.20 (d, J = 3.5 Hz, 1 H), 8.16 (s, 1	m/z 487.1;
yl)ethyl)amino)pyrimidin-4-yl)-4-	H), 7.92-7.96 (m, 1 H), 7.90 (s, 1	Rt = 0.86
(fluoromethyl)oxazolidin-2-one	H), 5.36 (d,	min.
	J = 7.0 Hz, 1 H), 4.78-4.91 (m, 1
	H), 4.24-4.72 (m, 4 H), 1.79 (d,
	J = 6.9 Hz, 3 H)
441: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-	(CDCl3) 8.88 (d, J = 6.0 Hz, 1 H),	LCMS (B)
methylpyridin-4-yl)phenyl)ethyl)amino)-5-	8.19 (d, J = 3.0 Hz, 1 H), 7.76 (d,	m/z 462.2;
fluoropyrimidin-4-yl)-4-	J = 6.2 Hz, 1 H), 7.72 (s, 1 H), 7.21-	Rt = 0.60
(fluoromethyl)oxazolidin-2-one	7.33 (m, 2 H), 5.19-5.30 (m, 1	min.
	H), 4.78 (br. s., 1 H), 4.64 (t, J = 8.8
	Hz, 1 H), 4.41-4.49 (m, 1 H), 4.09-
	4.37 (m, 2 H), 2.90 (s, 3 H), 1.63
	(d, J = 6.9 Hz, 3 H)
442: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(6-	(CDCl3) 9.01 (s, 1 H), 8.33 (d,	LCMS (B)
methylpyridin-3-yl)phenyl)ethyl)amino)-5-	J = 8.2 Hz, 1 H), 8.17 (d, J = 3.2 Hz,	m/z 462.1;
fluoropyrimidin-4-yl)-4-	1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.21-	Rt = 0.61
(fluoromethyl)oxazolidin-2-one	7.29 (m, 2 H), 5.18-5.29 (m, 1	min.
	H), 4.06-4.83 (m, 5 H), 2.89 (s, 3
	H), 1.62 (d, J = 7.0 Hz, 3 H)
443: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(6-	(CDCl3) 8.89 (s, 1 H), 8.15 (dd,	LCMS (B)
(trifluoromethyl)pyridin-3-	J = 3.7, 1.2 Hz, 1 H), 8.06 (d, J = 8.2	m/z 516.1;
yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4-	Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H),	Rt = 0.97
yl)-4-(fluoromethyl)oxazolidin-2-one	7.17-7.30 (m, 2 H), 5.28 (d, J = 5.7	min.
	Hz, 1 H), 4.77-4.90 (m, 1 H), 4.67
	(t, J = 8.8 Hz, 1 H), 4.49 (t, J = 7.8
	Hz, 1 H), 4.07-4.29 (m, 2 H), 1.66
	(d, J = 6.7 Hz, 3 H)
444: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-	(CDCl3) 8.85 (d, J = 5.0 Hz, 1 H),	LCMS (B)
(trifluoromethyl)pyridin-4-	8.15 (dd, J = 3.4, 2.4 Hz, 1 H), 7.84	m/z 516.0;
yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4-	(s, 1 H), 7.67 (d, J = 4.9 Hz, 1 H),	Rt = 0.96
yl)-4-(fluoromethyl)oxazolidin-2-one	7.21-7.33 (m, 2 H), 5.28 (br. s., 1	min.
	H), 4.81 (d, J = 14.6 Hz, 1 H), 4.67
	(t, J = 8.8 Hz, 1 H), 4.45-4.53 (m, 1
	H), 4.07-4.33 (m, 2 H), 1.63-
	1.68 (m, 3 H)
445: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(4-	(CDCl3) 8.82 (s, 1 H), 8.18 (d,	LCMS (B)
methyl-1H-imidazol-1-	J = 3.1 Hz, 1 H), 7.39 (dd, J = 10.3,	m/z 451.1;
yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4-	6.0 Hz, 1 H), 7.27-7.30 (m, 1 H),	Rt = 0.58
yl)-4-(fluoromethyl)oxazolidin-2-one	7.11 (s, 1 H), 5.19-5.28 (m, 1 H),	min.
	4.74 (br. s., 1 H), 4.64 (t, J = 8.6 Hz,
	1 H), 4.39-4.47 (m, 1 H), 4.13-
	4.32 (m, 2 H), 2.49 (s, 3 H), 1.63
	(d, J = 7.0 Hz, 3 H)
446: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 8.72 (s, 1 H), 8.18 (d,	LCMS m/z
(difluoromethyl)-3-fluorophenyl)-1H-	J = 3.1 Hz, 1 H), 7.79-7.91 (m, 1	483.0 (M +
imidazol-4-yl)ethyl)amino)-5-	H), 7.61 (br. s., 1 H), 7.33-7.48	H)+, Rt 0.68
fluoropyrimidin-4-yl)-4-((S)-1-	(m, 2 H), 6.94 (t, J = 54.0 Hz, 1 H),	min; HPLC
fluoroethyl)oxazolidin-2-one	5.34 (d, J = 6.7 Hz, 1 H), 4.71-5.05	2.801 min.
	(m, 2 H), 4.55-4.65 (m, 1 H), 4.50
	(dd, J = 8.4, 6.5 Hz, 1 H), 1.74 (d,
	J = 7.0 Hz, 3 H), 1.33 (dd, J = 23.5,
	6.7 Hz, 3 H)
447: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 8.81 (s, 1 H), 8.18 (d,	LCMS m/z
(difluoromethyl)phenyl)-1H-imidazol-4-	J = 3.1 Hz, 1 H), 7.76 (d, J = 8.2 Hz,	465.0 (M +
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	2 H), 7.62 (d, J = 8.2 Hz, 2 H), 6.74	H)+, Rt 0.65
((S)-1-fluoroethyl)oxazolidin-2-one	(t, J = 56.0 Hz, 1 H), 5.38 (q, J = 6.7	min; HPLC
	Hz, 1 H), 4.73-5.06 (m, 2 H), 4.59	2.624 min.
	(t, J = 8.8 Hz, 1 H), 4.45-4.53 (m, 1
	H), 1.76 (d, J = 7.0 Hz, 3 H), 1.34
	(dd, J = 23.5, 6.3 Hz, 3 H).
448: (R)-3-(2-(((S)-1-(1-(4-chloro-3-	(CDCl3) 8.73 (s, 1 H), 8.18 (d,	LCMS m/z
fluorophenyl)-1H-imidazol-4-	J = 3.1 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 1	467.0 (M +
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	H), 7.57 (br. s., 1 H), 7.29-7.44	H)+, Rt 0.69
((S)-1-fluoroethyl)oxazolidin-2-one	(m, 2 H), 5.34 (d, J = 6.7 Hz, 1 H),	min; HPLC
	4.73-4.87 (m, 1 H), 4.59 (t, J = 8.8	2.847 min.
	Hz, 1 H), 4.45-4.53 (m, 1 H), 1.74
	(d, J = 7.0 Hz, 3 H), 1.33 (dd,
	J = 23.1, 6.3 Hz, 3 H)
449: (R)-3-(2-(((S)-1-(1-(3,5-	(CDCl3) 8.58 (s, 1 H), 8.18 (d,	LCMS m/z
difluorophenyl)-1H-imidazol-4-	J = 2.7 Hz, 1 H), 7.53 (br. s., 1 H),	451.1 (M +
yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-	7.09 (d, J = 5.1 Hz, 2 H), 7.00 (t,	H)+, Rt 0.64
((S)-1-fluoroethyl)oxazolidin-2-one	J = 8.4 Hz, 1 H), 5.29-5.36 (m, 1	min; HPLC
	H), 5.00 (br. s., 1 H), 4.87 (br. s., 1	2.132 min.
	H), 4.70-4.83 (m, 1 H), 4.54-
	4.64 (m, 1 H), 4.46-4.53 (m, 1 H),
	1.73 (d, J = 7.0 Hz, 3 H), 1.33 (dd,
	J = 23.1, 6.3 Hz, 3H).
450: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-	(CDCl3) 8.64 (s, 1 H), 8.18 (d,	LCMS m/z
1H-imidazol-4-yl)ethyl)amino)-5-	J = 3.1 Hz, 1 H), 7.57 (d, J = 8.6 Hz,	449.0 (M +
fluoropyrimidin-4-yl)-4-((S)-1-	2 H), 7.51 (br. s., 1 H), 7.44 (d,	H)+, Rt 0.67
fluoroethyl)oxazolidin-2-one	J = 8.6 Hz, 2 H), 5.35 (d, J = 6.7 Hz,	min; HPLC
	1 H), 5.01 (br. s., 1 H), 4.89 (br. s.,	2.354 min.
	1 H), 4.71-4.86 (m, 1 H), 4.54-
	4.64 (m, 1 H), 4.44-4.53 (m, 1 H),
	1.74 (d, J = 7.0 Hz, 3 H), 1.33 (dd,
	J = 23.5, 6.7 Hz, 3 H).
451: (R)-3-(5-fluoro-2-(((S)-1-(1-(4-	(CDCl3) 8.61 (s, 1 H), 8.18 (d,	LCMS m/z
fluorophenyl)-1H-imidazol-4-	J = 2.7 Hz, 1 H), 7.48 (dd, J = 8.4,	433.1 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	4.1 Hz, 3 H), 7.28-7.34 (m, 2 H),	H)+, Rt 0.61
fluoroethyl)oxazolidin-2-one	5.35 (d, J = 6.7 Hz, 1 H), 4.70-4.85	min; HPLC
	(m, 1 H), 4.54-4.62 (m, 1 H), 4.45-	1.997 min.
	4.53 (m, 1 H), 1.75 (d, J = 7.0 Hz,
	3 H), 1.33 (dd, J = 23.1, 6.3 Hz, 3
	H).
452: (R)-3-(2-(((S)-1-(5-(4-	(CDCl3) 8.11 (d, J = 3.5 Hz, 1 H),	LCMS m/z
chlorophenyl)isoxazol-3-yl)ethyl)amino)-5-	7.69 (d, J = 8.6 Hz, 2 H), 7.46 (d,	450.0 (M +
fluoropyrimidin-4-yl)-4-((S)-1-	J = 8.6 Hz, 2 H), 6.54 (s, 1 H), 5.17	H)+, Rt 0.96
fluoroethyl)oxazolidin-2-one	(d, J = 5.1 Hz, 1	min; HPLC
	H), 4.69-4.92 (m, 2 H), 4.51-	4.131 min.
	4.65 (m, 2 H), 1.70 (d, J = 7.0 Hz, 3
	H), 1.30 (dd, J = 23.1, 6.3 Hz, 3 H).
453: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-	(CDCl3) 8.14 (d, J = 3.5 Hz, 1 H),	LCMS m/z
1H-pyrazol-4-yl)ethyl)amino)-5-	7.94 (s, 1 H), 7.68 (s, 1 H), 7.59 (d,	449.0 (M +
fluoropyrimidin-4-yl)-4-((S)-1-	J = 8.6 Hz, 2 H), 7.43 (d, J = 8.6 Hz,	H)+, Rt 0.92
fluoroethyl)oxazolidin-2-one	2 H), 5.08 (q, J = 6.7 Hz, 1 H), 4.65-	min; HPLC
	4.87 (m, 2 H), 4.59 (t, J = 8.8 Hz, 1	3.864 min.
	H), 4.47-4.55 (m, 1 H), 1.66 (d,
	J = 7.0 Hz, 3 H), 1.22 (dd, J = 23.5,
	6.7 Hz, 3 H).
454: (R)-3-(2-(((S)-1-(1-(3,5-	(CDCl3) 10.92 (d, J = 6.7 Hz, 1 H),	LCMS m/z
difluorophenyl)-1H-imidazol-4-	8.30 (br. s., 1 H), 7.99 (d, J = 6.7	433.2 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	Hz, 1 H), 7.88 (d, J = 7.0 Hz, 1 H),	H)+, Rt 0.59
fluoroethyl)oxazolidin-2-one	7.57 (br. s., 1 H), 6.92-7.11 (m, 3	min; HPLC
	H), 5.48 (d, J = 6.3 Hz, 1 H), 4.84-	1.946 min.
	5.14 (m, 2 H), 4.59-4.70 (m, 1 H),
	4.48-4.57 (m, 1 H), 1.69 (d, J = 6.7
	Hz, 3 H), 1.34 (dd, J = 23.5, 5.9 Hz,
	3 H).
455: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 10.91 (d, J = 7.0 Hz, 1 H),	LCMS m/z
(difluoromethyl)-3-fluorophenyl)-1H-	8.24 (br. s., 1 H), 7.98 (d, J = 6.7	465.2 (M +
imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-	Hz, 1 H), 7.88 (d, J = 7.0 Hz, 1 H),	H)+, Rt 0.63
4-((S)-1-fluoroethyl)oxazolidin-2-one	7.82 (t, J = 7.4 Hz, 1 H), 7.58 (br. s.,	min; HPLC
	1 H), 7.30-7.43 (m, 2 H), 6.94 (dt,	2.191 min.
	J = 55.6, 1.0 Hz, 1 H), 5.44 (br. s., 1
	H), 4.80-5.22 (m, 2 H), 4.64 (d,
	J = 9.0 Hz, 1 H), 4.54 (t, J = 8.8 Hz, 1
	H), 1.71 (d, J = 6.3 Hz, 3 H), 1.36
	(dd, J = 23.5, 6.3 Hz, 3 H).
456: (R)-3-(2-(((S)-1-(1-(4-	(CDCl3) 11.00 (d, J = 7.0 Hz, 1 H),	LCMS m/z
(difluoromethyl)phenyl)-1H-imidazol-4-	8.46 (s, 1 H), 7.99 (d, J = 7.0 Hz, 1	447.3 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	H), 7.90 (d, J = 7.0 Hz, 1 H), 7.75	H)+, Rt 0.58
fluoroethyl)oxazolidin-2-one	(d, J = 8.2 Hz, 2 H), 7.66 (s, 1 H),	min; HPLC
	7.59 (d, J = 8.2 Hz, 2 H), 6.74 (t,	1.898 min.
	J = 55.6 Hz, 1 H), 5.58 (t, J = 6.8 Hz,
	1 H), 4.91-5.14 (m, 2 H), 4.60-
	4.68 (m, 1 H), 4.49-4.59 (m, 1 H),
	1.72 (d, J = 6.7 Hz, 3 H), 1.36 (dd,
	J = 23.5, 6.3 Hz, 3 H).
457: (R)-3-(2-(((S)-1-(1-(3-chloro-4-	(CDCl3) 10.97 (d, J = 7.4 Hz, 1 H),	LCMS m/z
fluorophenyl)-1H-imidazol-4-	8.33 (s, 1 H), 7.99 (d, J = 6.7 Hz, 1	449.1 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	H), 7.90 (d, J = 7.0 Hz, 1 H), 7.50-	H)+, Rt 0.63
fluoroethyl)oxazolidin-2-one	7.65 (m, 2 H), 7.37 (d, J = 5.9 Hz, 2	min; HPLC
	H), 5.53 (t, J = 6.7 Hz, 1 H), 4.87-	2.193 min.
	5.19 (m, 2H), 4.60-4.70 (m, 1 H),
	4.44-4.59 (m, 1 H), 1.71 (d, J = 6.7
	Hz, 3 H), 1.36 (dd, J = 23.5, 5.9 Hz,
	3 H).
458: (R)-3-(2-(((S)-1-(1-(4-chloro-3-	(CDCl3) 10.94 (d, J = 7.0 Hz, 1 H),	LCMS m/z
fluorophenyl)-1H-imidazol-4-	8.27 (s, 1 H), 7.98 (d, J = 7.0 Hz, 1	449.2 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	H), 7.88 (d, J = 6.7 Hz, 1 H), 7.62 (t,	H)+, Rt 0.64
fluoroethyl)oxazolidin-2-one	J = 8.0 Hz, 1 H), 7.55 (s, 1 H), 7.31	min; HPLC
	(dd, J = 9.0, 2.3 Hz, 1 H), 7.23 (br.	2.279 min.
	s., 1 H), 5.48 (t, J = 6.8 Hz, 1 H),
	4.83-5.19 (m, 2 H), 4.60-4.69
	(m, 1 H), 4.46-4.58 (m, 1 H), 1.70
	(d, J = 6.7 Hz, 3 H), 1.35 (dd,
	J = 23.5, 6.3 Hz, 3 H).
459: (R)-3-(2-(((S)-1-(1-(3,4-	(CDCl3) 10.96 (d, J = 7.0 Hz, 1 H),	LCMS m/z
difluorophenyl)-1H-imidazol-4-	8.27 (s, 1 H), 7.98 (d, J = 7.0 Hz, 1	433.2 (M +
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	H), 7.89 (d, J = 7.0 Hz, 1 H), 7.53	H)+, Rt 0.59
fluoroethyl)oxazolidin-2-one	(s, 1 H), 7.31-7.45 (m, 2 H), 5.51	min; HPLC
	(t, J = 6.7 Hz, 1 H), 4.84-5.19 (m, 2	1.870 min.
	H), 4.60-4.72 (m, 1 H), 4.43-
	4.58 (m, 1 H), 1.70 (d, J = 6.7 Hz, 3
	H), 1.36 (dd, J = 23.5, 6.3 Hz, 3 H).
460: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(1-	(CDCl3) 10.96 (d, J = 6.7 Hz, 1 H),	LCMS m/z
methyl-1H-pyrazol-4-	7.99 (d, J = 7.0 Hz, 1 H), 7.71-7.89	447.3 (M +
yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-	(m, 3 H), 7.20 (ddd, J = 14.6, 10.7,	H)+, Rt 0.68
((S)-1-fluoroethyl)oxazolidin-2-one	6.1 Hz, 2 H), 5.33 (quin, J = 6.7 Hz,	min; HPLC
	1 H), 4.64-4.77 (m, 2 H), 4.52-	2.612 min.
	4.64 (m, 2 H), 4.45-4.51 (m, 1 H),
	3.99 (s, 3 H), 1.64 (d, J = 7.0 Hz, 3
	H), 1.23 (dd, J = 23.5, 6.7 Hz, 3 H).
461: (R)-3-(5-fluoro-2-(((S)-1-(1-(4-	(CD3OD) 9.32 (s, 1 H), 8.33 (d,	LCMS (B)
fluorophenyl)-1H-imidazol-4-	J = 2.7 Hz, 1 H), 7.94 (s, 1 H), 7.72	m/z 433.1;
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	(dd, J = 9.0, 4.3 Hz, 2 H), 7.37 (t,	Rt = 0.60
fluoroethyl)oxazolidin-2-one	J = 8.4 Hz, 2 H), 5.21 (q, J = 6.4 Hz,	min.
	1 H), 4.78-4.95 (m, 2 H), 4.63 (t,
	J = 9.2 Hz, 1 H), 4.41 (dd, J = 9.2,
	4.5 Hz, 1 H), 1.70 (d, J = 7.0 Hz, 3
	H), 1.12-1.29 (m, 3 H)
462: (R)-3-(5-fluoro-2-(((S)-1-(5-fluoro-2′-	(CD3OD) 8.74-8.84 (m, 2 H),	LCMS (B)
(trifluoromethyl)-[3,4′-bipyridin]-6-	8.24 (br. s., 1 H), 8.14 (s, 1 H),	m/z 513.2;
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	8.09 (dd, J = 10.8, 1.4 Hz, 1 H),	Rt = 0.87
fluoroethyl)oxazolidin-2-one	7.97 (d, J = 4.7 Hz, 1 H), 5.41 (d,	min
	J = 6.3 Hz, 1 H), 4.75-4.94 (m, 2
	H), 4.60 (t, J = 9.2 Hz, 1 H), 4.41
	(dd, J = 9.2, 4.9 Hz, 1 H), 1.59 (d,
	J = 7.0 Hz, 3 H), 1.04 (br. s., 3 H)
463: (R)-3-(2-(((S)-1-(5-fluoro-2′-	(CD3OD) 8.87 (s, 1 H), 8.82 (d,	LCMS (B)
(trifluoromethyl)-[3,4′-bipyridin]-6-	J = 5.1 Hz, 1 H), 8.15-8.27 (m, 3	m/z 495.2;
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	H), 8.00 (d, J = 4.7 Hz, 1 H), 7.81	Rt = 0.75
fluoroethyl)oxazolidin-2-one	(d, J = 6.7 Hz, 1 H), 5.63 (d, J = 5.5	min
	Hz, 1 H), 4.75-5.02 (m, 2 H), 4.64
	(dd, J = 9.0, 2.7 Hz, 1 H), 4.48-
	4.58 (m, 1 H), 1.68 (d, J = 7.0 Hz, 3
	H), 1.21-1.46 (m, 3 H)
464: (R)-3-(2-(((S)-1-(5-fluoro-2′-	(CD3OD) 8.76-8.88 (m, 2 H),	LCMS (B)
(trifluoromethyl)-[3,4′-bipyridin]-6-	8.11-8.25 (m, 3 H), 7.99 (d, J = 5.1	m/z 495.2;
yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-	Hz, 1 H), 7.67 (d, J = 4.7 Hz, 1 H),	Rt = 0.75
fluoroethyl)oxazolidin-2-one	5.57 (d, J = 6.7 Hz, 1 H), 5.10 (br. s.,	min
	1 H), 4.76-4.96 (m, 2 H), 4.47-
	4.62 (m, 2 H), 1.67 (d, J = 6.7 Hz, 3
	H), 0.92-1.21 (m, 3 H)
465: (R)-3-(5-fluoro-2-(((S)-1-(5-fluoro-2′-	(CD3OD) 8.73-8.86 (m, 2 H),	LCMS (B)
(trifluoromethyl)-[3,4′-bipyridin]-6-	8.24 (br. s., 1 H), 8.16 (s, 1 H),	m/z 513.2;
yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-	8.11 (d, J = 11.0 Hz, 1 H), 7.98 (d,	Rt = 0.95
fluoroethyl)oxazolidin-2-one	J = 5.1 Hz, 1 H), 5.43(d, J = 6.7 Hz, 1	min
	H), 4.85 (s, 2 H), 4.61 (t, J = 9.0 Hz,
	1 H), 4.42-4.52 (m, 1 H), 1.58 (d,
	J = 7.0 Hz, 3 H), 1.17 (d, J = 19.2 Hz,
	3 H)

The compounds listed in Table 39 are made using methods similar to those described for Examples 1-465 and as outlined in the general synthetic procedures.

TABLE 39
The compounds in Table 39 are prepared following chemistry similar to that
described for Examples 1-465 or as outlined in the Schemes given above.
Example                          Name
                                 (R)-4-(fluoromethyl)-3-(2- (((S)-1-(1-(4- fluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
                                 (R)-3-(2-(((S)-1-(1-(3- chloro-4-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-3-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(3,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- (difluoromethyl)-3- fluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl) 1H-imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4 ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(2′- (trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
                                 (R)-3-(5-fluoro-2-(((S)-1- (2′-(trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(2- (trifluoromethyl)pyridin-4- yl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
                                 (R)-3-(5-fluoro-2-(((S)-1- (5-(2- (trifluoromethyl)pyridin-4- yl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
                                 (R)-3-(5-fluoro-2-(((S)-1- (5-(3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(5-fluoro-2-(((S)-1- (5-(2-fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(2- fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(3- (trifluoromethyl)phenyl) pyridin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
Error! Not a valid embedded object. (R)-3-(5-fluoro-2-(((S)-1- (5-(3- (trifluoromethyl)phenyl) pyridin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(4- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
                                 (R)-3-(5-fluoro-2-(((S)-1- (5-(4- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(4- chloro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(4- fluoro-3- methylphenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(4- chloro-3- (trifluoromethyl)phenyl) pyrimidin-2-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(5-fluoro-2-(((S)-1- (5-(4-fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(4- fluoro-3- methylphenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(5-fluoro-2-(((S)-1- (5-(4-fluoro-3- methylphenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(4- chloro-3-fluorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(4- chloro-3-fluorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(3- chlorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(5-(3- chlorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(4-methyl-2′- (trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
                                 (R)-3-(5-fluoro-2-(((S)-1- (4-methyl-2′- (trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(2,5- difluoro-4-(4-methyl-1H- imidazol-1- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(2,5- difluoro-4-(1-methyl-1H- pyrazol-4- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- methylpyridin-4- yl)phenyl)ethyl)amino) pyrimidin-4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- methylpyridin-4- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4 - ((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- (trifluoromethyl)pyridin-4- yl)phenyl)ethyl)amino) pyrimidin-4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
                                 (R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- (trifluoromethyl)pyridin-4- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one

Biological Data

Mutant IDH1 Biochemical Assay: LC-MS Detection of 2-HG.

Mutant IDH1 R132H catalytic activity was monitored using the quantitative liquid chromatography/mass spectrometry (LC-MS) detection of 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.

More specifically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Costar, Cat. No. 781201) using a final reaction volume of 30 μL and the following assay buffer conditions: 50 mM HEPES pH 7.4, 10 mM MgCl₂, 50 mM KCl, 1 mM DTT, 0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.

The final reaction mixture contained 3.3% DMSO and inhibitors with concentrations ranging 0.02-50 μM. The IDH1 enzyme was used at a final concentration of 0.25 nM. Following 45 minutes incubation, the reaction mixtures were quenched by the addition of 10 μL of 16% formic acid containing 800 nM of 5-carbon labeled ¹³C-2-HG). The protein was then precipitated by the addition of 2.5 volumes of acetonitrile followed by centrifugation (3000×g, 20 minutes). The concentration of 2-HG in the resulting supernatants was measured by LC-MS (see below).

LC-MS method. Reaction mixture supernatants were submitted to chromatographic separation on a BiobasicAX column (2.1 mm×20 mm, 5 μm particle, Thermo Scientific Inc.). The chromatographic mobile phases were A) 25 mM ammonium biocarbonate and B) acetonitrile (0.1% ammonium hydroxide). Nicotinamide was eluted at 1 ml/min using a 85-5% B gradient over 0.9 minutes (Agilent 1200SL LC system, Thermofisher LX-4 autosampler) and analyzed by multiple reaction monitoring (MRM) on a API4000 QTrap mass spectrometer (ABSciex, Framingham, Mass.) in the positive electrospray ionization (ESI+) mode. The mass transition for 2-HG and ¹³C-2-HG were 147→129 and 152→134, respectively. The relative responses (2-HG/¹³C-2-HG) were measured at varied inhibitor concentrations and used to calculate inhibitory IC50 values (normalized IC50 regression curves).

R132 Protein Expression and Purification.

IDH1 R132H was cloned into the pET47b vector using the restriction sites Xmal/XhoI which yields an in frame, N-terminal His₆ site cleavable with Prescission protease. This plasmid was transformed into Rosetta™ 2(DE3) (Novagen) cells. In shake flasks, 8 L of cells were grown in Terrific Broth (Teknova) (plus kanamycin 50 μg/mL and chloramphenicol 34 μg/mL) at 37° C. to an OD₆₀₀ of 0.8 and protein expression was induced by addition of IPTG to a concentration of 0.20 mM. The cells were subsequently grown for 18 hours at 18° C.

His₆-IDH1 (R132H) Uncut Protein

(SEQ ID NO: 1)
MAHHHHHHSAALEVLFQGPGMSKKISGGSVVEMQGDEMTRIIWELIKEKL
IFPYVELDLHSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDE
KRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRLVSGWVKPIII
GHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAM
GMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEI
YDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDS
VAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPI
ASIFAWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACI
KGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL (stop)

IDH1 (R132H) Prescission Cut Protein (N-Term gpg is Cloning Artifact)

(SEQ ID NO: 2)
GPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIE
NRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNG
TIRNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFVVP
GPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSF
QMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFEAQKIWYE
HRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVC
PDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLD
NNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEF
MDKLGENLKIKLAQAKL (stop)

Purification

The cells were homogenized in Lysis Buffer with protease inhibitors (cOmplete EDTA-free protease inhibitor tablets (Roche), 1 tablet per 50 mL of buffer), DNAse, and to 200 μM PMSF and lysed in a Microfluidizer. After lysis, Triton X-100 was added to 0.1% and stirred at 4° C. for 30 minutes.

The cleared lysate was loaded onto 2×5 mL HisTrap FF crude columns (GE), washed extensively with Lysis Buffer until the A₂₈₀ stabilized and eluted with Ni Elution Buffer. Peak eluted fractions were concentrated to 30 mL, EDTA was added to 1 mM and GST-Prescission protease was added to 3 U/100 μg of protein. The sample was dialyzed against 2 L Dialysis Buffer I (MWCO 50 kDa) for 6 hours at 4° C. then dialyzed against 2 L of Dialysis Buffer II for at least 6 more hours. GST-Prescission cleaved sample was rocked with Glutathione Agarose Beads, spun down and then the supernatant was loaded through a 5 mL HisTrap HP column and the flow through was collected.

Flow through was then diluted with ice cold 20 mM Tris pH 7.4 and 1 mM TCEP until the conductivity dropped to less than 5 mS/cm (a roughly three fold dilution). This sample was then flowed through a HiTrap Q column and the flow through was concentrated to 10 mL and loaded onto an equilibrated 26/60 Superdex 200 column using SEC Buffer as the mobile phase. Peak fractions were collected, concentrated and aliquoted.

Lysis Buffer:

50 mM Tris pH=7.4, 500 mM NaCl, 20 mM Imidazole, and 1 mM TCEP

Ni Elution Buffer:

50 mM Tris pH=7.4, 150 mM NaCl, 200 mM Imidazole, and 1 mM TCEP

Dialysis Buffer I:

20 mM Tris pH=7.4, 150 mM NaCl, 1 mM TCEP, and 50 mM Imidazole

Dialysis Buffer II:

20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP

SEC Buffer:

20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP

The results of the mutant IDH1 biochemical assay (mIDH R132H) are given in Table 40. Some of the examples were run in the assay multiple times and therefore the IC₅₀ values are expressed as a range of activity.

Fluorescence Biochemical Assay

The IDH1 (R132H) mutant catalyzes the reduced form of NADP+ (NADPH) and α-ketoglutarate (α-KG) to form nicotinamide adenine dinucleotide phosphate (NADP+) and R (−)-2-hydroxyglutarate (2HG). The reaction can be monitored kinetically by following the oxidation of NADPH to NADP+ which is measured using fluorescence, excitation at 355 nm and emission at 530 nm. Reactions were monitored using the Perkin-Elmer Envision, Model 2101. More specifically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Cat. No. 781076) using a final reaction volume of 20 μL and the following assay buffer conditions: 50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.02% BSA, 0.02% Tween-20, 10 μM NADPH and 100 μM α-KG. The final reaction mixture contained 2.5% DMSO and test compounds with concentrations ranging 0.0000008-25 μM. The IDH1 (R132H) enzyme was used at a final concentration of 10 nM. Curve fitting for dose response 1050 determinations was done in the Helios module of the software package DAVID. The 4-parameter logistic model was used: y=min+((max−min)/1+(×/IC₅₀)^slope).

The results of the fluorescence biochemical assay (mIDH R132H) are given in Table 40. Some of the examples were run in the assay multiple times and therefore the IC₅₀ values are expressed as a range of activity.

TABLE 40
Results of the LC-MS and fluorescence biochemical assays.
	LC-MS	Fluorescence
Example	biochemical	biochemical
Number	assay IC50 (μM)	assay IC50 (μM)
1	—	1.410
2	—	0.406 to 0.412
3	—	—
4	2.010	1.420
5	3.684	17.800
6	1.185	1.270
7	1.609 to 4.527	2.950
8	0.314 to 2.79	2.040
9	3.019	2.200
10	1.710	11.700
11	2.453	3.050
12	0.892	3.270
13	>5	2.190
14	0.813	0.405
15	—	—
16	—	—
17	—	—
18	—	—
19	—	—
20	—	—
21	—	—
22	—	—
23	—	—
24	—	—
25	—	—
26	—	3.350
27	—	2.800
28	0.005	—
29	0.027	—
30	0.472	1.090
31	0.757	0.627
32	0.010	0.016
33	2.085	3.660
34	0.590	0.889 to 0.893
35	0.055	0.033
36	3.497	1.410
37	3.745	2.690
38	0.056	0.055
39	0.211	0.202
40	0.370	0.175
41	0.179	0.253
42	1.557	>25
43	0.045	—
44	0.033 to 0.034	0.029
45	1.237	1.000
46	1.930	2.530
47	0.036	0.033
48	0.775	0.463
49	0.094	—
50	0.043	0.037
51	0.016	0.013
52	0.194	0.131 to 0.289
53	0.059	0.042 to 0.051
54	0.119	0.116
55	0.323	0.267 to 0.291
56	1.549	2.920
57	1.131	1.270
58	0.029	0.027
59	0.033	0.079 to 0.085
60	0.201	1.100
61	0.156	0.313
62	0.087	0.53 to 0.599
63	0.005	<0.0159
64	0.008	<0.0159
65	0.582	0.797
66	0.066	0.061 to 0.082
67	1.437	1.010
68	0.112	0.050
69	>5	0.639
70	0.080	0.073
71	>5	>25
72	12.152	—
73	0.571	0.181
74	>5	—
75	—	—
76	0.546 to 0.568	—
77	0.911	—
78	2.560	1.630
79	>5	5.310
80	0.031	0.037
81	1.089	—
82	0.022	0.019
83	0.489	0.662 to 0.683
84	0.013	0.012 to 0.083
85	0.524	1.930
86	0.019	0.032 to 0.049
87	>5	6.690
88	0.034	0.048 to 0.058
89	1.776	1.360
90	0.013	0.034
91	—	0.274
92	2.301 to 3.074	2.74 to 8.91
93	0.029 to 0.134	0.043 to 0.383
94	25.642	14.900
95	1.113	1.530
96	>50	—
97	0.984	0.972
98	0.487	0.351
99	3.057	9.790
100	18.066	—
101	0.572	—
102	>50	—
103	6.354	—
104	>50	>25
105	1.720	2.430
106	32.926	>25
107	1.416	1.220
108	5.902	11.700
109	0.136 to 0.167	0.0486 to 0.193
110	23.402	>25
111	3.511	2.780
112	>50	>25
113	42.325	>25
114	>50	>25
115	3.760	7.890
116	>50	>25
117	2.010	1.410
118	1.539	3.560
119	0.029 to 0.042	0.045
120	2.668	—
121	0.045 to 0.081	0.182
122	0.268	0.370
123	0.024 to 0.029	0.017 to 0.044
124	18.8	>25
125	0.158	0.206
126	0.216	0.274
127	0.025 to 0.033	0.032
128	0.071	0.050
129	2.814	1.800
130	2.999	1.510
131	0.153 to 0.171	0.056
132	1.421	0.956
133	0.004 to 0.008	0.007
134	2.360	1.460
135	0.016	0.011
136	>5	11.300
137	0.294	1.190
138	0.024	0.012
139	0.146	0.260
140	4.032	10.600
141	0.116	0.660
142	3.977	>25
143	0.572	0.756
144	1.685	1.670
145	0.036	0.020
146	>5	—
147	0.368	—
148	>5	9.590
149	0.168 to 0.216	0.194
150	>5	—
151	0.012	0.043 to 0.044
152	>5	5.990
153	0.288	0.329
154	3.839	1.790
155	0.857	0.756
156	1.145	2.700
157	0.032	0.033
158	4.374	—
159	0.006	<0.0159
160	1.115	1.230
161	0.305	0.158
162	>5	3.620
163	0.152	0.079
164	>5	4.680
165	0.304	0.152
166	0.243	0.871
167	0.067 to 0.076	0.131
168	>5	3.200
169	0.044 to 0.086	0.038
170	1.884	3.690
171	0.031 to 0.052	0.056
172	3.407	—
173	0.040	0.051 to 0.078
174	0.238	0.230
175	0.049	0.298 to 0.538
176	4.591	12.400
177	1.587	1.230
178	0.077	0.364
179	0.005 to 0.006	0.007
180	2.728	>25
181	0.122	0.138
182	1.378	1.920
183	0.243	0.128
184	0.757	0.502
185	0.021	0.023
186	2.583	2.32 to 2.58
187	0.010	0.022
188	—	8.380
189	0.156	0.064
190	0.014	0.037
191	—	>50
192	0.010	—
193	0.358	—
194	—	0.051
195	—	2.930
196	0.005	<0.0159
197	—	2.010
198	—	0.020
199	—	1.200
200	0.005	0.043
201	—	0.344
202	1.093	1.680
203	0.008	0.016
204	0.02 to 0.05	0.026 to 0.059
205	2.052	2.700
206	0.022	0.03 to 0.051
207	<0.0228624	0.011
208	—	0.101
209	0.164	0.087
210	0.374	0.153
211	2.628	0.496
212	0.057	0.035
213	0.018	0.011 to 0.019
214	0.107	0.046
215	0.106 to 0.138	0.055
216	0.011	0.004
217	0.019 to 0.025	0.012 to 0.033
218	0.018 to 0.044	0.019
219	0.015	0.014
220	0.017	0.014
221	0.046	0.061
222	0.053	0.047
223	0.014	0.023 to 0.046
224	<0.022 to 0.027	<0.016 to 0.029
225	0.038 to 0.063	0.028 to 0.042
226	—	0.009
227	0.22 to 0.023	0.015
228	0.014 to 0.045	0.018 to 0.019
229	0.081	0.054
230	—	>25
231	—	>25
232	0.026	0.024
233	—	0.377
234	—	0.213
235	—	0.964
236	0.023	0.024 to 0.042
237	0.013	0.02 to 0.025
238	0.012	0.017 to 0.024
239	0.020	0.049 to 0.058
240	0.067	0.142
241	0.157	0.114
242	0.053	0.042
243	0.172	0.141
244	—	0.300
245	—	0.115
246	—	0.273
247	—	0.079
248	—	0.172
249	—	0.635
250	—	0.025 to 0.047
251	—	0.020
252	0.353 to 0.482	0.309
253	0.121	0.109
254	—	0.234
255	—	0.450
256	0.489	0.570
257	—	1.200
258	0.435	0.737
259	0.103	0.049 to 0.105
260	0.039	0.040
261	0.089	0.064
262	0.167	0.088
263	—	0.014
264	0.249	0.152
265	0.036	—
266	—	0.453
267	0.095	0.048
268	—	0.338
269	—	0.251
270	0.163	0.174
271	—	0.339
272	—	0.117
273	0.585	—
274	0.265	—
275	0.311	—
276	0.051	—
277	0.086	—
278	0.119	0.301
279	—	12.700
280	—	3.640
281	0.064	0.026
282		4.270
283	0.248	0.068
284	—	0.266
285	0.146	0.053
286	0.145	0.036
287	46.301	2.250
288	0.178	0.055
289	—	2.110
290	0.053	0.034
291	—	>25
292	—	1.850
293	—	>7.91
294	0.563	0.466
295	—	>25
296	0.277	0.251
297	—	2.960
298	0.038	0.020
299	—	0.457
300	0.017	0.010
301	0.033	0.021
302	—	0.045
303	0.097	0.009
304	—	0.304
305	0.772 to 1.781	0.968
306	—	2.570
307	0.038	0.029 to 0.049
308	0.073	0.049 to 0.097
309	0.004 to 0.005	0.003
310	0.128	0.072
311	0.445	0.518
312	0.144	0.066
313	0.019	0.020
314	0.157 to 0.182	0.106 to 0.121
315	0.35 to 0.463	0.161 to 0.514
316	0.261	0.123 to 0.29
317	—	3.7 to 5.63
318	—	>25
319	0.086	0.035
320	0.381	0.426
321	0.087	0.013
322	0.042	0.055 to 0.088
323	0.072	0.071 to 0.122
324	—	0.030
325	0.181	0.041
326	—	0.063
327	0.562	0.236
328	—	1.800
329	0.435	0.863
330	0.850	0.268
331	0.780	0.190
332	0.704	1.020
333	0.640	0.944
334	0.943	0.341
335	0.166 to 0.167	0.257
336	0.048 to 0.049	0.027
337	0.119	0.313
338	0.093	0.091
339	0.024 to 0.027	0.017
340	0.120	0.061
341	—	7.050
342	4.001	0.465
343	0.225	0.073
344	0.300	0.190
345	0.378	0.201
346	0.290	0.189
347	0.564	0.395
348	0.128	0.177
349	—	0.681
350	—	0.413
351	—	0.168
352	—	0.770
353	0.117	0.103
354	0.286	0.051
355	0.381	0.152
356	0.132	0.120
357	0.439	0.358
358	—	0.123
359	0.193	0.171
360	0.119	0.056
361	0.170	0.107
362	0.142	0.072
363	0.009	0.007
364	0.286 to 0.472	0.124
365	0.137	0.033
366	0.345	0.151
367	0.209	0.127
368	0.127	0.091
369	1.277	0.397
370	1.303	0.441
371	0.110	0.125
372	0.029	0.014 to 0.044
373	—	0.051
374	0.021	0.032
375	0.241	0.093
376	0.027	0.023
377	—	0.052
378	—	0.025 to 0.028
379	—	0.053
380	0.050	0.036 to 0.055
381	0.059	0.139
382	0.098	0.219
383	—	0.164
384	—	10.5 to >25
385	—	<0.016 to 0.027
386	—	0.059
387	—	0.032 to 0.036
388	0.006	<0.0159
389	—	0.020
390	0.022	0.022 to 0.037
391	—	0.038 to 0.067
392	—	0.101 to 0.142
393	—	0.057 to 0.081
394	—	0.037 to 0.046
395	—	0.034 to 0.045
396	—	0.024 to 0.041
397	—	0.064 to 0.067
398	—	0.038 to 0.04
399	—	0.018
400	—	0.018 to 0.033
401	—	0.023 to 0.03
402	—	0.044 to 0.05
403	—	0.137
404	—	0.021 to 0.025
405	—	0.027 to 0.037
406	—	0.028 to 0.03
407	0.071	—
408	0.043	—
409	0.501 to 0.515	0.209
410	0.034	0.020
411	1.601	0.756
412	0.223 to 0.347	0.108
413	—	0.023
414	—	2.210
415	0.204	0.483 to 0.859
416	0.110	0.097
417	0.078 to 0.147	0.207
418	0.016 to 0.075	0.015 to 0.044
419	0.039 to 0.06	0.096
420	0.047 to 0.078	0.089
421	0.021	0.023
422	—	1.76 to 2.03
423	—	0.036 to 0.042
424	6.429	7.710
425	0.202 to 0.214	0.303
426	—	<0.0159
427	—	0.039 to 0.55
428	—	0.0678
429	—	<0.016
430	—	0.050
431	—	0.047
432	—	0.016
433	—	0.032
434	—	0.017
435	—	0.017
436	—	0.06
437	—	0.036
438	—	0.045
439	—	0.392
440	—	0.172
441	—	<0.016
442	—	0.038
443	—	0.029
444	—	<0.016
445	—	0.112
446	—	0.0268
447	—	0.028
448	—	<0.016
449	—	0.0297
450	—	<0.016
451	—	0.0435
452	—	0.0293
453	—	0.0357
454	—	0.0234
455	—	<0.016
456	—	<0.016
457	—	0.017
458	—	<0.016
459	—	0.0246
460	—	0.024 to 0.043
461	—	0.045 to 0.064
462	—	0.0738
463	—	0.0395
464	—	0.0937
465	—	0.0681

ENUMERATED EMBODIMENTS

Embodiment 1

A compound according to formula (I)

wherein:
R¹ is hydrogen, methyl or ethyl;
R^2a is hydrogen, methyl or C_1-3 haloalkyl;
R^2b is OH, halo, C_1-6 alkoxy, C_1-3 haloalkyl, NH₂, NH(CH₃) or N(CH₃)₂;
R³ and R⁴ are each independently hydrogen, methyl or ethyl or R³ and R⁴ are joined together forming cyclopropyl, cyclobutyl or oxetanyl;
R⁵ and R⁶ are each independently hydrogen, deuterium, halo, —C(O)OCH₃, C_1-3 alkyl or C_1-3 haloalkyl;

R⁷ is

wherein:

• • ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms;
  • ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
  • X is N or CH;
  • each R⁸ is independently hydrogen, halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy or C_1-3 haloalkoxy;
  • n is 1 or 2;
  • R⁹ is hydrogen, halo, C_1-3 haloalkyl, optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR^9a, —SO₂R^9a, —C(O)NHR^9a, CH₂R^9b or CHCH₃R^9b, provided that when X is N, R⁹ is hydrogen, C_1-3 haloalkyl, optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO₂R^9a or —C(O)NHR^9a,
  • wherein:
    • said C_1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and
    • said C_3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C_1-6 alkyl, C_1-6 haloalkyl, C_1-3 alkoxy, and C_1-3 haloalkoxy;
  • R^9a is optionally substituted C_1-6 alkyl, C_1-6 haloalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic,
  • wherein:
    • said C_1-6 alkyl is optionally substituted with one C_3-6 cycloalkyl,
    • said C_3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH₂OH, —NRR, cyano, C_1-3 alkyl, C_1-3 haloalkyl, and C_1-3 alkoxy, and
    • Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C_1-6 alkyl, C_1-6 haloalkyl, C_1-3 alkoxy, and C_1-3 haloalkoxy;
  • R^9b is optionally substituted C_3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
    • said C_3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH₂OH, —NRR, —NRC(O)CH₃, 4 to 6 membered heterocyclic, cyano, halo, C_1-3 alkyl, C_1-3 haloalkyl, and C_1-3 alkoxy, and
    • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_1-3 alkoxy, and C_1-3 haloalkoxy; and
  • each R is independently selected from the group consisting of H, C_1-3 alkyl and C_3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

Embodiment 2

The compound according to embodiment 1 wherein R³ and R⁴ are both hydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 3

The compound according to embodiment 1 or 2 wherein R¹ is hydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 4

The compound according to any one of embodiments 1-3 according to formula (II):

or a pharmaceutically acceptable salt thereof.

Embodiment 5

The compound according to any one of embodiments 1-4 wherein:

• • R⁵ is hydrogen or halo; and
  • R⁶ is hydrogen, halo, methyl, CH₂F, CHF₂, or CF₃; or a pharmaceutically acceptable salt thereof.

Embodiment 6

The compound according to embodiment 5 wherein R⁵ is hydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 7

The compound according embodiment 5 wherein R⁶ is hydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 8

The compound according to embodiment 5 wherein R⁵ and R⁶ are both hydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 9

The compound according to any one of embodiments 1-8 wherein R^2a is methyl; or a pharmaceutically acceptable salt thereof.

Embodiment 10

The compound according to any one of embodiments 1-9 wherein R^2b is OH, fluoro, methoxy, t-butoxy, CHF₂, CF₃, NH₂ or NH(CH₃); or a pharmaceutically acceptable salt thereof.

Embodiment 11

The compound according to any one of embodiments 1-10 having the following formula:

wherein R^2b is OH, NH₂ or fluoro; or a pharmaceutically acceptable salt thereof.

Embodiment 12

The compound according to any one of embodiments 1-11 according to formula (IV):

wherein R^2b is OH or NH₂; or a pharmaceutically acceptable salt thereof.

Embodiment 13

The compound according to embodiment 12 wherein R^2b is OH; or a pharmaceutically acceptable salt thereof.

Embodiment 14

The compound according to embodiment 12 wherein R^2b is NH₂; or a pharmaceutically acceptable salt thereof.

Embodiment 15

The compound according to any one of embodiments 1-11 according to formula (V):

or a pharmaceutically acceptable salt thereof.

Embodiment 16

The compound according to embodiment 15 wherein R^2a is methyl; or a pharmaceutically acceptable salt thereof.

Embodiment 17

The compound according to any one of embodiments 1-16 wherein R⁷ is:

or a pharmaceutically acceptable salt thereof.

Embodiment 18

The compound according to any one of embodiments 1-17 wherein R⁹ is hydrogen, halo, C_1-3 haloalkyl, optionally substituted C_1-6 alkyl or optionally substituted C_3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

Embodiment 19

The compound according to any one of embodiments 1-17 wherein R⁹ is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH₂OH, C_1-4 alkyl, C_1-4 haloalkyl and C_1-3 haloalkoxy; or a pharmaceutically acceptable salt thereof.

Embodiment 20

The compound according to any one of embodiments 1-17 wherein R⁹ is pyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which is optionally substituted; or a pharmaceutically acceptable salt thereof.

Embodiment 21

The compound according to any one of embodiments 1-17 wherein R⁹ is CH₂R^9b wherein R^9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, halo, CH₂OH, —NRR, cyano, C_1-3 alkyl, C_1-3 haloalkyl, and C_1-3 alkoxy.

Embodiment 22

The compound according to embodiment 1 according to formula (IV)

wherein:

R^2b is OH;

R⁵ is hydrogen or fluoro;

R⁶ is hydrogen, chloro, methyl or CH₂F;

R⁷ is

R⁸ is hydrogen, methyl or fluoro;
n is 1 or 2; and

R⁹ is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C_1-4 alkyl, CF₂H and CF₃ or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF₃ and C(CH₃)₂CF₃; or a pharmaceutically acceptable salt thereof.

Embodiment 23

The compound according to embodiment 22 wherein:

R⁵ is hydrogen and R⁶ is chloro, methyl or CH₂F or
R⁶ is hydrogen and R⁵ is fluoro; or a pharmaceutically acceptable salt thereof.

Embodiment 24

The compound according to embodiment 22 wherein R⁵ and R⁶ are both hydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 25

The compound according to embodiment 1 according to formula (V)

wherein:
R^2b is fluoro;
R⁵ is hydrogen or fluoro;
R⁶ is hydrogen;

R⁷ is

R⁸ is hydrogen or methyl;
n is 1; and
R⁹ is phenyl optionally substituted with one chloro; or a pharmaceutically acceptable salt thereof.

Embodiment 26

The compound according to embodiment 1 selected from the group consisting of:

• (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
• (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

Embodiment 27

The compound according to embodiment 1 selected from the group consisting of:

• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
• (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
• (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
• (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
• (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

Embodiment 28

The compound according to embodiment 1 selected from the group consisting of:

• (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
• (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
• (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

Embodiment 29

The compound according to embodiment 1 selected from the group consisting of:

• (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one; and
• (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

Embodiment 29

The compound according to embodiment 1 selected from the group consisting of:

• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
• (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
• (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and
• (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

Embodiment 30

A pharmaceutical composition comprising a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Embodiment 31

A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, to subject in need of thereof.

Embodiment 32

A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, and another therapeutic agent to subject in need of thereof.

Claims

1. A compound according to formula (I) wherein:

R1 is hydrogen, methyl or ethyl;

R2a is hydrogen, methyl or C1-3 haloalkyl;

R2b is OH, halo, C1-6 alkoxy, C1-3 haloalkyl, NH2, NH(CH3) or N(CH3)2;

R3 and R4 are each independently hydrogen, methyl or ethyl or R3 and R4 are joined together forming cyclopropyl, cyclobutyl or oxetanyl;

R5 and R6 are each independently hydrogen, deuterium, halo, —C(O)OCH3, C1-3 alkyl or C1-3 haloalkyl;

R7 is

wherein: ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms; ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S; X is N or CH; each R8 is independently hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; n is 1 or 2; R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR9a, —SO2R9a, —C(O)NHR9a, CH2R9b or CHCH3R9b, provided that when X is N, R9 is hydrogen, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO2R9a or —C(O)NHR9a, wherein: said C1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and Said C3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; R9a is optionally substituted C1-6 alkyl, C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic, wherein: said C1-6 alkyl is optionally substituted with one C3-6 cycloalkyl, Said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; R9b is optionally substituted C3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic, said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, —NRC(O)CH3, 4 to 6 membered heterocyclic, cyano, halo, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C1-6 alkyl, Cl—6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; and each R is independently selected from the group consisting of H, C1-3 alkyl and C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R3 and R4 are both hydrogen; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R1 is hydrogen; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 according to formula (II): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein:

R5 is hydrogen or halo; and

R6 is hydrogen, halo, methyl, CH2F, CHF2, or CF3; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 wherein R5 is hydrogen; or a pharmaceutically acceptable salt thereof.

7. The compound according claim 5 wherein R6 is hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 5 wherein R5 and R6 are both hydrogen; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R2a is methyl; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R2b is OH, fluoro, methoxy, t-butoxy, CHF2, CF3, NH2 or NH(CH3); or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 having the following formula:

wherein R2b is OH, NH2 or fluoro; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 according to formula (IV): wherein R2b is OH or NH2; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 wherein R2b is OH; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 12 wherein R2b is NH2; or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 according to formula (V): or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15 wherein R2a is methyl; or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 wherein R7 is: or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 wherein R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl or optionally substituted C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 wherein R9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH2OH, C1-4 alkyl, C1-4 haloalkyl and C1-3 haloalkoxy; or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 wherein R9 is pyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which is optionally substituted; or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 wherein R9 is CH2R9b wherein R9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, halo, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy.

22. The compound according to claim 1 according to formula (IV)

wherein:

R2b is OH;

R5 is hydrogen or fluoro;

R6 is hydrogen, chloro, methyl or CH2F;

R7 is

R8 is hydrogen, methyl or fluoro;

n is 1 or 2; and

R9 is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C1-4 alkyl, CF2H and CF3 or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF3 and C(CH3)2CF3; or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 22 wherein:

R5 is hydrogen and R6 is chloro, methyl or CH2F or

R6 is hydrogen and R5 is fluoro; or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 22 wherein R5 and R6 are both hydrogen; or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1 according to formula (V) wherein:

R2b is fluoro;

R5 is hydrogen or fluoro;

R6 is hydrogen;

R7 is

R8 is hydrogen or methyl;

n is 1; and

R9 is phenyl optionally substituted with one chloro; or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1 selected from the group consisting of:

(R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and

(R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1 selected from the group consisting of:

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;

(R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;

(R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;

(R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and

(R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 1 selected from the group consisting of:

(R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;

(R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and

(R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1 selected from the group consisting of:

(R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one; and

(S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 1 selected from the group consisting of:

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;

(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;

(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and

(S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

32. A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to subject in need of thereof.

33. A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and another therapeutic agent to subject in need of thereof.