2H-CHROMENE COMPOUND AND DERIVATIVE THEREOF

- ASTELLAS PHARMA INC.

Provided is a 2H-chromene compound or a derivative thereof which has an excellent S1P1 agonist action. The 2H-chromene compound or derivative is particularly useful for preventing and/or treating a disease induced by undesirable lymphocyte infiltration or a disease induced by abnormal proliferation or accumulation of cells.

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Description
TECHNICAL FIELD

The present invention relates to a 2H-chromene compound and a derivative thereof, which are useful as an active ingredient for a pharmaceutical composition, particularly a pharmaceutical composition for preventing or treating diseases induced by undesirable lymphocyte infiltration or diseases induced by abnormal proliferation or accumulation of cells.

BACKGROUND ART

Sphingosine 1-phosphate is a metabolite of sphingolipid which is a physiologically active substance secreted from an activated platelet (Annual Review Biochemistry, 2004, Vol. 73, pp. 321-354). The sphingosine 1-phosphate receptor is a G-protein-binding type, and belongs to an Edg-family which is the endothelial differentiation gene. Up to now, five receptors of S1P1 (Edg1), S1P2 (Edg5), S1P3 (Edg3), S1P4 (Edg6), and S1P5 (Edg8) have been found. All of these receptors are broadly distributed in cells and tissues throughout the body, but S1P1, S1P3, and S1P4 are predominantly expressed in lymphocyte and endothelial cells, S1P2 is predominantly expressed in vascular smooth muscle cells, S1P5 is predominantly expressed in brain and spleen, and amino acid sequences thereof are well-conserved among humans and rodents (Annual Review Biochemistry, 2004, Vol. 73, pp. 321-354).

Many receptors bind to G-proteins by stimulation of sphingosine 1-phosphate. S1P1 binds to Gi/0, S1P2 and S1P3 binds to Gi/0, Gq, G12/13, and Gs, S1P4 binds to Gi/0, G12/13, and Gs, S1P5 binds to Gi/0 and G12/13, and cell proliferation caused by activation of MAPK, changes in the cytoskeletal system and cell infiltration caused by activation of Rac (and/or Rho), and production of cytokine and mediators caused by activation of PLC and calcium influx into cell, and the like (Annual Review Biochemistry, 2004, Vol. 73, pp. 321-354) are induced.

It has been known that through the stimulating action of S1P1 of sphingosine 1-phosphate, migration of lymphocyte, inhibition of apoptosis, production of cytokine, and sequestration of lymphocytes in the thymus and other secondary lymphoid tissues are induced, and angioplasty in vascular endothelial cells is promoted (Nature Review Immunology, 2005, Vol. 5, pp. 560-570). On the other hand, expression of S1P3 is also found on cardiomyocyte, and a transient decrease in the heart rate (infrequent pulse) or in the blood pressure through the stimulation of sphingosine 1-phosphate is observed (Japanese Journal of Pharmacology, 2000, Vol. 82, pp. 338-342). Infrequent pulse is not observed through the stimulation of sphingosine 1-phosphate in knockout mice wherein S1P3 is genetically deficient (Journal of Pharmacology and Experimental Therapeutics, 2004, Vol. 309, pp. 758-768).

It has been known that FTY720 and an FTY720 phosphate which is an active main body thereof have an excellent S1P1 agonist action and thus induce lymphocyte sequestration, and their effects on skin graft or multiple sclerosis, which are autoimmune diseases, is reported (Cellular & Molecular Immunology, 2005, Vol. 2, No. 6, pp. 439-448; and The New England Journal of Medicine, 2006, Vol. 355, pp. 1124-40). However, there have also been reported side effects such as infrequent pulse, reduced lung function (Transplantation, 2006, 82, pp. 1689-1967). It is reported that the FTY720 phosphate has a non-selective agonist action on S1P3, S1P4, and S1P5 (Science, 2002, Vol. 296, pp. 346-349), and between them, a clinical trial result that infrequent pulse induced by a stimulating action through S1P3 is expressed with high frequency as an undesirable side-effect has been reported (Journal of American Society of Nephrology, 2002, Vol. 13, pp. 1073-1083).

As a compound having an S1P1 agonist action, Patent Document 1 discloses a compound of the following general formula (A):

[wherein n represents 1 or 2; A represents —C(O)OR9 or the like; R9 represents hydrogen or alkyl; X represents a bond, C1-4 alkylene, —X1OX2—, or the like, in which X1 and X2 are independently selected from a bond and C1-3 alkylene; Y represents a condensed 5,6- or 6,6-hetero bicyclic ring system containing at least one aromatic ring, in which the condensed bicyclic ring system of Y may be substituted, if desired; R1 is selected from C6-10 aryl and C2-9 heteroaryl, in which any aryl or heteroaryl is substituted with C6-10 aryl C0-4 alkyl, C2-9 heteroaryl, C0-4 alkyl, C1-6 alkyl, or the like, if desired, R2, R3, R5, R6, R7, and R8 independently represent hydrogen, C1-6 alkyl, halo, or the like; R4 represents hydrogen or C1-6 alkyl; or R7 and any one of R2, R4 or R5 are combined with an atom to which they bind to form a 4- to 7-membered ring; in which the 4- to 7-membered ring is saturated or partially unsaturated] and a pharmaceutically acceptable salt, a hydrate, a solvate, an isomer, and a prodrug thereof (for details, refer to Patent Document 1), and as a specific compound thereof, for example, the benzothienyl compound above is disclosed as Example 1.

Furthermore, Patent Document 2 discloses that a compound of the following general formula (B):

[in the general formula, Ring A represents a cyclic group; Ring B represents a cyclic group which may have a substituent; X represents a spacer having one to eight atoms in the main chain, or the like; Y represents a spacer having one to ten atoms in the main chain, or the like; n represents 0 or 1; in the case where n is 0, m represents 1, and further, R1 represents a hydrogen atom or a substituent; in the case where n is 1, m represents 0 or an integer of 1 to 7, and further, R1 represents a substituent (when m is 2 or more, a plurality of R1 may be the same as or different from each other)], a salt thereof, a solvate thereof, or a prodrug thereof (for details, refer to Patent Document 2) has an S1P receptor-binding ability, and as a specific compound thereof, for example, a tetrahydronaphthalene derivative is disclosed as Example 31-06.

Moreover, Patent Document 3 discloses that a compound of the following general formula (C):

[wherein Ring A represents a cyclic group, Ring B represents a cyclic group which may further have a substituent, X represents a binding arm or a spacer having one to eight atoms in the main chain, in which one atom of the spacer may be combined with a substituent of the Ring B to form a ring which may have a substituent, Y represents a binding arm or a spacer having one to ten atoms in the main chain, in which one atom of the spacer may be combined with a substituent of the Ring B to form a ring which may have a substituent, Z represents an acidic group which may be protected, and n represents 0 or 1, provided that in the case where n is 0, m represents 1, and further, R1 represents a hydrogen atom or a substituent, in the case where n is 1, m represents 0 or an integer of 1 to 7, and further, R1 represents a substituent (when m is 2 or more, a plurality of R1s may be the same as or different from each other)], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as a compound having an S1P receptor-binding ability. As a specific compound thereof, for example, a tetrahydronaphthalene derivative represented by Example 37-6 is disclosed.

However, up to now, there has been a desire for a novel and highly stable S1P1 agonist having the potent S1P1 agonist action of a sphingosine 1-phosphate, and correspondingly, having an excellent lymphocyte sequestering action, and further, having no undesirable actions such as infrequent pulse, reduced lung function, and the like, which have been reported with regard to conventional S1P1 agonists.

PRIOR ART DOCUMENT Patent Document

  • [Patent Document 1] Pamphlet of International Publication WO 2005/000833
  • [Patent Document 2] Pamphlet of International Publication WO 2005/020882
  • [Patent Document 3] Pamphlet of International Publication WO 2006/064757

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

A compound which is useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for preventing or treating diseases induced by undesirable lymphocyte infiltration or diseases induced by abnormal proliferation or accumulation of cells, on the basis of an S1P1 agonist action, is provided.

Means for Solving the Problems

The present inventors have made extensive studies on a compound having an S1P1 agonist action, and as a result, they have found that a 2H-chromene compound represented by the formula (I) below or a derivative thereof has an excellent S1P1 agonist action and is useful as an active ingredient of a pharmaceutical composition for preventing or treating diseases induced by lymphocytic infiltration or diseases induced by abnormal proliferation or accumulation of cells, thereby completing the present invention.

Thus, the present invention relates to a 2H-chromene compound represented by the following formula (1):

(wherein

A represents lower alkyl, cycloalkyl, aryl, or heteroaryl,

wherein aryl and heteroaryl may respectively be substituted with one to five R1s which are the same as or different from each other,

R1 represents halogen, —CN, —NO2, lower alkyl, lower alkenyl, lower alkynyl, halogeno-lower alkyl, aryl, heteroaryl, cycloalkyl, —OH, —O-(lower alkyl), —O-(halogeno-lower alkyl), —O-(aryl), —O-(cycloalkyl), —O-(heteroaryl), —NH2, —NH(lower alkyl), —NH(halogeno-lower alkyl), —N(lower alkyl)2, or cyclic amino,

wherein aryl, heteroaryl, cycloalkyl, and cyclic amino may respectively be substituted with one to five substituents which are the same as or different from each other and selected from the group consisting of halogen, —CN, lower alkyl and halogeno-lower alkyl,

L represents lower alkylene, lower alkenylene, lower alkynylene, -(lower alkylene)-O—, —O-(lower alkylene)-, or -(lower alkylene)-O-(lower alkylene)-,

Q represents S or —C(R2B)═C(R2C)—,

R2A, R2B, and R2C are the same as or different from each other and represent —H, halogen, lower alkyl, halogeno-lower alkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl),

Y represents O, S, or —CH2—, provided that wherein Y is —CH2—, Q is S,

m represents 0 or 1,

R3 represents —H, halogen, lower alkyl, or aryl,

R4A represents —H or lower alkyl,

R4B represents lower alkyl substituted with a group selected from Group G or cycloalkyl substituted with a group selected from Group

or R4A and R4B are combined with N to which they bind to form cyclic amino substituted with a group selected from Group G, in which the cyclic amino may further contain one to four substituents which are the same as or different from each other and selected from the group consisting of halogen, lower alkyl, and halogeno-lower alkyl, and

Group G represents, —C(═O)OH, tetrazolyl, —C(═O)NHS(═O)2(lower alkyl), -(lower alkylene)-C(═O)OH, or

or a derivative thereof, or a salt thereof.

In this regard, in a case where the symbols in any of the chemical formulae in the present specification are also used in other chemical formulae, the same symbols denote the same meanings, unless specifically described otherwise.

Further, the present invention relates to a pharmaceutical composition, which includes the 2H-chromene compound of the formula (I), or a derivative thereof or a salt thereof and a pharmaceutically acceptable excipient, in particular, (1) an S1P1 agonist, (2) a pharmaceutical composition for preventing or treating diseases induced by undesirable lymphocyte infiltration associated with S1P1, (3) a pharmaceutical composition for preventing or treating rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, autoimmune diseases, or inflammatory diseases in humans or animals, (4) a pharmaceutical composition for preventing or treating rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation in humans or animals, (5) a pharmaceutical composition for preventing or treating multiple sclerosis, (6) a pharmaceutical composition for preventing or treating diseases induced by abnormal proliferation or accumulation of cells associated with S1P1, and (7) a pharmaceutical composition for preventing or treating cancer or leukemia.

Furthermore, the present invention relates to a method for preventing or treating diseases induced by undesirable lymphocyte infiltration associated with S1P1, particularly, rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, or multiple sclerosis in humans or animals, which involves administering to a patient an effective amount of the 2H-chromene compound of the formula (I) or a derivative thereof or a salt thereof. Further, the present invention includes use of the 2H-chromene compound of the formula (I) or a derivative thereof or a salt thereof for prevention or treatment of diseases induced by undesirable lymphocyte infiltration associated with S1P1, particularly rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, or multiple sclerosis in humans or animals, and the 2H-chromene compound of the formula (I) or a derivative thereof or a salt thereof to be used for prevention or treatment of diseases induced by undesirable lymphocyte infiltration associated with S1P1, particularly rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, or multiple sclerosis in humans or animals.

Effects of the Invention

The compound of the formula (I) or a salt thereof of the present invention has an S1P1 agonist action and can be used for prevention or treatment of diseases induced by undesirable lymphocyte infiltration, for example, autoimmune diseases or inflammatory diseases such as rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, lung disorders, asthma, atopic dermatitis, inflammatory bowel disease, arteriosclerosis, ischemic reperfusion disorder, and diseases induced by abnormal proliferation or accumulation of cells, for example, cancer, leukemia, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinbelow, the present invention will be explained in detail.

In the specification, the “halogen” means F, Cl, Br, or I. Preferably, examples thereof include F and Cl.

In the present specification, the “lower alkyl” is linear or branched alkyl having one to six carbon atoms (hereinafter simply referred to as C1-6), and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like, in another embodiment, C1-4 alkyl, and in a further embodiment, methyl, ethyl, and isopropyl.

The “lower alkenyl” is linear or branched C2-6 alkenyl, and examples thereof include vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, and the like, and in another embodiment, C2-4 alkenyl.

The “lower alkylene” is linear or branched C1-6 alkylene and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene, and the like, in another embodiment, C1-4 alkylene, and in a further embodiment, methylene and ethylene.

The “lower alkenylene” is linear or branched C2-6 alkenylene and examples thereof include vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, 1,3-pentadienylene, and the like, in another embodiment, C2-4 alkenylen, and in a further embodiment, vinylene and ethylidene.

The “lower alkynylene” is linear or branched C2-6 alkynylene and examples thereof include ethynylene, propynylene, butynylene, pentynylene, hexynylene, 1,3-butadiynylene, 1,3-pentadiynylene, and the like, in another embodiment, C2-4 alkynylene, and in a further embodiment, ethynylene, propynylene, butynylene, and pentynylene.

The “halogeno-lower alkyl” is C1-6 alkyl substituted with one or more halogen atoms, in another embodiment, lower alkyl substituted with one to five halogen atoms, in a further embodiment, C1-3 lower alkyl substituted with one to five halogen atoms, and in an even further embodiment, examples thereof include —CF3, —CH2CF3, —CH(CH3)CF3, and —CH(CH2F)2.

The “cycloalkyl” is a C3-10 saturated hydrocarbon ring group, which may have a bridge. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like, in another embodiment, C3-8 cycloalkyl, in a further embodiment, C3-6 cycloalkyl, and in an even further embodiment, cyclopropyl, cyclopentyl, and cyclohexyl.

The “aryl” is a C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and examples thereof include phenyl and naphthyl, and in another embodiment, phenyl.

The “heteroaryl” is 5- to 6-membered monocyclic heteroaryl containing one to four hetero atoms selected from N, S, and O, and bicyclic heteroaryl formed by condensation thereof with a benzene ring or 5- to 6-membered monocyclic heteroaryl, and may be partially saturated. In another embodiment, examples thereof include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, benzothiazolyl, and indolyl, in another embodiment, heteroaryl of a 5-membered ring, which may be condensed with a benzene ring, and in an even further embodiment, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzothiazolyl, and indolyl.

The “nitrogen-containing monocyclic heteroaryl” means monocyclic heteroaryl, in which one of the ring-constituting atoms is necessarily N and may have one to two hetero atoms selected from N, S, and O as the ring-constituting atom, and in another embodiment, examples thereof include a 5- to 6-membered ring, in a further embodiment, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, and the like, in an even further embodiment, 5-membered ring, and in an even further embodiment, pyrrolyl and imidazolyl.

The “cyclic amino” means monocyclic to tricyclic heterocycloalkyl, in which one of the ring-constituting atoms is necessarily N, may have one to two hetero atoms selected from N, S, and O as the ring-constituting atom, and may have a partially unsaturated bond. In another embodiment, it is a ring having a reduction number of 4 to 9, in a further embodiment, examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, homopiperidinyl, 3-azabicyclo[3.1.0]hexanyl, tetrahydropyridyl, octahydrocyclopenta[c]pyrrolyl, quinuclidinyl, and the like, in an even further embodiment, examples thereof include cyclic amino of a 6-membered ring, in an even further embodiment, examples thereof include piperidinyl, piperazinyl, morpholinyl, and tetrahydropyridyl, and in an even further embodiment, examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, and tetrahydropyridyl.

In the present specification, the expression “which may be substituted with one to five R1s which are the same as or different from each other” means non-substitution or having one to five R1s as the substituents. Further, in the case where a plurality of R1s are present, the R1s may be the same as or different from each other.

Embodiments of the present invention will be described below.

(1) The 2H-chromene compound or a salt thereof, wherein Y is O, Q is —C(R2B)═C(R2C)—, and m is 0.

(2) The 2H-chromene compound or a salt thereof, wherein R4A and R4B are combined with N to which they bind to form cyclic amino selected from azetidinyl, pyrrolidinyl, piperidinyl, and tetrahydropyridyl, which is substituted with group(s) selected from Group G and may be substituted with lower alkyl or halogen.

(3) The 2H-chromene compound or a salt thereof, wherein the group represented by Group G is —C(═O)OH or —C(═O)NHS(═O)2CH3.

(4) The 2H-chromene compound or a salt thereof, wherein A is phenyl, pyridyl, or thienyl, which may be substituted with one to three R1s which may be the same as or different from each other.

(5) The 2H-chromene compound or a salt thereof, wherein L is -(lower alkylene)-O—, lower alkenylene, or lower alkynylene.

(6) The 2H-chromene compound or a salt thereof, wherein R2A is —H or lower alkyl, R2B is —H, R2C is —H or halogen, R3 is —H or halogen, R1 is halogen, lower alkyl, halogeno-lower alkyl, phenyl, pyrrolyl, cycloalkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl), and further, L is —CH2—O—, —CH═CH—, or 3-butynylene.

(7) The 2H-chromene compound or a salt thereof, wherein R4A and R4B are combined with N to which they bind to form piperidinyl or tetrahydropyridyl, which is substituted with —C(═O)OH, L is —CH2—O—, R2A is —H, R2B is —H, R2C is —H or halogen, R3 is —H, and A is phenyl or pyridyl, which is substituted with two R1s which are the same as or different from each other, in which R1 is halogen, halogeno-lower alkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl).

(8) The 2H-chromene compound or a salt thereof, wherein R4A and R4B are combined with N to which they bind to piperidinyl which is substituted with —C(═O)OH and A is phenyl which is substituted with two R1s which are the same as or different from each other.

(9) The 2H-chromene compound or a salt thereof, wherein R4A and R4B are combined with N to which they bind to form tetrahydropyridyl which is substituted with —C(═O)OH, A is pyridyl which is substituted with two R1s which are the same as or different from each other.

Examples of the specific compound included in the present invention include the following compounds or the salts thereof:

  • 1-{[7-({3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
  • 1-({7-[(3-chloro-4-isopropylbenzyl)oxy]-2H-chromen-3-yl}methyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
  • 1-[(7-[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
  • 1-{[7-({3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,3,6-tetrahydropyridine-4-carboxylic acid,
  • 1-{[7-(5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-yl}methoxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
  • (3R)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl]oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
  • 1-[(7-{[4-cyclopentyl-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
  • (3R)-1-{[7-({3-chloro-4-[(1,3-difluoropropan-2-yl)oxy]benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
  • (3S)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
  • (3R)-1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
  • (3R)-1-[(7-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
  • (3S)-1-[(7-[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
  • (3R)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}-N-(methylsulfonyl)piperidine-3-carboxamide, or
  • 1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-4-carboxylic acid.

The compound of the formula (I) may exist in the form of tautomers or geometrical isomers depending on the kind of the substituents. In the present specification, the compound of the formula (I) shall be described in only one form of isomer, yet the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.

In addition, the compound of the formula (I) may have asymmetric carbon atoms or axial chirality in some cases, and correspondingly, it may exist in the form of optical isomers. The present invention includes both an isolated form of the optical isomers of the compound of the formula (I) or a mixture thereof.

Moreover, the present invention also includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like through solvolysis or under physiological conditions. Examples of the group forming the prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) and Pharmaceutical Research and Development, Drug Design, Hirokawa Publishing Company (1990), Vol. 7, 163-198.

Furthermore, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may form an acid addition salt or a salt with a base depending on the kind of substituents. Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditolyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.

Moreover, the present invention also includes various hydrates or solvates, and polymorphic crystal substances of the compound of the formula (I) and a salt thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

In the present specification, the following abbreviations may be used in some cases.

ADDP=1,1′-(azodicarbonyl)dipiperidine, AIBN=2,2′-azobisisobutyronitrile, AcOH=acetic acid, CDI=1,1′-carbonylbis-1H-imidazole, DAST=(diethylamino)sulfur trifluoride, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DCC=dicyclohexylcarbodiimide, DCE=dichloroethane, DCM=dichloromethane, DIBAL=diisobutylaluminum hydride, DIBOC=di-tert-butyl dicarbonate, DIC=N,N′-diisopropylcarbodiimide, DIPEA=diisopropylethylamine, DMA=N,N′-dimethylacetamide, DMAP=4-(N,N′-dimethylamino)pyridine, DME=dimethoxyethane, DMF=N,N′-dimethylformamide, DMSO=dimethylsulfoxide, DPPA=diphenylphosphorylazide, DPPP=1,3-bis(diphenylphosphino)propane, EDCI.HCl=N-[3-(dimethylamino)propyl]-N′-ethylcarboxamide hydrochloride, Et=ethyl, Et2O=diethylether, TEA=triethylamine, EtOAc=ethyl acetate, EtOH=ethanol, HOBt=1-hydroxy-1H-benzotriazole, IPE=diisopropylether, t-BuOK=potassium tertiary butoxide, LAH=lithium aluminum hydride, MS4 Angstrom=molecular sieves 4 Angstrom, MeCN=acetonitrile, MeOH=methanol, MgSO4=anhydrous magnesium sulfate, NB S=N-bromosuccinimide, NCS=N-chlorosuccinimide, NMP=N-methylpyrrolidone, NT=not tested, Na2SO4=anhydrous sodium sulfate, NaBH(OAc)3=sodium triacetoxyborohydride, NaBH4=sodium borohydride, NaOEt=sodium ethoxide, NaOH=sodium hydroxide, NaOMe=sodium methoxide, TBP=tri-normal butylphosphine, PDC=pyridinium dichromate, POCl3=phosphorous oxychloride, PPh3=triphenylphosphine, Pd(OAc)2=palladium (II) acetate, Pd(PPh3)4=tetrakis(triphenylphosphine)palladium (0), TEA=triethylamine, TFA=trifluoroacetic acid, THF=tetrahydrofuran, TMEDA=N,N,N′N′-tetramethylethylenediamine, Tf=CF3S(═O)2—, brine=saturated brine, i-PrOH=2-propanol, n-BuLi=normal butyllithium, n-BuOH=normal butylalcohol, t-BuOH=tertiary butylalcohol, and tert=tertiary.

(Preparation Methods)

The compound of the formula (I) and a salt thereof can be prepared using the characteristics based on the basic structure or the type of substituents thereof and by applying various known synthesis methods. During the preparation, replacing the relevant functional group with a suitable protective group (a group that can be easily converted into the functional group) at the stage from starting material to an intermediate may be effective depending on the type of the functional group in production technology in some cases. The protective group for such a functional group may include, for example, the protective groups described in “Greene's Protective Groups in Organic Synthesis (4th Ed., 2006)” written by P. G. M. Wuts and T. W. Greene, and one of these may be selected and used as necessary depending on the reaction conditions. In this kind of method, a desired compound can be obtained by introducing the protective group, by carrying out the reaction and by eliminating the protective group, as necessary.

In addition, the prodrug of the compound of the formula (I) can be prepared by introducing a specific group or by carrying out the reaction using the obtained compound of the formula (I) at the stage from a starting material to an intermediate, just as in the case of the above-mentioned protective group. The reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, and the like.

Hereinbelow, the representative preparation methods for the compound of the formula (I) will be described. Each of the production processes may also be carried out with reference to the References appended in the present description. Further, the preparation methods of the present invention are not limited to the examples as shown below.

<Production Process 1>

The compound (I) of the present invention can be obtained by subjecting a compound (A) and a compound (B) to reductive amination.

The process in Step 1 is reductive amination. The compound (A) and the compound (B) are used in equivalent amounts or with either thereof in an excess amount, and the mixture is stirred under any condition from at −45° C. to under refluxing, particularly, from 0° C. to room temperature, usually for 0.1 hour to 5 days, in a vehicle which is inert to the reaction, in the presence of a reducing agent. Examples of the vehicle include alcohols such as MeOH, EtOH, and the like; ethers such as Et2O, THF, dioxane, DME, and the like; halogenated hydrocarbons such as DCM, DCE, chloroform, and the like; and a mixed vehicle thereof. Examples of the reducing agent include NaBH3CN, NaBH(OAc)3, NaBH4, and the like. It may be preferable in some cases to carry out the reaction in the presence of a dehydrating agent such as molecular sieves and the like, or an acid such as acetic acid, hydrochloric acid, a titanium (IV) isopropoxide complex, and the like. An imine that is a reaction intermediate may be isolated as a stable intermediate, and by reducing the imine intermediate, the compound (I) can be obtained. Further, the reaction can be carried out in a vehicle such as MeOH, EtOH, EtOAc, and the like in the presence or absence of an acid such as acetic acid, hydrochloric acid, and the like, using a reduction catalyst (for example, palladium on carbon, Raney nickel, and the like), instead of the reducing agent. In this case, the reaction is carried out under a hydrogen atmosphere from normal pressure to 50 atmospheres, under any temperature condition from cooling to heating.

  • [References] (1) “Comprehensive Organic Functional Group Transformations II” written by A. R. Katritzky and R. J. K. Taylor, Vol. 2, Elsevier Pergamon, 2005, (2) “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

<Production Process 2>

(wherein Hal represents halogen).

The compound (I) of the present invention can be obtained by alkylating the compound (C) with the compound (B).

The process in Step 2 is alkylation. The compound (B) and the compound (C) are used in equivalent amounts or with either thereof in an excess amount, and the mixture is stirred under any temperature condition from cooling to heating and refluxing, preferably from 0° C. to 80° C., usually for 0.1 hour to 5 days, in a vehicle which is inert to the reaction or without a vehicle. Examples of the vehicle include aromatic hydrocarbons; ethers; halogenated hydrocarbons; DMF, DMSO, EtOAc, and MeCN; and a mixed vehicle thereof. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or N-methylmorpholine, and the like, or an inorganic base such as K2CO3, Na2CO3 or KOH, and the like. It may be advantageous in some cases for the smooth progress of the reaction to add an inorganic salt such as NaI and the like to a reaction system.

  • [Reference] “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

<Intermediate Production Process 1>

(wherein Tf represents CF3S(═O)2— and L1 represents lower alkylene or lower alkenylene).

The compound (A-1) can be prepared by a Sonogashira reaction from a compound (D).

The Step 3-1 is triflation. The compound (E) can be prepared by subjecting a compound (D) to undergo a reaction with trifluoromethanesulfonic anhydride. As the vehicle that usually does not disturb the reaction among the halogenated hydrocarbons, the reaction is carried out in the presence of organic bases such as pyridine, TEA, DIPEA, and the like under any temperature condition from −10° C. to ice-cooling. Further, the organic base may be used in combination with a vehicle.

Step 3-2 is a so-called Sonogashira reaction. The compound (A-1) can be prepared by adding a catalytic amount of a Pd(0) catalyst and a base to a compound (E) to allow terminal acetylene to undergo a reaction. It may be advantageous in some cases for the smooth progress of the reaction to add copper iodide to a reaction system. Examples of the vehicle include ethers; aromatic hydrocarbons such as toluene, xylene, and the like; DMF, DMSO, EtOAc; and a mixed vehicle thereof. For example, a base such as TEA, pyrrolidine, and the like may be used in combination with a vehicle. As for a reaction temperature, the reaction can be carried out under any temperature condition from room temperature to under reflux.

  • [Reference] K. Sonogashira, Tetrahedron Letters, 1975, 50, pp. 4467.

<Intermediate Production Process 2>

The compound (A-2) can be prepared by reducing a compound (G) and dehydrating it, and formylating the obtained compound (J).

The Step 4-1 is a reduction reaction of a ketone. The compound (G) is treated with an equivalent amount or excess amount of a reducing agent under any temperature condition from cooling to heating, preferably from −20° C. to 80° C., usually for 0.1 hour to 3 days, in a vehicle which is inert to the reaction. Examples of the vehicle include ethers; alcohols; aromatic hydrocarbons; DMF, DMSO, EtOAc, and a mixed vehicle thereof. As the reducing agent, hydride reducing agents such as NaBH4, DIBAL, and the like, metal reducing agents such as sodium, zinc, iron, and the like, and further, the reducing agents in the following References are suitably used.

  • [References] (1) “Reductions in Organic Chemistry, 2nd ed. (ACS Monograph: 188)” written by M. Hudlicky, ACS, 1996, (2) “Comprehensive Organic Transformations” written by R. C. Larock, 2nd ed., VCH Publishers, Inc., 1999, (3) “Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)” written by T. J. Donohoe, Oxford Science Publications, 2000, (4) “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

The Step 4-2 is a dehydration reaction. Usually, a starting material is stirred in concentrated sulfuric acid under a warming condition, and then distillation is continued until the eluent no longer exits.

The Step 4-3 is formylation. The compound (A-2) is obtained by the reaction of the compound (J) with a formamide derivative. Here, the formamide derivative means a formamide compound in which lower alkyls or aryls which are the same as or different from each other bind to nitrogen atoms of the formamide. For a Vilsmeier complex prepared by the reaction of the formamide derivative with POCl3, the aromatic ring is subjected to nucleophilic substitution to produce an ammonium salt. This can be hydrolyzed under a basic condition to obtain a formyl product. In this reaction, a compound (J) and a DMF equivalent are used in equivalent amounts or with either thereof in an excess amount, and the mixture is stirred in a vehicle which is inert to the reaction or without a vehicle, in the presence of a halogenating agent. This reaction is carried out under any temperature condition from room temperature to heating and refluxing, usually for 0.1 hour to 5 days. Examples of the vehicle include halogenated hydrocarbons; ethers; or MeCN. The halogenating agent is used so as to derive a DMF derivative into a Vielsmeier complex, and usually, it is not particularly limited as long as it is a reagent used for halogenations of alcohols, but phosphorous pentachloride, POCl3, or the like may be appropriately used.

  • [Reference] (1) “Strategic Applications of Named Reactions in Organic Synthesis” written by L. Kurti and B. Czako, Elsevier Inc, 2005, pp. 468-469

<Intermediate Production Process 3>

(wherein Lv represents a leaving group).

The compound (A-3) is obtained by the reaction of a compound (K) with a compound (L).

The Step 5-1 is alkylation. Examples of the leaving group Lv include halogen, methanesulfonyloxy, p-toluenesulfonyloxy groups, and the like.

The compound (K) and the compound (L) are used in equivalent amounts or with either thereof in an excess amount, and the mixture is stirred in a vehicle which is inert to the reaction or without a vehicle, under any temperature condition from cooling to heating and refluxing, preferably from 0° C. to 80° C., usually for 0.1 hour to 5 days. Examples of the vehicle include aromatic hydrocarbons; ethers; halogenated hydrocarbons; DMF, DMSO, EtOAc, MeCN; and a mixed vehicle thereof. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of organic bases such as TEA, DIPEA, N-methylmorpholine, and the like, or inorganic bases such as K2CO3, Na2CO3, KOH, and the like. It may be advantageous in some cases for the smooth progress of the reaction to add inorganic salts such as NaI and the like to a reaction system.

  • [Reference] “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

<Intermediate Production Process 4>

The compound (C) can be obtained from the compound (A) via the compound (M).

The Step 6-1 is reduction. The compound (M) can be obtained by stirring the compound (A) with an equivalent amount or excess amount of a reducing agent in a vehicle which is inert to the reaction, under any temperature condition from cooling to heating, preferably from −20° C. to 80° C., usually for 0.1 hour to 3 days. Examples of the vehicle used are not particularly limited, but include ethers such as diethylether, THF, dioxane, and dimethoxyethane, alcohols such as MeOH, EtOH, 2-propanol, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, DMF, DMSO, EtOAc, and a mixed vehicle thereof. As the reducing agent, hydride reducing agents such as NaBH4, DIBAL, and the like, metal reducing agents such as sodium, zinc, iron, and the like, and the reducing agents in the following References are suitably used.

REFERENCES

  • “Reductions in Organic Chemistry, 2nd ed. (ACS Monograph: 188)” written by M. Hudlicky, ACS, 1996
  • “Comprehensive Organic Transformations” written by R. C. Larock, 2nd ed., VCH Publishers, Inc., 1999
  • “Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)” written by T. J. Donohoe, Oxford Science Publications, 2000
  • “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

The Step 6-2 is halogenation. The compound (C) can be obtained by subjecting the compound (M) to halogenation. As the halogenating agent, a halogenating agent for converting a hydroxyl group to halogen is used. The halogenating agent is not particularly limited, but, for example, PBr3, HBr, BBr3, PCl3, PCl5, or the like is used. As the vehicle, ethers are preferable, and for example, THF, diethylether, dimethoxyethane, methyl-t-butylether, dioxane, 2-methyltetrahydrofuran, or the like is used.

<Intermediate Production Process 5>

(wherein X represents —O— or a bond, R represents a protecting group of a carboxylic group, R′ and R″ represent lower alkyl, n and p each represent an integer of 0 to 4, which are the same as or different from each other, and further, a sum of n and p represents 4 or less. represents a single bond or a double bond).

The compound (T) can be prepared by sequentially performing a Wittig reaction, reduction, oxidation, and construction of a chromene skeleton from the compound (N). The compound (T) in whichis a single bond is obtained by carrying out a reduction reaction at a step which does not disturb the reaction.

The Step 7-1 is a phosphorus ylide-forming reaction. The compound (O) is obtained by reacting the compound (N) with, for example, triethyl phosphite or the like, usually in a vehicle which does not disturb the reaction. Examples of the vehicle include aromatic hydrocarbons; ethers; halogenated hydrocarbons; ketones such as acetone, ethylmethylketone, and the like; DMF, DMSO, EtOAc, MeCN; and a mixed vehicle thereof. As for a reaction temperature, the reaction can be carried out under any temperature condition from −20° C. to heating.

The Step 7-2 is a so-called Wittig reaction. The compound (O) can be reacted with an aldehyde compound (P) to prepare a compound (Q). By the aldehyde addition of phosphoryl group-substituting carbanions, olefins can be obtained through a Wittig-like mechanism. The reaction temperature is any of the conditions from 0° C. to warming.

  • [References] (1) J. Boutagy CRV, 79, 87, 1974, (2) W. S. Wadsworth Jr OR, 25, 73, 1977.

The Step 7-3 is a reduction reaction. As the reducing agent, LiAlH4, LiAlH(OMe)3, or DIBAL is used, and the reaction can be carried out in a vehicle which is inert to the reaction, such as THF, ethers, and the like, usually under any temperature condition from cooling to heating.

The Step 7-4 is an oxidation reaction. As the oxidizing agent, manganese dioxide or PDC is used. Examples of the vehicle usually include halogenated hydrocarbons and the like. As for the reaction temperature, the reaction is carried out under any temperature condition from 0° C. to heating, usually at room temperature. As other methods, there is a method using a DMSO-POCl3-based reagent. A method using a reagent such as DCC, acid anhydrides, chlorine, or Me2S—NCS-based reagents (Corey-Kim oxidation) or using a Dess-Martin Periodinane, instead of POCl3, can also be used. The reaction usually proceeds under any temperature condition from room temperature to warming. Examples of the vehicle are not particularly limited, but include aromatic hydrocarbons; ethers; halogenated hydrocarbons; MeCN, and a mixed vehicle thereof.

The Step 7-5 is a chromene ring-constituting reaction. The compound (T) can be prepared by adding an acrolein derivative to the compound (S), followed by stirring under any temperature condition from room temperature to heating in the presence of an inorganic base such as K2CO3 and the like. Examples of the vehicle include aromatic hydrocarbons; ethers; halogenated hydrocarbons; MeCN, and a mixed vehicle thereof. Usually, ether-based vehicles such as THF, DME, dioxane, and the like are used.

The compound in whichof a compound (T) is a single bond is obtained by reducing some compounds among the compound (P) through the compound (S). This is a so-called reduction reaction of olefins. Usually, the compound is stirred in a vehicle which is inert to the reaction in the presence of a metal catalyst, usually for 1 hour to 5 days, under a hydrogen atmosphere. This reaction is usually carried out under any temperature condition from cooling to heating, preferably at room temperature. Examples of the vehicle are not particularly limited, but include alcohols such as MeOH, EtOH, i-PrOH, and the like; ethers; water, EtOAc, DMF, DMSO; and a mixed vehicle thereof. As the metal catalyst, palladium catalysts such as palladium on carbon, palladium black, palladium hydroxide, and the like, platinum catalysts such as a platinum plate, platinum oxide, and the like, nickel catalysts such as reduced nickel, Raney nickel, and the like, rhodium catalysts, iron catalysts such as reduced iron and the like, etc. are suitably used. Instead of hydrogen gas, formic acid or ammonium formate in an equivalent amount or in an excess amount can also be used as a hydrogen source for the compound.

  • [References] (1) “Reductions in Organic Chemistry, 2nd ed. (ACS Monograph: 188)” written by M. Hudlicky, ACS, 1996, (2) “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)” edited by The Chemical Society of Japan, Vol. 19 (2005) (Maruzen)

Furthermore, some compounds represented by the formula (I) can also be prepared by any combination of the steps that can usually be employed by a person skilled in the art, such as known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, deprotection, halogenation, and the like, from the compound of the present invention prepared as above.

For example, for alkylation, an alkylation reaction that is usually used by a person skilled in the art can be employed, and the alkylation can be carried out in an organic vehicle which is inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons; DMF, MeCN; aprotic polar vehicles, and the like, under cooling, from under cooling to room temperature, or from at room temperature to under heating, in the presence of bases such as NaH; carbonic acid alkali; hydrogen carbonate alkali; alkoxide; tertiary amine; organic bases, and the like.

Further, for example, acylation can employ an acylation reaction that is usually used by a person skilled in the art can be employed, but the acylation is carried out in an organic vehicle which is inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons; esters such as EtOAc, and the like; MeCN; aprotic vehicles, and the like, using a condensing agent such as EDCI.HCl, CDI, diphenylphosphorylanide, and the like, depending on the reaction condition, but usually under cooling, under any temperature condition from cooling to room temperature, or under any temperature condition room temperature to heating, particularly in the presence of HOBt.

The compounds of the formula (I) can be isolated and purified as their free compounds, salts, hydrates, solvates, or polymorphic crystal substances thereof. The salts of the compound of the formula (I) can be prepared by carrying out a conventional salt-forming reaction.

Isolation and purification are carried out by employing ordinary chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.

Various isomers can be prepared by selecting an appropriate starting compound or separated by using the difference in the physicochemical properties between the isomers. For example, the optical isomers can be obtained by means of a general method for designing optical resolution of racemic products (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), and further, the isomers can also be prepared from an appropriate optically active starting compound.

The pharmacological activity of the compound of the formula (I) was confirmed by the tests shown below.

Test Example 1 Evaluation of In Vitro S1P1 Receptor Agonist Activity in Biological Body

(Method 1) Method for Evaluation on Receptor Agonist Action by GTP[γ-35S] Binding Assay Using Membrane of Human S1P1 Expressing Cell

The in vitro S1P1 agonist action of the compound of the present invention was evaluated by the increase in the functional binding activity of GTP[γ-35S] to G-protein using the membrane of a human S1P1 expressing cell. A cDNA encoding a human S1P1 was cloned from a human colorectal cDNA library and introduced to an expression vector pcDNA3.1 to construct a S1P1-pcDNA3.1. Then, by Lipofectamine 2000 (GIBCO), the S1P1-pcDNA3.1 was transfected into a CHO cell, and cultured in a Ham's F-12 culture medium containing 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 1 mg/mL G418 disulfate, to obtain a stable, G418-resistant strain. The cultured human S1P1 expressing cells were isolated in a 1 mM EDTA.2Na-containing PBS, and disrupted under ice-cooling by a homogenizer made of glass in a 1 mM Tris HCl (pH 7.4) buffer solution containing 0.1 mM EDTA and a protein inhibitor. It was centrifuged at 1,400×10 min, and a supernatant was further centrifuged at 4° C. for 60 min at 100,000×g, and suspended in a 10 mM Tris HCl (pH 7.4) buffer solution containing 1 mM EDTA to purify the membrane. The obtained membrane (0.13 mg/mL) and 50 pM GTP[γ-35S] (NEN; inactive 1250 Ci/mmol) were reacted in a 20 mM HEPES (pH 7.0) buffer solution (total amount: 150 μL) containing 100 mM NaCl, 10 mM MgCl2, 0.1% fatty acid-free BSA, and 5 μM GDP for 1 hour together with the compound of the present invention (10−12 to 10−5 M), and then a membrane was recovered on a GF-C filter plate with a Cell Harvester (Packard, FilterMate). The filter plate was dried at 50° C. for 60 min, and Microscinti-o (Packard) was added thereto for measurement by a liquids scintillation counter for a microplate (Packard, TOP count). For evaluation of the human S1P1 agonist action of the compound of the present invention and the comparative compound, the percentages with the rate of a maximum reaction to make the GTP[γ-35S] bonds saturated in the presence of the compound being set at 100%, and the rate of the reaction of the GTP[γ-35S] bonds in the absence of the compound being set at 0% were used, a non-linear regression curve was plotted, and a concentration to cause an agonist action operating 50% of the maximum reaction was defined as an EC50 value (nM).

(Method 2) Method for Evaluation of Receptor Agonist Action by Ca2+ Influx Assay Using Human S1P1 Expressing Cell

The in vitro S1P1 agonist action of the compound of the present invention was evaluated by the increase in the Ca2+ concentration in a human S1P1 expressing cell. A cDNA encoding a human S1P1 was cloned from a human colorectal cDNA library and introduced to an expression vector pcDNA3.1 to construct a S1P1-pcDNA3.1. Then, by Lipofectamine 2000 (GIBCO), the S1P1-pcDNA3.1 was transfected into a CHO cell, and cultured in a Ham's F-12 culture medium containing 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 1 mg/mL G418 disulfate, to obtain a stable, G418-resistant strain. The cultured human S1P1 expressing cells were isolated in a 1 mM EDTA.2Na-containing PBS and suspended in a Ham's F-12 culture medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. This cell suspension was dispensed to a 96-well plate at 50000 cells/well, and cultured at a CO2 incubator (5% CO2, 37° C.) overnight. The culture medium was replaced with a calcium-sensitive fluorescent reagent (FLIPR (registered trademark) calcium 3 assay kit, molecular device)-containing loading buffer (Hank's balance salt solution, 20 mM HEPES, 2.5 mM probenecid) and left stand at a CO2 incubator (5% CO2, 37° C.) for 1 hour. The plate was set at a Functional Drug Screening System FDSS6000 (Hamamatsu Photonics K. K.), and persistently measured 124 times every 1.02 second at an excitation wavelength of 480 nm. The test compound (final concentration 1042 to 10−5 M) was added at the same time as the 12th measurement, and the change in the Ca2+concentration in cells was evaluated by the change in the fluorescent strength. For evaluation of the human S1P1 agonist action of the compound of the present invention and the comparative compound, the percentages with the rate of a maximum reaction to make the increase in the Ca2+ concentration in cells saturated after the addition of the compound being set at 100% and the rate of the increase in the Ca2+ concentration in cells by the addition of a vehicle alone being set at 0% were used, a non-linear regression curve was plotted, and a concentration to cause an agonist action operating 50% of the maximum reaction was defined as an EC50 value (nM).

Test Example 2 Evaluation of Reduction of Number of Peripheral Blood Lymphocytes in Rat

The action on the peripheral blood lymphocytes were evaluated using rats. 6-to 10-week-old male Lewis rats (Japan Charles River Laboratories Japan, Inc.) were randomly divided into groups (n=3), and the compound of the present invention was suspended in 0.5% methyl cellulose-containing distilled water, and orally administered with a sonde. At 4 hours or 24 hours after administration, 0.2 ml of blood was collected from the ocular fundus under ether anesthesia. To the blood sample were immediately added EDTA.4K and heparin to prevent clotting, and the number of the lymphocytes in blood was measured with an automatic hematocyte analyzer (Sysmex Corp.; XT-2000i). For the reduction of the number of the lymphocytes in peripheral blood by the compound of the present invention, the percentage with the number of the lymphocytes in groups administered with 0.5% methyl cellulose-containing distilled water being set at 100%, as performed at the same time, were used, and the dose to cause 50% reduction of the number of the lymphocytes in the peripheral blood by administration of the compound of the present invention was defined as an ED50 value (mg/kg).

The results of Test Example 1 and Test Example 2 on some compounds of the formula (I) are shown in Tables 1 and 2. In the tables, Column A shows in vitro S1P1 agonist action, EC50 values (nM) by the method 1 of Test Example 1 provided that the value with * shows the EC50 values measured by the method 2. Further, Column B shows the action of reducing the number of the lymphocytes in the peripheral blood at 4 hours or 24 hours after administration of the drug of Test Example 2 with ED504 h (mg/kg) or ED5024 h (mg/kg), respectively.

As shown in Table 1 and 2, it was confirmed that the compound of the formula (I) of the present invention has an excellent S1P1 agonist action and has a potent action of reducing the number of the lymphocytes in the peripheral blood even at 4 hours or 24 hours after administration in the pharmacological test using rats.

TABLE 1 A: EC50 B: ED504 h No (nM) (mg/kg) Ex1 1.7 0.016 Ex25 1.7 0.013 Ex31 1.2 0.065 Ex34 2 0.010 Ex43 6.2 0.26 Ex44 3.7 0.37 Ex45 1.5 0.10 Ex56 2.3 0.067 Ex62 2.5 0.21 Ex66 10 0.21 Ex69 6.3 0.087 Ex74 5.6 0.59 Ex81 4.6 0.25 Ex85 11 0.19 Ex89 6.1 0.16 Ex109 5.4 0.26 Ex116 8.5 0.10 Ex132 22 0.16 Ex137 9.4 0.11 Ex141 5.9 0.099 Ex143 NT 0.32 Ex144 NT 0.16

TABLE 2 A: EC50 B: ED5024 h No (nM) (mg/kg) Ex149 8.7  0.12 Ex151 1.1* 0.35 Ex152 6.3* 0.28 Ex156 16*   0.086 Ex160 2.2* 0.26 Ex171 9.0* 0.14 Ex178 55    0.12 Ex181  0.68* 0.29 Ex183 5.5* 0.21 Ex212 1.1* 0.21 Ex216 7.8* 0.25 Ex223 1.1* 0.32 Ex230 7.0* 0.19 Ex236 32*   0.10

Test Example 3 Evaluation of Increase in Lung Weight in Rats

The increased lung weight in rats, one of the undesirable effects observed for conventional S1P1 agonists, was evaluated. 6- to 10-week-old male Lewis or SD rats (Japan Charles River Laboratories Japan, Inc.) were randomly divided into groups (n=3 to 4), and the compound of the present invention was suspended in 0.5% methyl cellulose-containing distilled water, and orally administered with a sonde. For single-time administration, at 24 hours after administration, the weight of the rat was measured, the blood was removed under anesthesia with pentobarbital, and the lung was taken out and its weight was measured. For repeated administration, the administration was made once a day for 7 days, and at 24 hours after the final administration, the weight and the lung weight were measured. For the increased lung weight, the increase rate of the average of the relative weights of the group administered with a suspension of the compound of the present invention in 0.5% methyl cellulose-containing distilled water to the average of the relative weights of the group administered with 0.5% methyl cellulose-containing distilled water was denoted as a percentage and the administration amount showing 10% or more of the increased lung weight was determined as positive.

It was confirmed that among the compounds of the present invention, the compounds of Examples 31, 43, 44, 45, 56, 62, 66, 69, 74, 81, 85, 89, 109, 116, 137, 143, 149, 151, 152, 160, 171, 178, 181, 183, 212, 216, 223, 230, and 236 had an increased lung weight of less than 10% even at a dose of 1 mg/kg and a weak action on the lung.

Test Example 4 Evaluation of Rejection Inhibiting Action in Heterotopic Rat Abdominal Heart Transplant

A heterotopic rat abdominal heart transplant model can be carried out in accordance with the method of Ono and Lindsey (Transplantation, 1969, 517, pp. 225-229). As a donor, 6- to 8-week male ACI rats (CLEA Japan, Inc.) were employed, and the hearts were exposed under anesthesia with pentobarbital. The left and right vena cava other than aorta and pulmonary artery, pulmonary veins, and inferior vena cava were ligated at once and the aorta and the pulmonary vein were detached and removed as a graft. 6- to 8-week male Lewis rats (Japan Charles River Laboratories Japan, Inc.) were used as recipients. Under anesthesia with pentobarbital, the pulmonary artery end of the graft and the abdominal aorta of the recipient were anastomosed and the pulmonary artery end of the graft and the vena cava of the recipient were anastomosed to prepare a model (grouped into 6 to 10 examples per group). The rejection determination of the transplanted heart promotes the recipient's abdominal palpation every 29 days after transplantation, and the presence or absence of the beating of the graft is determined on the rejection. The compound of the present invention is suspended in 0.5% methylcellulose-containing distilled water and orally administered once or twice a day for 14 days from the date of the transplant. As a control, 0.5% methylcellulose-containing distilled water is orally administered the same number of times during the same period. Simultaneously, 0.02 mg/mL/kg of tacrolimus are administered intramuscularly to all of the groups. By this test, the rejection inhibiting action of the compound of the present invention when tacrolimus is used in combination can be determined.

Test Example 5 Evaluation of Infrequent Pulse Expression Using Awake Rats

Male Lewis rats were anesthetized with isoflurane inhalation and a polyethylene tube was intubated into the femoral artery and vein. It was connected to a blood pressure measuring amplifier·heart rate unit via a pressure transducer from an arterial line, and the arterial blood pressure and the heart rate were measured. Intravenous line from Vehicle (10% HCO40/tween80/PEG, 90% saline) and the present compounds were intravenously infused persistently at a rate of 1 mL/kg/min for 10 minutes. The measurement data were read (for a total evaluation time of 20 minutes) from a chart of the values before administration, at 1, 2, 5, and 10 min after the start of constant infusion, and at 1, 2, 5, and 10 min after the completion of infusion, and thus, for the heart rate and the blood pressure before administration, the decrease rates (%) before and after infusion were calculated.

It was confirmed that among the compounds of the present invention, for example, the compound of Example 230 does not have an influence on the heart rate and the blood pressure at 1 mg/kg administration by the present evaluation, and the infrequent pulse is not expressed.

As the results of the tests above, it was confirmed that the compound of the formula (I) of the present invention has an excellent S1P1 agonist action and has a lymphocytic infiltration inhibiting action. Further, as shown in Test Examples 3 and 4 above, Example compounds of some embodiments of the present invention can be an S1P1 agonist action, which has weak undesirable actions in which the undesirable actions are observed in conventional S1P1 agonists, such as increased lung weight, infrequent pulse, and the like and small side-effects.

Accordingly, the compound of the formula (I) of the present invention is useful for preventing or treating diseases induced by undesirable lymphocyte infiltration, for example, rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, autoimmune diseases or inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, lung disorders, asthma, atopic dermatitis, inflammatory bowel disease, arteriosclerosis, ischemic reperfusion disorder, and the like, and diseases induced by abnormal proliferation or accumulation of cells, for example, cancer, leukemia, and the like, particularly for preventing or treating rejection or graft-versus-host diseases during organs, bone marrow, or tissue transplantation, and multiple sclerosis.

In addition, the compound of the present invention can be administered as an S1P1 agonist alone, or in combination with at least one agent, in the same or different doses, through the same or different administration routes. Examples of the agent that can be combined include, but are not limited thereto, cyclosporin A, tacrolimus, sirolimus, everolimus, mycophenolate, azathioprine, brequinar, Leflunomide, fingolimod, an anti-IL-2 receptor antibody (for example, daclizumab and the like), an anti-CD3 antibody (for example, OKT3), anti-T cell immunoglobulin (for example, AtGam and the like), belatacept, abatacept, cyclophosphamide, n-interferon, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, anti-inflammatory steroid (for example, prednisolone, and dexamethasone), and the like.

A pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared using excipients that are usually used in the art, that is, excipients for pharmaceutical preparations, carriers for pharmaceutical preparations, and the like, according to the methods usually used.

Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration injections, such as intraarticular, intravenous, or intramuscular injections, and the like, suppositories, ophthalmic solutions, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.

The solid composition for oral administration is used in the form of tablets, powders, granules, or the like. In such a solid composition, one or more active ingredient(s) are mixed with at least one inactive excipient, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminometasilicate, and/or the like. According to a usual method, the composition may contain inactive additives, including lubricants such as magnesium stearate like, disintegrating agents such as carboxymethyl starch sodium, stabilizing agents, and solubilization assisting agents. If necessary, tablets or pills may be coated with sugar or a film of a gastric or enteric coating substance.

The liquid composition for oral administration contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also contains generally used inert diluents, for example, purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain auxiliary agents, such as a solubilization assisting agent, a moistening agent, and a suspending agent, as well as sweeteners, flavors, aromatics, and antiseptics.

The injections for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions, or emulsions. As the aqueous solvent, for example, distilled water for injection or physiological saline is included. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and the like, alcohols such as ethanol and the like, polysorbate 80 (pharmacopeia), etc. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizer, or a solubilizing aid. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with bactericides, or irradiation. In addition, these can also be used by producing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile vehicle for injection prior to its use.

Examples of the formulation for external use include ointments, plasters, creams, jellies, patches, sprays, lotions, eye-drops, eye ointments, and the like. The drug contains generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, or the like. Examples of the ointment bases or lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.

Regarding a transmucosal agent such as an inhalation, a transnasal agent, and the like, the transmucosal agents in a solid, liquid or semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known excipient, as well as a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizer, a thickener, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or insufflation may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension by combining it with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device and the like. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form of a pressurized aerosol spray which uses an appropriate ejection agent, for example, chlorofluoroalkane, hydrofluoroalkane, or a suitable gas such as carbon dioxide and the like.

Usually, in the case of oral administration, the daily dose is suitably from 0.001 to 100 mg/kg per body weight, preferably from 0.1 to 30 mg/kg, and more preferably from 0.1 to 10 mg/kg, and this is administered in one portion or dividing it into 2 to 4 portions. In the case of intravenous administration, the daily dose is suitably from about 0.0001 to 10 mg/kg per body weight, and this is administered once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, and this is administered once a day or two or more times a day. The dose is appropriately decided in response to an individual case by taking the symptoms, the age, the gender, and the like into consideration.

The compound of the formula (I) can be used in combination with various agents for treating or preventing the diseases, in which the compound of the formula (I) as described above is considered effective. The combined preparation may be administered simultaneously or separately and persistently or at a desired time interval. The preparations to be administered simultaneously may be a blend or may be prepared individually.

EXAMPLES

Furthermore, the following abbreviations may be used in some cases in the Examples, Preparation Examples, and Tables described later.

Pr=Preparation Example No., Ex=Example No., RefEx=Reference Example No., Str=Structural Formula, MS=Mass Spectrometric Data, ESI (EI)=Electrospray Ionization Anaylsis Data, FAB=Mass Spectrometric Data according to Fast Atom Bombardment Ionization, Hz=Hertz, CDCl3=deuterated chloroform, DMSO-d6=dimethylsulfoxide d6.

Further, the crossed double bonds in the structural formula mean a mixture of a cis-form and a trans-form. In the 1H-NMR data, tetramethylsilane is used as an internal standard unless otherwise specifically described, and δ (ppm) (integrated value, disintegrated pattern) of signals in 1H-NMR in which DMSO-d6 is used as a measurement vehicle. In the present specification, NMR represents 1H-NMR: Proton

Nuclear Magnetic Resonance. Further, the suffixes + and − of MS and ESI (EI) each represents positive mass data and negative mass data.

Preparation Example 1

7-[(5-Bromo-4-phenyl-2-thienyl)methoxy]-2H-chromene-3-carbaldehyde (120 mg) was dissolved in DMF (2.4 mL). To this reaction liquid were added Zn(CN)2 (65 mL) and Pd(PPh3)4 (65 mg) at room temperature. The reaction mixture was stirred at 100° C. for 5 hours and then poured into 1:1 a mixed vehicle of aqueous NaHCO3 and EtOAc, followed by stirring for 1 hour. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain 5-{[(3-formyl-2H-chromen-7-yl)oxy]methyl}-3-phenylthiophene-2-carbonitrile (83 mg) as a pale yellow solid.

Preparation Example 2

To a solution of methyl 5-bromo-4-phenylthiophene-2-carboxylate in dioxane were added 2-isopropenyl-4,4,5,5-tetramethyl 1,3,2-dioxaborolane and a 2 M aqueous Na2CO3 solution. To the reaction mixture were added palladium acetate and PPh3, followed by stirring at 100° C. for 5 hours. After leaving to be cooled, a saturated aqueous NH4Cl solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (hexane:EtOAc=95:5 to 80:20) to obtain methyl 5-isopropenyl-4-phenylthiophene-2-carboxylate as a colorless liquid.

In the same manner as in Preparation Example 2, the compounds of Preparation Example 2-1 through Preparation Example 2-4 shown in Tables described later were prepared.

Preparation Example 3

To a solution of DMF (2.5 mL) in DCM (3 mL) was added dropwise POCl3 (2 mL) at 0° C., followed by stirring at room temperature for 30 minutes. Subsequently, to the reaction liquid were added dropwise 8-(benzyloxy-3,4-dihydro-1-benzoxepin-5(2H)-one in DCM (4 mL), followed by stirring at room temperature for 1 hour and at 50° C. for 3 hours. To the reaction liquid was added water, followed by extraction with EtOAc twice. The organic layer was combined, washed with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device; hexane:EtOAc=97:3 to 90:10) to obtain 8-(benzyloxy)-5-chloro-2,3-dihydro-1-benzoxepin-4-carbaldehyde (445 mg).

Preparation Example 4

To a solution of DMF (2 mL) in DCM (7.5 mL) was added dropwise POCl3 (1.39 mL) at 0° C., followed by stirring at room temperature for 30 minutes. Subsequently, to the reaction liquid was added dropwise a solution of 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-one (2.00 g) in DCM (11 mL), followed by stirring at room temperature for 1 hour and at 50° C. for 3 hours. To the reaction liquid was added water, followed by extraction with EtOAc twice. The organic layer was combined, washed with water and brine, and dried over MgSO4, and the liquid was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 4-chloro-7-hydroxy-2H-chromene-3-carbaldehyde (720 mg).

Preparation Example 5

7-(benzyloxy)-2,3-dihydro-4H-chromen-4-one was dissolved in THF, a solution (0.97 M, 5 mL) of methylmagnesium bromide in THF was added dropwise thereto at 0° C., followed by stirring at room temperature for 1 hour, and a solution (0.97 M, 5 mL) of methylmagnesium bromide in THF was added dropwise thereto, followed by stirring at room temperature for 2 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution and subsequently 2 M hydrochloric acid (20 mL), followed by stirring at room temperature for 2 hours and then extracting with EtOAc three times. The organic layer was combined, washed with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 90:10) to obtain 7-(benzyloxy)-4-methyl 2H-chromene (445 mg) as a colorless transparent liquid.

In the same manner as in Preparation Example 5, the compound of Preparation Example 5-1 shown in Tables described later was prepared.

Preparation Example 6

To a solution of 2-hydroxy-4-[(2-methoxy-4-propylphenoxy)methyl]benzaldehyde (120 mg) in dioxane (2.4 mL) were added K2CO3 (55.2 mg) and acrolein (0.267 mL) at 25° C. The reaction mixture was warmed to 100° C., followed by stirring at 100° C. for 15 hours. The reaction mixture was left to be cooled to 25° C., and then filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 7-[(2-methoxy-4-propylphenoxy)methyl]-2H-chromene-3-carbaldehyde (104.2 mg) as a colorless liquid.

In the same manner as in Preparation Example 6, the compounds of Preparation Example 6-1 through Preparation Example 6-9 and Preparation Example 6-11 shown in Tables described later were prepared.

Preparation Example 6-10

K2CO3 (835 mg) was suspended in dioxane (40 mL), and 2-hydroxy-4-(methoxymethoxy)benzaldehyde (1 g) and 3-methyl 2-butanal (0.787 mL) were added thereto, followed by stirring at 110° C. overnight. EtOAc was added thereto, the insoluble materials were removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 70:30) to obtain 7-(methoxymethoxy)-2,2-dimethyl-2H-chromene-3-carbaldehyde (320 mg) as a yellow oil.

Preparation Example 7

At 0° C., to a mixed vehicle of concentrated HCl (8 mL) and AcOH (1.6 mL) was added tert-butyl 3-cyano-3-(fluoromethyl)azetidine-1-carboxylate (800 mg). The liquid was warmed to 25° C., followed by stirring at 25° C. for 1 hour and then at 100° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, followed by azeotroping with toluene (30 mL) three times. The residue was dissolved in a mixed vehicle of acetone (4.8 mL) and water (8.0 mL), and at 0° C., Na2CO3 (593.7 mg) and DIBOC (1223 mg) were added thereto. The reaction liquid was warmed to 25° C., followed by stirring at 25° C. for 15 hours. Fifteen hours later, the reaction solution was concentrated and acetone was evaporated. The residue was extracted three times (50 mL×3) by the addition of ether (50 mL). The aqueous layer was combined and cooled to 0° C., and at 0° C., 2 M HCl (10 mL) was added thereto to prepare a solution at pH=2 to 3. The precipitated white solid was collected by filtration and washed with hexane (50 mL) to obtain 1-(tert-butoxycarbonyl)-3-(fluoromethyl)azetidine 3-carboxylic acid (801.2 mg) as a white solid.

Preparation Example 8

tert-Butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (5.0 g) was dissolved in DCM (100 mL). At 0° C., DAST (3.74 mL) was added thereto, followed by stirring at 0° C. for 3 hours. Three hours later, to the reaction liquid was added an aqueous NaHCO3 solution (100 mL), followed by extraction with DCM (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyano-3-(fluoromethyl)azetidine-1-carboxylate (1.24 g) as a brown solid.

Preparation Example 9

2-Fluoro-4,6-dihydroxybenzaldehyde (12 g) was dissolved in MeCN (250 mL), and cesium carbonate (25.1 g) and chloromethylmethylether (6.95 mL) were added thereto, followed by stirring at room temperature for 1 hour. The insoluble materials were removed by filtration through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 94:6) to obtain 2-fluoro-6-hydroxy-4-(methoxymethoxy)benzaldehyde (11.89 g) as a white powder.

In the same manner as in Preparation Example 9, the compounds of Preparation Example 9-1 through Preparation Example 9-4 shown in Tables described later were prepared.

Preparation Example 10

7-Hydroxy-2,3-dihydro-4H-chromen-4-one (900 mg) was dissolved in DMF (10 mL), and tert-butyl(chloro)diphenylsilane (1.711 mL) and 1H-imidazole (448 mg) were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=90:10 to 80:20) to obtain 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-one (2.08 g) as a colorless transparent syrup.

In the same manner as in Preparation Example 10, the compound of Preparation Example 10-1 shown in Tables described later was prepared.

Preparation Example 11

To a solution of 7-hydroxy-2H-chromene-3-carbaldehyde in DCM was added pyridine at 0° C. To the reaction liquid was added dropwise trifluoromethanesulfonic anhydride at 0° C. After stirring at room temperature for 1 hour, water was added thereto at 0° C. The mixture was extracted with EtOAc. The organic layer was washed with 1 M HCl, water, and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=95:5 to 80:20) to obtain 3-formyl-2H-chromen-7-yl trifluoromethanesulfonate as a yellow oily substance.

In the same manner as in Preparation Example 11, the compound of Preparation Example 11-1 shown in Tables described later was prepared.

Preparation Example 12

To DMF (1 mL) was added dropwise POCl3 (0.25 mL) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 7-(benzyloxy)-4-methyl 2H-chromene (280 mg) in DCM (1 mL), followed by stirring at room temperature for 3 hours. The reaction liquid was poured into ice-water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=85:15 to 70:30) to obtain 7-(benzyloxy)-4-methyl-2H-chromene-3-carbaldehyde (234 mg) as a pale yellow powder.

In the same manner as in Preparation Example 12, the compound of Preparation Example 12-4 was prepared from the compound of Preparation Example 12-1 shown in Tables described later.

Preparation Example 13

A solution of NaH (105.63 mg) in DMF (5.5 mL) was cooled to 0° C., and methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (550 mg) was added thereto. The reaction mixture was warmed to 25° C., then stirred for 1 hour, and cooled to 0° C. again, and 2-methoxy-4-propylbenzaldehyde (235.34 mg) was added thereto. The reaction mixture was warmed to 25° C. and then stirred for 15 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution (50 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 70:30) to obtain methyl 2-hydroxy-4-[(E)-2-(2-methoxy-4-propylphenyl)vinyl]benzoate (304.2 mg) as a white solid.

In the same manner as in Preparation Example 13, the compound of Preparation Example 13-1 shown in Tables described later was prepared.

Preparation Example 14

To DMF (40 mL) was added 60% NaH (634 mg) under ice-cooling, and a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (2 g) in DMF (20 mL) was slowly added thereto. After stirring at room temperature for 5 hours, the reaction was quenched with a saturated NH4Cl solution, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then filtered. The filtrate was concentrated to obtain 4-isopropoxy-3-(trifluoromethyl)benzonitrile (2.4 g) as a pale yellow solid.

In the same manner as in Preparation Example 14, the compounds of Preparation Example 14-1 through Preparation Example 14-16 shown in Tables described later were prepared.

Preparation Example 15

To a solution of methyl 4-fluoro-2-(trifluoromethyl)benzoate in DMF were added K2CO3 and piperidine, followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to 0° C., and water was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain methyl 4-piperidin-1-yl-2-(trifluoromethyl)benzoate as a colorless oily substance.

In the same manner as in Preparation Example 15, the compounds of Preparation Example 15-1 through Preparation Example 15-4 shown in Tables described later were prepared.

Preparation Example 16

To a solution of methyl 1H-indole-5-carboxylate (1.5 g) in DMF (30 mL) was added NaH (410 mg) at 0° C. The reaction mixture was warmed to 25° C., followed by stirring for 0.5 hours. Then, the reaction mixture was cooled to 0° C. again, and then methyliodide (1.38 mL) was added thereto. The reaction mixture was warmed to 25° C., followed by stirring for 3 hours. To the reaction liquid was added water (50 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, CHCl3:MeOH=100:0 to 98:2) to obtain methyl 1-ethyl-1H-indole-5-carboxylate (1465 mg) as a white solid.

Preparation Example 17

To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid in MeOH were added concentrated sulfuric acid at 0° C. The reaction mixture was heated and refluxed for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4, and then concentrated under reduced pressure to obtain methyl 4-fluoro-2-(trifluoromethyl)benzoate as a colorless oily substance.

Preparation Example 18

The suspension of 4-bromo-5-ethylthiophene-2-carboxylic acid (800 mg) in MeOH (4 mL) was added dropwise SOCl2 (0.50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, warmed to 60° C., and then stirred for 15 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 70:30) to obtain methyl 4-bromo-5-ethylthiophene-2-carboxylate (765.0 mg) as a colorless liquid.

In the same manner as in Preparation Example 18, the compounds of Preparation Example 18-1 through Preparation Example 18-6 shown in Tables described later were prepared.

Preparation Example 19

To a solution of N-isopropylpropan-2-amine (165.5 mg) in THF (1 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 0.98 mL) at −78° C., followed by warming to 25° C. and then stirring for 30 minutes. After cooling to −78° C. again, a solution of 1-tert-butyl-3-methylpyrrolidine-1,3-dicarboxylate (300 mg) in THF (1 mL) was added dropwise thereto. The reaction mixture was warmed to −40° C. and then stirred for 1 hour. The reaction mixture was cooled to −78° C. again, and a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (495.1 mg) in THF (1 mL) was added dropwise thereto. The reaction mixture was stirred at −78° C. for 1 hour, then warmed to 25° C., and stirred for 15 hours. Fifteen hours later, to the reaction liquid was added a saturated aqueous NH4Cl solution (30 mL), followed by extraction with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 1-tert-butyl 3-methyl-3-fluoropyrrolidine-1,3-dicarboxylate (154.3 mg) as a yellow liquid.

Preparation Example 20

To a solution of methyl 4-phenylthiophene-2-carboxylate (1.8 g) in DCM (18 mL) was added portionwise pyridinium tribromide (13.2 g) at 0° C. The reaction liquid was warmed to 25° C. and then stirred for 45 hours. The reaction mixture was cooled to 0° C., and a saturated aqueous Na2S2O3 solution (100 mL) was slowly added dropwise. The reaction mixture was extracted with DCM (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 90:10) to obtain methyl 5-bromo-4-phenylthiophene-2-carboxylate (2.06 g) as a colorless liquid.

Preparation Example 21

To a solution of 4-chloro-5,5,5-trifluoro-3-phenylpent-3-en-2-one (950 mg) and methylsulfanylacetate (446 mg) in MeCN (23.8 mL) was added dropwise DBU (0.63 mL) at 25° C., followed by stirring at the same temperature for 15 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution (50 mL), followed by extraction with diethylether (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 90:0) to obtain methyl 3-methyl-4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylate (1.08 g) as a colorless liquid.

Preparation Example 22

To a solution of benzyl 3-cyanopyrrolidine-1-carboxylate (1.0 g) and TEA hydrochloride (2.99 g) in toluene was added sodium azide (1.41 g) at 25° C., followed by stirring at 115° C. for 5 hours. The reaction liquid was left to be cooled and DCM (10 mL) was added thereto. Then, to a 5% aqueous salicylic acid solution (100 mL) was added dropwise the reaction liquid, followed by stirring at 25° C. for 1 hour. The reaction liquid was extracted with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain benzyl 3-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate (10.8 g) as a colorless liquid.

Preparation Example 23

To a solution of methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-methylbenzoate (3.4 g) in carbon tetrachloride (68 mL) were added, and NBS (2.16 g) and AIBN (398 mg) were added thereto at room temperature, followed by stirring at 80° C. for 1 hour. Completion of the reaction was confirmed by means of TLC, and to the reaction liquid was added water to stop the reaction, followed by extraction with EtOAc. The organic layer was washed with brine, dried using MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 95:5) to obtain methyl 4-(bromomethyl)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (3.79 g) as a colorless liquid.

Preparation Example 23-1

To a solution of (2S)-3-(4-chlorophenyl)-2-methylpropan-1-ol (300 mg) in DCM (20 mL) were added N-bromosuccinimide (347 mg) and triphenylphosphine (511 mg) under ice-cooling. The reaction liquid was stirred at room temperature for 2 hours, and then the reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over MgSO4, and then vehicle was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain 1-[(2S)-3-bromo-2-methylpropyl]-4-chlorobenzene (373 mg) as a colorless liquid.

Preparation Example 24

To a solution of N-isopropylpropan-2-amine (11.54 mL) in THF (50 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 51.45 mL) at −78° C. The reaction mixture was warmed to 0° C. and then stirred for 30 minutes. The reaction mixture was cooled to −78° C. again, and then a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (5.0 g) in THF (30 mL) was added dropwise, followed by stirring at −78° C. for 1 hour. To the reaction mixture was added dropwise a solution of 1H-benzotriazol-1-yl-methanol (8.19 g) in THF (20 mL) at −78° C., followed by stirring at −78° C. for 3 hours. To the reaction mixture was added a saturated aqueous NH4Cl solution (100 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (5.68 g) as a white solid.

Preparation Example 25

A solution of methyl 4-amino-(2-trifluoromethyl)benzoate hydrochloride (1.24 g) and 2,5-dimethoxytetrahydrofuran (773 mg) in AcOH (20 mL) was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene, and AcOH was evaporated. The obtained yellowish brown oily substance was dissolved in chloroform, and a saturated aqueous NaHCO3 solution was added thereto. The organic layer was washed with a saturated aqueous NaHCO3 solution, water, and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=97:3) to obtain methyl 4-(1H-pyrrolo-1-yl)-2-(trifluoromethyl)benzoate (11.8 g).

In the same manner as in Preparation Example 25, the compound of Preparation Example 25-1 shown in Tables described later was prepared.

Preparation Example 26

To a solution of trimethyl(pro-1-pyn-1-yl)silane (877 mg) in THF (60 mL) were added a solution of n-BuLi in hexane (1.58 M, 4.5 mL) was added at −78° C. The reaction mixture was stirred at −78° C. for 3 hours, and then a solution of 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (2 g) in THF (10 mL) was added dropwise thereto, followed by stirring for 1 hour. To the reaction liquid was added an aqueous NH4Cl solution, followed by extraction with ether. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0) to obtain {4-[2,4-bis(trifluoromethyl)phenyl]but-1-yn-1-yl}(trimethyl)silane (1.8 g) as a colorless liquid.

Preparation Example 27

1-(chloromethyl)-2-methoxy-4-propylbenzene (1.1 g) was dissolved in DMF (20 mL), and 7-hydroxy-2H-chromene-3-carbaldehyde (975 mg) and K2CO3 (1.15 g) were added thereto, followed by stirring at 80° C. for 1 hour. Further, sodium iodide (416 mg) was added thereto, followed by stirring at 80° C. for 1 hour. After confirming completion of the reaction, to the reaction liquid was added water to stop the reaction, followed by extraction with EtOAc three times. The organic layer was combined, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 80:20) to obtain 7-[(2-methoxy-4-propylbenzyl)oxy]-2H-chromene-3-carbaldehyde (1.21 g) as a yellow powder.

In the same manner as in Preparation Example 27, the compounds of Preparation Example 27-1 through Preparation Example 27-6 shown in Tables described later were prepared.

Preparation Example 28

7-Hydroxy-2H-chromene-3-carbaldehyde (200 mg) was dissolved in DMF (5 mL), and K2CO3 (235 mg) and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (0.234 mL) were added thereto, followed by stirring at 80° C. for 30 minutes. The reaction liquid was poured into water, and the resulting powder was collected by filtration and dried under reduced pressure to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2H-chromene-3-carbaldehyde (455 mg) as a pale yellow powder.

In the same manner as in Preparation Example 28, the compounds of Preparation Example 28-1 through Preparation Example 28-27 shown in Tables described later were prepared.

Preparation Example 29

To a solution of 3-formyl-2H-chromen-7-yltrifluoromethanesulfonate (520 mg) in DMF (10.4 mL) were added 1-ethynyl-4-(trifluoromethyl)benzene (330 μL), bis(triphenylphosphine)palladium (II) dichloride (355 mg), and copper iodide (I) (161 mg), and TEA (470 μL) at room temperature. The reaction mixture was stirred at 100° C. for 5 hours. To the reaction mixture was added water under ice-cooling, the insoluble materials were separated by filtration, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain 7-{[4-(trifluoromethyl)phenyl]ethynyl}-2H-chromene-3-carbaldehyde (189 mg).

In the same manner as in Preparation Example 29, the compounds of Preparation Example 29-1 through Preparation Example 29-15 shown in Tables described later were prepared.

Preparation Example 30

To a solution of Pd(PPh3)4 (542 mg) and TEA (4 mL) in DMF (16 mL) were added 1-bromo-4-isobutylbenzene (1 g) and ethynyl(trimethyl)silane (553 mg) at room temperature, followed by stirring at 60° C. for 4 hours. To the reaction liquid was added 1 M hydrochloric acid, followed by extraction with ether. The insoluble materials were filtered through celite. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to obtain [(4-isobutylphenyl)ethynyl](trimethyl)silane (459 mg) as a yellow liquid.

In the same manner as in Preparation Example 30, the compound of Preparation Example 30-1 shown in Tables described later was prepared.

Preparation Example 31

To a solution of copper chloride (10 mg) and Pd(PPh3)4 (60 mg) in DMF (2 mL) were added [(4-isobutylphenyl)ethynyl](trimethyl)silane (288 mg) and 5-fluoro-3-formyl-2H-chromen-7-yl trifluoromethanesulfonate (340 mg) at room temperature, followed by stirring at 80° C. for 12 hours. The reaction liquid was concentrated and the residue was purified by silica gel column chromatography (CHCl3) to obtain 5-fluoro-7-[(4-isobutylphenyl)ethynyl]-2H-chromene-3-carbaldehyde (83 mg) as a yellow solid.

In the same manner as in Preparation Example 31, the compound of Preparation Example 31-1 shown in Tables described later was prepared.

Preparation Example 32

To a solution of 1-[4-phenyl-5-(trifluoromethyl)-2-thienyl]ethanone (1.0 g) in THF (20 mL) was added dropwise DIBAL (0.99 M solution in toluene, 9.34 mL) at −78° C. The reaction mixture was warmed to 25° C. and stirred for 3 hours and a saturated aqueous Rochelle salt solution (50 mL) was added thereto, followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 90:10) to obtain 1-[4-phenyl-5-(trifluoromethyl)-2-thienyl]ethanol (0.99 g) as a colorless liquid.

Preparation Example 33

To a solution of 3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzoic acid (1.085 g) in THF (43 mL) was added dropwise a solution of BH3.THF in THF (1 M, 14 mL) at 0° C. The reaction mixture was warmed to room temperature and then stirred for 15 hours. To the reaction liquid was added 1 M hydrochloric acid at 0° C. to stop the reaction, followed by stirring for 30 minutes and extracting with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain {3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (570 mg) as a white oily substance.

In the same manner as in Preparation Example 33, the compounds of Preparation Example 33-1 through Preparation Example 33-21 shown in Tables described later were prepared.

Preparation Example 34

To a solution of methyl 4-piperidin-1-yl-2-(trifluoromethyl)benzoate (955 mg) in THF (19 mL) were added dropwise a solution of DIBAL in hexane (1 M, 10.0 mL) under ice-cooling, followed by stirring at the same temperature for 2 hours. To the reaction liquid was added dropwise MeOH, and then a saturated aqueous Rochelle salt solution was added thereto, followed by stirring at room temperature for 1 hour. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain [4-piperidin-1-yl-2-(trifluoromethyl)phenyl]methanol (846 mg).

In the same manner as in Preparation Example 34, the compounds of Preparation Example 34-1 through Preparation Example 34-30 shown in Tables described later were prepared.

Preparation Example 35

Methyl 2-hydroxy-4-[(2-methoxy-4-propylphenoxy)methyl]benzoate (300 mg) was dissolved in THF (15 mL). To the reaction liquid was added LAH (103.4 mg) at 0° C., followed by warming from 0° C. to 25° C. and then stirring for 3 hours. To the reaction liquid was added a saturated aqueous Rochelle salt solution (30 mL), followed by extraction with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 2-(hydroxymethyl)-5-[(2-methoxy-4-propylphenoxy)methyl]phenol (245.2 mg) as a white solid.

In the same manner as in Preparation Example 35, the compounds of Preparation Example 35-1 through Preparation Example 35-3 shown in Tables described later were prepared.

Preparation Example 36

To a solution of NaBH4 (93.1 mg) in EtOH (15 mL) was added dropwise a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2,3-dihydro-4H-thiochromen-4-one (1.0 g) in EtOH (5 mL) at 0° C. The reaction mixture was warmed to 25° C., followed by stirring for 3 hours. The reaction liquid was concentrated under reduced pressure and to the residue were added DCM (20 mL) and then saturated aqueous NH4Cl (30 mL) at 0° C., followed by stirring for 1 hour and extracting with DCM three times (30 mL×3). The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 60:40) to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}thiochroman-4-ol (845 mg) as a white solid.

In the same manner as in Preparation Example 36, the compounds of Preparation Example 36-1 through Preparation Example 36-2 shown in Tables described later were prepared.

Preparation Example 37

At a normal pressure under a hydrogen gas atmosphere, to a solution of methyl 4-phenyl-5-vinylthiophene-2-carboxylate (250 mg) in EtOH (5 mL) was added Pd/C (50% wet) (50 mg) at 25° C., followed by stirring for 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain methyl 5-ethyl-4-phenylthiophene-2-carboxylate (247.3 mg) as a colorless liquid.

In the same manner as in Preparation Example 37, the compounds of Preparation Example 37-1 through Preparation Example 37-3 shown in Tables described later were prepared.

Preparation Example 38

To a solution of 5-fluoro-7-hydroxy-2H-chromene-3-carbaldehyde (275 mg) and 2-(hydroxymethyl)-5-methyl-4-phenyl-thiazole (436 mg) in toluene (8.2 mL) were added ADDP (393 mg) and TBP (315 mg) under ice-cooling. The reaction liquid was stirred at room temperature for 15 hours, then IPE was added thereto, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:EtOAc=90:20 to 70:30) to obtain 5-fluoro-7-[(5-5-methyl-4-phenyl-1,3-thiazol-2-yl)methoxy]-2H-2H-chromene-3-carbaldehyde (381 mg) as a pale yellow solid.

In the same manner as in Preparation Example 38, the compounds of Preparation Example 38-1 through Preparation Example 38-61 shown in Tables described later were prepared.

Preparation Example 39

To a solution of 5-({[2′-fluoro-2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-2-(hydroxymethyl)phenol (520 mg) in chloroform (10 mL) was added manganese dioxide (1 g) at room temperature. The reaction liquid was stirred at room temperature for 16 hours, and then filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:EtOAc=95:5 to 80:20) to obtain 4-({[2′-fluoro-2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-2-hydroxybenzaldehyde (180 mg) as a white solid.

In the same manner as in Preparation Example 39, the compounds of Preparation Example 39-1 through Preparation Example 39-6 shown in Tables described later were prepared.

Preparation Example 40

To a solution of [2-({[2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-4,5-dihydro-1-benzothien-6-yl]methanol (1.0 g) in DCM (20 mL) were added PDC (1.36 g) and MS4 Angstrom (1.36 g) at 25° C. The reaction liquid was stirred for 3 hours, and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 2-({[2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-4,5-dihydro-1-benzothiophene-6-carbaldehyde (345 mg) as a colorless liquid.

Preparation Example 41

To a solution of [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (200 mg) in dioxane (1 mL) was added a 4 M hydrogen chloride dioxane solution (1 mL). The reaction liquid was stirred at room temperature for 15 hours, and then concentrated under reduced pressure to obtain piperidin-4-yl acetic acid hydrochloride (140 mg) as a white solid.

In the same manner as in Preparation Example 41, the compounds of Preparation Example 41-1 through Preparation Example 41-5 shown in Tables described later were prepared.

Preparation Example 42

Benzyl 3-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate (300 mg) was added to a mixed solution of concentrated hydrochloric acid (3 mL) and AcOH (0.6 mL), followed by stirring at 100° C. for 5 hours. The reaction liquid was concentrated and then azeotroped with toluene three times (30 mL×3). The residue was dissolved in a mixed solution of acetone (0.9 mL) and water (1.5 mL), and then cooled to 0° C., and Na2CO3(174.5 mg) and DIBOC (359.4 mg) were added thereto. The reaction mixture was warmed to 25° C. and then stirred for 15 hours. The reaction liquid was concentrated. To the residue was added diethylether (30 mL) for extraction three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain tert-butyl 3-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate (102.7 mg) as a colorless liquid.

Preparation Example 43

To 1-tert-butyl 3-methyl 3-fluoropyrrolidine-1,3-dicarboxylate (100 mg) was added a mixed solution of concentrated hydrochloric acid (1 mL) and AcOH (0.2 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and then stirred at 100° C. for 5 hours. After confirming that the starting materials were lost, the resultant was concentrated under reduced pressure and then azeotroped with toluene three times. The residue was dissolved in a mixed liquid of acetone (0.6 mL) and water (1 mL), and Na2CO3 (64 mg) and DIBOC (132 mg) were added thereto at 0° C., followed by warming to room temperature and then stirring for 15 hours. The reaction mixture was concentrated under reduced pressure and acetone was evaporated. To the residue was added diethylether for liquid separation. The aqueous layer was combined, cooled to 0° C., and adjusted to pH=2 to 3 with 2 M hydrochloric acid. EtOAc was added thereto for extraction. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain 1-(tert-butoxycarbonyl)-3-fluoropyrrolidine-3-carboxylic acid (70 mg) as a white solid.

Preparation Example 44

5-Fluoro-7-(methoxymethoxy)-2H-chromene-3-carbaldehyde (1.5 g) was dissolved in acetone (25 mL), and 1 M HCl (20 mL) was added thereto, followed by heating and refluxing for 5 hours. The reaction liquid was concentrated and the residue was dissolved in EtOAc, washed with water and brine, and dried over MgSO4, and the filtrate was concentrated. The residue was washed with chloroform to obtain 5-fluoro-7-hydroxy-2H-chromene-3-carbaldehyde (0.95 g) as a yellow powder.

In the same manner as in Preparation Example 44, the compounds of Preparation Example 44-1 through Preparation Example 44-6 shown in Tables described later were prepared.

Preparation Example 45

7-(Methoxymethoxy)-2,2-dimethyl-2H-chromene-3-carbaldehyde (300 mg) was dissolved in EtOH (10 mL), and (1S)-(+)-10-camphor sulfonic acid (421 mg) was added thereto, followed by stirring at 80° C. overnight. To the reaction liquid was added silica gel, followed by concentration. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=90:10 to 70:30) to obtain 7-hydroxy-2,2-dimethyl-2H-chromene-3-carbaldehyde (175 mg) as a red powder.

Preparation Example 46

To a solution of KOH (358 mg) in MeOH (30 mL) was added {4-[2,4-bis(trifluoromethyl)phenyl]but-1-yn-1-yl}(trimethyl)silane (1.8 g), followed by stirring at room temperature for 18 hours. The reaction liquid was neutralized with 1 M hydrochloric acid and extracted with ether. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0) to obtain 1-but-3-yn-1-yl-2,4-bis(trifluoromethyl)benzene (426 mg) as a colorless liquid.

Preparation Example 47

To 7-(benzyloxy)-4-methyl-2H-chromene-3-carbaldehyde (230 mg) and 1,2,3,4,5-pentamethylbenzene (608 mg) was added TFA (3 mL), followed by stirring at room temperature overnight. The reaction liquid was poured into an aqueous NaHCO3 solution, followed by extraction with EtOAc three times. The organic layer was combined, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=80:20 to 20:80) to obtain 7-hydroxy-4-methyl-2H-chromene-3-carbaldehyde (130 mg) as a pale yellow powder.

In the same manner as in Preparation Example 47, the compounds of Preparation Example 47-1 through Preparation Example 47-2 shown in Tables described later were prepared.

Preparation Example 48

2-Fluoro-4,6-dimethoxybenzaldehyde (22 g) was dissolved in DCM (110 mL), and a solution of BBr3 in DCM (1 M, 300 mL) was added dropwise thereto under ice-cooling, followed by stirring at room temperature overnight. After confirming completion of the reaction, the reaction liquid was poured into ice-water (100 mL), followed by stirring for 1 hour and then extracting with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=80:20 to 60:40) to obtain 2-fluoro-4,6-dihydroxybenzaldehyde (12 g) as a white powder.

Preparation Example 49

To a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}thiochroman-4-ol (800 mg) in toluene (16 mL) was added 4-methylbenzenesulfonic acid (33.7 mg), followed by stirring at 120° C. for 3 hours. To the reaction liquid was added a saturated aqueous NaHCO3 solution (50 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 2,4-bis(trifluoromethyl)benzyl 2H-thiochroman-7-yl ether (753.2 mg) as a colorless liquid.

Preparation Example 50

A mixture of methyl 4-(bromomethyl)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (0.30 g) and triethylphosphite (0.17 g) was mixed at 25° C. and then stirred at 130° C. for 24 hours. The reaction liquid was concentrated under reduced pressure and azeotroped with toluene twice (30 mL×2). The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=40:60 to 10:90) to obtain methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (0.23 g) as a colorless liquid

Preparation Example 51

To a solution of 7-[(4-bromo-5-ethyl-2-thienyl)methoxy]-2H-chromene-3-carbaldehyde (150 mg) in dioxane (4.5 mL) were added [2-(trifluoromethyl)phenyl]boric acid and a 2 M aqueous Na2CO3 solution at 25° C. Then, to the reaction mixture were added palladium acetate (4.44 mg) and PPh3 (20.75 mg), followed by warming to 100° C. and stirring for 5 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution (30 mL), followed by extraction with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 80:20) to obtain 7-({5-ethyl-4-[2-(trifluoromethyl)phenyl]-2-thienyl}methoxy)-2H-chromene-3-carbaldehyde (134.8 mg) as a pale yellow liquid.

In the same manner as in Preparation Example 51, the compounds of Preparation Example 51-1 through Preparation Example 51-5 shown in Tables described later were prepared.

Preparation Example 52

Under a nitrogen atmosphere, to a solution of [3-chloro-4-(trifluoromethyl)phenyl]methanol (800 ng) and phenylboric acid (1.90 g) in toluene (16 mL) were added potassium phosphate (1.61 g), palladium acetate (42.6 mg), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (195.0 mg) at 25° C. The reaction mixture was warmed to 100° C. and then stirred for 15 hours. To the reaction liquid was added water (30 mL), followed by extraction with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=70:30 to 50:50) to obtain [6-(trifluoromethyl)biphenyl-3-yl]methanol (678.3 mg) as a yellow solid.

In the same manner as in Preparation Example 52, the compounds of Preparation Example 52-1 through Preparation Example 52-4 shown in Tables described later were prepared.

Preparation Example 53

A solution of {3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (284 mg) and SOCl2 (179 μL) in DCM (7 mL) was stirred at room temperature for 2 hours. The reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain 2-chloro-4-(chloromethyl)-1-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzene (285 mg) as a colorless liquid.

In the same manner as in Preparation Example 53, the compounds of Preparation Example 53-1 through Preparation Example 53-4 shown in Tables described later were prepared.

Preparation Example 54

To a solution of methyl 4-bromo-3-benzoate (300 mg) in THF (1 mL) were added cyclopentylzinc bromide (9.6 mL) and palladium-tri-tert-butylphosphine (1:2) (123 mg). The reaction liquid was stirred at room temperature for 20 hours. A saturated aqueous NH4Cl solution was added thereto at 0° C., followed by filtration through celite and extraction with EtOAc. The organic layer was washed with brine and dried over MgSO4. The vehicle was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain methyl 3-chloro-4-cyclopentyl benzoate (280 mg) as a yellow solid.

Preparation Example 55

To a solution of (7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methanol (200 mg) in MeCN (5 mL) was added triphenylphosphine dibromide (240 mg). The reaction liquid was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue were added EtOAc and IPE, the resulting solid was removed by filtration, and the filtrate was concentrated to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (230 mg) as a brown liquid. 60% sodium hydride (24 mg) was added to a DMF solution (5 mL) at 0° C., and subsequently, ethyl 1H-pyrazole-4-carboxylate (76 mg) was added thereto. The mixture was stirred at room temperature for 0.5 hours, and a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (220 mg) in DMF (5 mL) was added thereto at 0° C. The reaction liquid was stirred at room temperature for 13 hours, quenched with a saturated NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (111 mg) as a pale yellow solid.

In the same manner as in Preparation Example 55, the compound of Preparation Example 55-1 shown in Tables described later was prepared.

Preparation Example 56

A solution of 4-isopropoxy-3-(trifluoromethyl)benzonitrile (2.4 g) and 5 M NaOH (50 mL) in EtOH (50 mL) was heated and refluxed for 18 hours. The solution was cooled to room temperature, acidified by hydrochloric acid, and then extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:MeOH=100:0 to 95:5). The product was washed with hexane to obtain 4-isopropoxy-3-(trifluoromethyl)benzoic acid (2.2 g) as a white solid.

In the same manner as in Preparation Example 56, the compounds of Preparation Example 56-1 through Preparation Example 56-6 shown in Tables described later were prepared.

Preparation Example 57 5-Bromo-3-(trifluoromethyl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]oxy}pyridine (500 mg) was dissolved in a mixed vehicle of DMSO (5 mL) and MeOH (5 mL). Then, TEA (0.42 mL) was added thereto at 25° C., and then Pd(OAc)2 (17 mg) and DPPP (60 mg) were added thereto at 25° C., followed by stirring at 70° C. for 15 hours under a CO atmosphere. To the reaction solution was added water (30 mL), followed by extraction with EtOAc (20 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, developing solution; hexane:EtOAc=100:0 to 80:20) to obtain methyl 5-(trifluoromethyl)-6-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}nicotinate (403 mg) as a yellow solid. Preparation Example 58

To a solution of ethyl (1-methyl-1,2,3,6-tetrahydropyridin-4-yl)acetate (2.05 g) in dichloroethane (14 mL) was added 1-chloroethyl-chlorofomrate (1.5 mL) at 0° C. The reaction liquid was heated and refluxed for 2.5 hours, and then concentrated under reduced pressure. The residue was dissolved in MeOH (14 mL), and heated and refluxed for 1 hour. After concentration under reduced pressure, the residue was purified by amino column chromatography (chloroform:methanol=100:0 to 80:20) to obtain ethyl 1,2,3,6-tetrahydropyridin-4-ylacetate (130 mg) as a brown liquid.

In the same manner as in Preparation Example 58, the compound of Preparation Example 58-1 shown in Tables described later was prepared.

Preparation Example 59

Methyl 5,6-dichloronicotinate (1.5 g) and 60% sodium hydride (640 mg) were dissolved in THF (45 mL). 1,3-Difluoropropan-2-ol (1.5 g) was added thereto at 0° C., followed by stirring at 0° C. for 3 hours, and the reaction solution was quenched with aqueous NH4Cl. After extraction with EtOAc, the organic layer was dried over MgSO4 and then filtered, and the desiccant was removed. The vehicle was evaporated under reduced pressure, followed by purification by silica gel column chromatography (hexane:AcOEt=100:0 to 50:50) to obtain methyl 5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]nicotinate (1.56 g) as a colorless liquid.

To a solution of methyl 5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]nicotinate (1 g) in THF (20 mL) was added dropwise a 0.99 M solution of DIBAL in toluene (11.3 mL) at 0° C., followed by stirring at 0° C. for 2 hours. Then, the reaction solution was poured into an aqueous Rochelle salt solution, followed by stirring at room temperature for 1 hour. After extraction with an EtOAc-water system, the organic layer was washed with brine, dried over MgSO4, and then filtered, and the desiccant was removed.

The vehicle was evaporated under reduced pressure, followed by purification by silica gel column chromatography (Hex:AcOEt=98:2 to 70:30) to obtain {5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]pyridin-3-yl}methanol (650 mg) as a colorless liquid.

Preparation Example 60

To 5,6-dichloronicotinic acid (2.2 g) was added 1,1,1-trimethoxyethane (4.3 mL), followed by irradiation with microwave at 120° C. for 15 minutes. The reaction mixture was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4 and the vehicle was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=85:15 to 80:20) to obtain methyl 5,6-dichloronicotinate (2.2 g) as a white solid.

Preparation Example 61

To a solution of ethyl 4-pyridyl acetate (2 g) in MeCN (20 mL) was added methyliodide (2.3 mL). The reaction liquid was stirred at room temperature overnight and then concentrated under reduced pressure. To the residue was added IPE and the resulting solid was collected by filtration. The solid was dissolved in MeOH, and sodium borohydride (916 mg) was added there at 15° C. or lower.

The reaction liquid was stirred at room temperature for 6 hours, and then water was added thereto, followed by extraction with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:MeOH=100:0 to 90:10) to obtain ethyl (1-methyl-1,2,3,6-tetrahydropyridin-4-yl)acetate (2.08 g) as a pale yellow liquid.

Preparation Example 62

To a solution of {3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (200 mg) in dichloroethane (5 mL) were added thionyl chloride (111 μL) and a catalytic amount of DMF, followed by stirring at 60° C. for 2 hours. The reaction liquid was concentrated under reduced pressure and then to the residue were added a solution of ethyl (3R)-1-[(7-hydroxy-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (175 mg) in DMF (8.75 mL) and potassium carbonate (152 mg) in this order, followed by stirring at 80° C. for 2 hours. The reaction liquid was cooled to room temperature and poured into water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order and then dried over anhydrous sodium sulfate, and the vehicle was evaporated. The residue was purified by silica gel column chromatography to obtain ethyl (3R)-1-[(7-{[3-(trifluoromethyl)-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (271 mg) as a yellow oily substance.

In the same manner as in Preparation Example 62, the compounds of Preparation Example 62-1 through Preparation Example 62-19 shown in Tables described later were prepared.

Preparation Example 63

To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1.5 g), iron (III) acetylacetonate (130 mg), and 1-methylpyrrolidin-2-one (4 mL) in THF (45 mL) was added a 1 M solution of cyclopentyl magnesium bromide in THF (8.8 mL) at 5° C., followed by stirring at room temperature for 0.5 hours and diluting with diethylether. 1 M hydrochloric acid was slowly added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 95:5) to obtain 4-cyclopentyl-3-(trifluoromethyl)benzonitrile (367 mg) as a white solid.

Preparation Example 64

To a solution of 7-(methoxymethoxy)-2H-chromene-3-carbaldehyde (5.00 g) and ethyl (3R)-piperidine-3-carboxylate (4.20 mL) in dichloroethane (150 mL) was added sodium triacetoxyborohydride (12.0 g), followed by stirring at 80° C. for 4 hours. The reaction liquid was cooled to room temperature and then saturated aqueous NaHCO3 was added thereto, followed by extraction with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the vehicle was evaporated. The residue was purified by silica gel column chromatography (hexane:EtOAc=4:1) to obtain ethyl (3R)-1-{[7-(methoxymethoxy)-2H-chromen-3-yl]methyl}piperidine-3-carboxylate (7.30 g) as a yellow oily substance.

In the same manner as in Preparation Example 64, the compounds of Preparation Example 64-1 through Preparation Example 64-7 shown in Tables described later were prepared.

For the Preparation Example Compounds, the structures are shown in Tables 3 to 57, and the physicochemical data and preparation methods are shown in Tables 99 to 107.

Example 1

To a solution of 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]pyrrolidine-3-carboxylic acid (98 mg) in DMF (2 mL) was added CDI (46 mg), followed by stirring at 70° C. for 12 hours. To the reaction liquid were added methanesulfonamide (27 mg) and DBU (43 mg) in this order, followed by stirring for 12 hours. To the reaction liquid was added AcOH, followed by concentration under reduced pressure, and the residue was purified by reverse phase column chromatography (H2O:MeCN=100:0 to 90:10) to obtain a yellow amorphous substance (70 mg). This yellow amorphous substance was dissolved in dioxane (1 mL), and a 4 M HCl/dioxane solution (1 mL) was added thereto, followed by stirring and then concentrating under reduced pressure. The residue was washed with hexane to obtain 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-N-(methylsulfonyl)pyrrolidine-3-carboxamide hydrochloride (60 mg) as a pale yellow solid.

Example 2

To a solution of pyrrolidine-3-carboxylic acid hydrochloride in MeOH was added TEA, followed by stirring at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and a solution of 7-{[4-phenyl-5-(trifluoromethyl)-2-thienyl]methoxy}-2H-chromene-3-carbaldehyde in MeOH and AcOH were added thereto at room temperature. The reaction mixture was heated to 70° C., stirred for 2 hours, and left to be cooled to 25° C., and NaBH3CN was added thereto at room temperature, followed by stirring at 70° C. for 5 hours. The reaction liquid was purified by reverse phase column chromatography (MeCN:H2O=20:80 to 50:50) and the resulting white solid was washed with diisopropylether to obtain 1-[(7-{[4-phenyl-5-(trifluoromethyl)-2-thienyl]methoxy}-2H-chromen-3-yl)methyl]pyrrolidine-3-carboxylic acid as a white solid.

Example 3

Pyrrolidine-3-carboxylic acid hydrochloride (165 mg) was dissolved in MeOH, and TEA was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then a solution of 7-[2,4-bis(trifluoromethyl)phenyl]ethynyl}-5-fluoro-2H-chromene-3-carbaldehyde in MeOH (8 mL) and AcOH (0.5 mL) were added thereto at room temperature, followed by stirring at 70° C. for 0.5 hours. After leaving to be cooled to room temperature, to the reaction mixture was added NaBH3CN (57 mg) at room temperature, followed by stirring at 50° C. for 2 hours. After confirming completion of the reaction by means of LC, the reaction liquid was purified by reverse phase chromatography (MeCN:H2O=20:80 to 50:50), the resulting amorphous substance (233 mg) was dissolved in dioxane (1 mL), and a 4 M HCl/dioxane solution (1 mL) was added thereto. The reaction liquid was concentrated under reduced pressure and the residue was washed with MeCN to obtain 1-[(7-{[2,4-bis(trifluoromethyl)phenyl]ethynyl}-5-fluoro-2H-chromen-3-yl)methyl]pyrrolidine-3-carboxylic acid hydrochloride (185 mg) as a pale yellow solid.

Example 154

A solution of ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (100 mg) and a 1 M aqueous NaOH solution (0.55 mL) in EtOH/THF (3 mL/1 mL) was stirred at 100° C. for 2 hours, neutralized with 1 M HCl, and extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) and the obtained solid was washed with IPE to obtain 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylic acid (71 mg) as a white solid.

Example 156

To a solution of ethyl (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (271 mg) in EtOH (5.4 mL)-THF (2.7 mL) was added a 1 M aqueous NaOH solution (923 μL), followed by stirring at 50° C. for 2 hours. The reaction liquid was cooled to room temperature, then 1 M hydrochloric acid (923 μL) was added thereto, and the vehicle was evaporated. The residue was purified by reverse phase chromatography (H2O:MeCN=100:0 to 30:70) to obtain a yellow oily substance, which was dissolved in dioxane (3 mL), treated with 4 N HCl/dioxane (1 mL), and washed with IPE to obtain (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid hydrochloride (215 mg) as a white powder.

In the same manner as the methods of Examples 1 to 3, 154, or 156, the compounds of Examples shown in Tables described later were prepared. For the Example Compounds, the structures are shown in Tables 58 to 98, and the physicochemical data and the preparation methods are shown in Tables 108 to 131.

TABLE 3 No Str Pr1 Pr2 Pr2-1 Pr2-2 Pr2-3

TABLE 4 Pr2-4 Pr3 Pr4 Pr5 Pr5-1 Pr6

TABLE 5 Pr6-1 Pr6-2 Pr6-3 Pr6-4 Pr6-5 Pr6-6

TABLE 6 Pr6-7 Pr6-8 Pr6-9 Pr6-10 Pr6-11 Pr7 Pr8

TABLE 7 Pr9 Pr9-1 Pr9-2 Pr9-3 Pr9-4 Pr10 Pr10-1 Pr11

TABLE 8 Pr11-1 Pr12 Pr12-1 Pr12-2 Pr12-3 Pr12-4 Pr13

TABLE 9 Pr13-1 Pr14 Pr14-1 Pr14-2 Pr14-3 Pr14-4

TABLE 10 Pr14-5 Pr14-6 Pr14-7 Pr14-8 Pr14-9 Pr14-10 Pr14-11

TABLE 11 Pr14-12 Pr14-13 Pr14-14 Pr14-15 Pr14-16 Pr15 Pr15-1

TABLE 12 Pr15-2 Pr15-3 Pr15-4 Pr16 Pr17 Pr18 Pr18-1

TABLE 13 Pr18-2 Pr18-3 Pr18-4 Pr18-5 Pr18-6 Pr19 Pr20

TABLE 14 Pr21 Pr22 Pr23 Pr23-1 Pr24 Pr25 Pr25-1

TABLE 15 Pr26 Pr27 Pr27-1 Pr27-2 Pr27-3 Pr27-4

TABLE 16 Pr27-5 Pr27-6 Pr28 Pr28-1 Pr28-2 Pr28-3 Pr28-4

TABLE 17 Pr28-5 Pr28-6 Pr28-7 Pr28-8 Pr28-9 Pr28-10

TABLE 18 Pr28-11 Pr28-12 Pr28-14 Pr28-15 Pr28-16 Pr28-17

TABLE 19 Pr28-18 Pr28-19 Pr28-20 Pr28-21 Pr28-22 Pr28-23

TABLE 20 Pr28-24 Pr28-25 Pr29-26 Pr28-27 Pr29 Pr29-1

TABLE 21 Pr29-2 Pr29-3 Pr29-4 Pr29-5 Pr29-6 Pr29-7 Pr29-8

TABLE 22 Pr29-9 Pr29-10 Pr29-11 Pr29-12 Pr29-13 Pr29-14 Pr29-15

TABLE 23 Pr30 Pr30-1 Pr31 Pr31-1 Pr32 Pr33

TABLE 24 Pr33-1 Pr33-2 Pr33-3 Pr33-4 Pr33-5 Pr33-6 Pr33-7

TABLE 25 Pr33-8 Pr33-9 Pr33-10 Pr33-11 Pr33-12 Pr33-13 Pr33-14 Pr33-15

TABLE 26 Pr33-16 Pr33-17 Pr33-18 Pr33-19 Pr33-20 Pr33-21 Pr34

TABLE 27 Pr34-1 Pr34-2 Pr34-3 Pr34-4 Pr34-5 Pr34-6 Pr34-7

TABLE 28 Pr34-8 Pr34-9 Pr34-10 Pr34-11 Pr34-12 Pr34-13

TABLE 29 Pr34-14 Pr34-15 Pr34-16 Pr34-17 Pr34-18 Pr34-19 Pr34-20

TABLE 30 Pr34-21 Pr34-22 Pr34-23 Pr34-24 Pr34-25 Pr34-26 Pr34-27

TABLE 31 Pr34-28 Pr34-29 Pr34-30 Pr35 Pr35-1 Pr35-2 Pr35-3

TABLE 32 Pr36 Pr36-1 Pr36-2 Pr37 Pr37-1 Pr37-2

TABLE 33 Pr37-3 Pr38 Pr38-1 Pr38-2 Pr38-3

TABLE 34 Pr38-4 Pr38-5 Pr38-6 Pr38-7 Pr38-8

TABLE 35 Pr38-9 Pr38-10 Pr38-11 Pr38-12 Pr38-13

TABLE 36 Pr38-14 Pr38-15 Pr38-16 Pr38-17 Pr38-18 Pr38-19

TABLE 37 Pr38-20 Pr38-21 Pr38-22 Pr38-23 Pr38-24

TABLE 38 Pr38-25 Pr38-26 Pr38-27 Pr38-28 Pr38-29

TABLE 39 Pr38-30 Pr38-31 Pr38-32 Pr38-33 Pr38-34

TABLE 40 Pr38-35 Pr38-36 Pr38-37 Pr38-38 Pr38-39 Pr38-40 Pr38-41

TABLE 41 Pr38-42 Pr38-43 Pr38-44 Pr38-45 Pr38-46 Pr38-47

TABLE 42 Pr38-48 Pr38-49 Pr38-50 Pr38-51 Pr38-52 Pr38-53 Pr38-54

TABLE 43 Pr-38-55 Pr38-56 Pr38-57 Pr38-58 Pr38-59 Pr38-60

TABLE 44 Pr38-61 Pr39 Pr39-1 Pr39-2 Pr39-3 Pr39-4

TABLE 45 Pr39-5 Pr39-6 Pr40 Pr41 Pr41-1 Pr41-2 Pr41-3

TABLE 46 Pr41-4 Pr41-5 Pr42 Pr43 Pr44 Pr44-1 Pr44-2 Pr44-3 Pr44-4

TABLE 47 Pr44-5 Pr44-6 Pr45 Pr46 Pr47 Pr47-1 Pr47-2 Pr48 Pr48-1

TABLE 48 Pr49 Pr50 Pr51 Pr51-1 Pr51-2 Pr51-3

TABLE 49 Pr51-4 Pr51-5 Pr52 Pr52-1 Pr52-2 Pr52-3

TABLE 50 Pr52-4 Pr53 Pr53-1 Pr53-2 Pr53-3 Pr53-4 Pr54

TABLE 51 Pr55 Pr55-1 Pr56 Pr56-1 Pr56-2 Pr56-3 Pr56-4

TABLE 52 Pr56-5 Pr56-6 Pr57 Pr58 Pr58-1 Pr59 Pr60 Pr61

TABLE 53 Pr62 Pr62-1 Pr62-2 Pr62-3 Pr62-4 Pr62-5

TABLE 54 Pr62-6 Pr62-7 Pr62-8 Pr62-9  Pr62-10  Pr62-11

TABLE 55 Pr62-12 Pr62-13 Pr62-14 Pr62-15 Pr62-16 Pr62-17

TABLE 56 Pr62-18 Pr62-19 Pr63 Pr64 Pr64-1 Pr64-2

TABLE 57 Pr64-3 Pr64-4 Pr64-5 Pr64-6 Pr64-7

TABLE 58 No Str Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6

TABLE 59 Ex 7  Ex 8  Ex 9  Ex 10 Ex 11 Ex 12 Ex 13 Ex 14

TABLE 60 Ex 15 Ex 16 Ex 17 Ex 18 Ex 19 Ex 20 Ex 21

TABLE 61 Ex 22 Ex 23 Ex 24 Ex 25 Ex 26 Ex 27

TABLE 62 Ex 28 Ex 29 Ex 30 Ex 31 Ex 32 Ex 33

TABLE 63 Ex 34 Ex 35 Ex 36 Ex 37 Ex 38

TABLE 64 Ex 39 Ex 40 Ex 41 Ex 42 Ex 43

TABLE 65 Ex 44 Ex 45 Ex 46 Ex 47 Ex 48

TABLE 66 Ex 49 Ex 50 Ex 51 Ex 52 Ex 53 Ex 54

TABLE 67 Ex 55 Ex 56 Ex 57 Ex 58 Ex 59

TABLE 68 Ex 60 Ex 61 Ex 62 Ex 63 Ex 64

TABLE 69 Ex65 Ex66 Ex67 Ex68

TABLE 70 Ex69 Ex70 Ex71 Ex72 Ex73

TABLE 71 Ex74 Ex75 Ex76 Ex77 Ex78

TABLE 72 Ex79 Ex80 Ex81 Ex82 Ex83 Ex84

TABLE 73 Ex85 Ex86 Ex87 Ex88 Ex89

TABLE 74 Ex90 Ex91 Ex92 Ex93

TABLE 75 Ex94 Ex95 Ex96 Ex97 Ex98

TABLE 76 Ex99 Ex100 Ex101 Ex102

TABLE 77 Ex103 Ex104 Ex105 Ex106 Ex107

TABLE 78 Ex108 Ex109 Ex110 Ex111 Ex112

TABLE 79 Ex113 Ex114 Ex115 Ex116 Ex117 Ex118

TABLE 80 Ex119 Ex120 Ex121 Ex122 Ex123 Ex124 Ex125

TABLE 81 Ex126 Ex127 Ex128 Ex129 Ex130 Ex131 Ex132

TABLE 82 Ex133 Ex134 Ex135 Ex136 Ex137 Ex138

TABLE 83 Ex139 Ex140 Ex141 Ex142 Ex143 Ex144

TABLE 84 Ex145 Ex146 Ex147 Ex148 Ex149 Ex150

TABLE 85 Ex151 Ex152 Ex153 Ex154 Ex155 Ex156

TABLE 86 Ex157 Ex158 Ex159 Ex160 Ex161 Ex162

TABLE 87 Ex163 Ex164 Ex165 Ex166 Ex167 Ex168 Ex169

TABLE 88 Ex170 Ex171 Ex172 Ex173 Ex174 Ex175

TABLE 89 Ex176 Ex177 Ex178 Ex179 Ex180 Ex181

TABLE 90 Ex182 Ex183 Ex184 Ex185 Ex186 Ex187

TABLE 91 Ex188 Ex189 Ex190 Ex191 Ex192 Ex193

TABLE 92 Ex194 Ex195 Ex196 Ex197 Ex198 Ex199

TABLE 93 Ex200 Ex201 Ex202 Ex203 Ex204 Ex205

TABLE 94 Ex206 Ex207 Ex208 Ex209 Ex210 Ex211

TABLE 95 Ex212 Ex213 Ex214 Ex215 Ex216 Ex217

TABLE 96 Ex218 Ex219 Ex220 Ex221 Ex222 Ex223 Ex224

TABLE 97 Ex225 Ex226 Ex227 Ex228 Ex229 Ex230

TABLE 98 Ex231 Ex232 Ex233 Ex234 Ex235 Ex236

TABLE 99 Pr DATA Pr1 MS+: 396 Pr2 MS+: 281 Pr2-1 MS+: 267 Pr2-2 MS+: 385 Pr2-3 MS+: 281 Pr2-4 MS−: 387 Pr3 NMR: 2.56(2H, t, J = 6.0 Hz), 4.44(2H, t, J = 6.0 Hz), 5.18(2H, s), 5.81(1H, d, J = 2.6 Hz), 6.98(1H, dd, J = 2.6, 8.9 Hz), 7.32-7.48(5H, m), 7.73(1H, d, J = 8.9 Hz), 10.22(1H, s) Pr4 MS−: 209 Pr5 MS+: 253 Pr5-1 MS+: 267 Pr6 MS+: 361 Pr6-1 NMR: 2.36(3H, s), 3.36(3H, s), 4.86(2H, d), 5.21(2H, s), 6.41(1H, d), 6.56(1H, dd), 7.76(1H, d), 9.57(1H, s) Pr6-2 MS+: 261 Pr6-3 MS+: 273 Pr6-4 NMR: 0.91(3H, t), 1.55-1.66(2H, m), 2.57(2H, t), 3.86(3H, s), 4.96(2H, s), 6.81(1H, d), 6.88(1H, s), 7.05(1H, s), 7.16(1H, d), 7.21(1H, dd), 7.38(1H, d), 7.46(1H, d), 7.56(1H, d), 7.63(1H, s), 9.57(1H, s) Pr6-5 MS−: 335 Pr6-6 MS+: 397 Pr6-7 MS+: 395 Pr6-8 MS+: 257 Pr6-9 MS+: 451 Pr6-10 MS+: 271 Pr6-11 MS+: 221 Pr7 MS+: 256 Pr8 MS+: 237 Pr9 ESI−: 199 Pr9-1 MS−: 195 Pr9-2 MS+: 235 Pr9-3 MS−: 195 Pr9-4 MS+: 183 Pr10 MS+: 425 Pr10-1 MS+: 303 Pr11 NMR: 5.04(2H, d, J = 1.3 Hz), 7.09-7.16(2H, m), 7.59(1H, d, J = 8.4 Hz), 7.67(1H, s), 9.61(1H, s) Pr11-1 NMR: 5.08(2H, d), 7.04-7.07(1H, m), 7.29(1H, dd), 7.74-7.77(1H, m), 9.68(1H, s) Pr12 MS+: 303 Pr12-1 MS+: 317 Pr12-2 NMR: 3.87(3H, s), 3.90(3H, s), 6.51-6.56(2H, m), 10.15(1H, d) Pr12-3 ESI−: 151 Pr12-4 NMR: 3.67(2H, s), 5.41(2H, s), 6.90(1H, dd), 7.05(1H, d), 7.47(1H, d), 7.56(1H, s), 8.02(1H, d), 8.08-8.20(2H, m), 9.57(1H, s) Pr13 MS+: 327 Pr13-1 MS+: 387

TABLE 100 Pr14 NMR: 1.31(2H, d), 4.89-4.99(1H, m), 7.49(1H, d), 8.09(1H, dd), 8.13(1H, dd) Pr14-1 MS+: 319 Pr14-2 4.56(2H, dt), 6.45(1H, tt), 7.41(1H, d), 7.86(1H, dd), 8.07(1H, d) Pr14-3 ESI+: 349, 351 Pr14-4 ESI+: 284 Pr14-5 NMR: 1.46(3H, d), 3.91(3H, s), 5.66-5.76(1H, m), 7.56(1H, d), 7.85(1H, d), 7.96 (1H, s) Pr14-6 ESI+: 283 Pr14-7 EI+: 316 Pr14-8 ESI+: 299 Pr14-9 ESI+: 222 Pr14-10 EI: 302 Pr14-11 EI: 215 Pr14-12 NMR: 1.49(3H, d), 3.87(3H, s), 5.12-5.21(1H, m), 8.00(2H, s) Pr14-13 ESI+: 230 Pr14-14 EI+: 227 Pr14-15 ESI+: 338 Pr14-16 EI: 243 Pr15 MS+: 310 Pr15-1 MS+: 293 Pr15-2 MS+: 271 Pr15-3 ESI+: 262 Pr15-4 ESI+: 274 Pr16 MS+: 226 Pr17 NMR: 3.87(3H, s), 7.66-7.73(1H, m), 7.80-7.87(1H, m), 7.94-8.00(1H, m) Pr18 NMR: 1.24(3H, t), 2.81(2H, q), 3.82(3H, s), 7.72(1H, s) Pr18-1 EI+: 223 Pr18-2 NMR: 3.87(3H, s), 7.58(1H, t), 7.98(1H, ddd), 8.10(1H, dd) Pr18-3 EI+: 222 Pr18-4 ESI+: 245 Pr18-5 ESI+: 245 Pr18-6 EI+: 238 Pr19 MS+: 270 Pr20 MS+: 319, 321 Pr21 MS+: 323 Pr22 MS+: 296 Pr23 MS+: 381, 383 Pr23-1 NMR: 0.93(3H, d), 2.00-2.13(1H, m), 2.46-2.53(1H, m), 2.69(1H, dd), 3.39(1H, dd), 3.51(1H, dd), 7.23(2H, d), 7.35(2H, d) Pr24 MS+: 235 Pr25 MS+: 292 Pr25-1 NMR: 3.93(3H, s), 6.30(2H, dd), 7.01(2H, dd), 7.69(1H, d), 8.32(2H, s) Pr26 NMR: 0.06(9H, s), 2.60(2H, t), 3.02(2H, t), 7.84(1H, d), 7.97(1H, s), 8.04(1H, d) Pr27 NMR: 0.91(3H, t, J = 7.3 Hz), 1.55-1.66(2H, m), 2.56(2H, t, J = 7.9 Hz), 3.81(3H, s), 4.92(2H, d, J = 1.0 Hz), 5.03(2H, s), 6.54(1H, d, J = 2.3 Hz), 6.66(1H, dd, J = 2.4, 8.5 Hz), 6.78(1H, dd, J = 1.3, 7.6 Hz), 6.88(1H, d, J = 1.3 Hz), 7.26(1H, d, J = 7.6 Hz), 7.34 (1H, d, J = 8.5 Hz), 7.58(1H, s), 9.51(1H, s) Pr27-1 MS+: 319 Pr27-2 MS+: 409

TABLE 101 Pr27-3 MS+: 375 Pr27-4 MS+: 435, 437 Pr27-5 MS+: 389 Pr27-6 MS+: 395 Pr28 MS−: 401 Pr28-1 MS+: 389 Pr28-2 MS+: 351 Pr28-3 NMR: 4.93(2H, d), 5.28(2H, s), 6.59(1H, d), 6.71(1H, dd), 7.35(1H, d), 7.58(1H, m), 7.66(2H, d), 7.78(2H, d), 9.51(1H, s) Pr28-4 NMR: 4.93(2H, d), 5.27(2H, s), 6.57(1H, d), 6.69(1H, dd), 7.36(1H, d), 7.58-7.63 (2H, m), 7.72-7.75(2H, m), 7.81(1H, d), 9.52(1H, s) Pr28-5 MS−: 415 Pr28-6 NMR: 2.71(2H, t, J = 6.4 Hz), 4.50(2H, t, J = 6.4 Hz), 5.18(2H, s), 6.63(1H, d, J = 2.4 Hz), 6.71(1H, dd, J = 2.4, 8.8 Hz), 7.32-7.47(5H, m), 7.69(1H, d, J = 8.8 Hz) Pr28-7 MS+: 439 Pr28-8 MS+: 331 Pr28-9 NMR: 2.57(2H, t, J = 6.0 Hz), 4.50(2H, t, J = 6.0 Hz), 5.42(2H, s), 6.85(1H, d, J = 2.6 Hz), 7.00(1H, dd, J = 2.6, 8.9 Hz), 7.77(1H, d, J = 8.9 Hz), 8.04(1H, d, J = 8.1Hz), 8.12 (1H, s), 8.17(1H, d, J = 8.1 Hz), 10.23(1H, s) Pr28-10 MS+: 431 Pr28-11 MS−: 435 Pr28-12 NMR: 4.97(2H, d), 5.39(2H, s), 6.48-6.51(1H, m), 6.70(1H, dd), 7.70(1H, d), 8.02 (1H, d), 8.11(1H, s), 8.17(1H, d), 9.59(1H, s) Pr28-14 MS+: 455 Pr28-15 MS−: 415 Pr28-16 MS−: 419 Pr28-17 MS+: 429 Pr28-18 ESI+: 469 Pr28-19 NMR: 0.91(3H, d), 2.10-2.21(1H, m), 2.45-2.53(1H, m), 2.77(1H, dd), 3.79-3.89 (2H, m), 4.95(2H, d), 6.36-6.38(1H, m), 6.55(1H, dd), 7.22(2H, d), 7.34(2H, d), 7.69(1H, s), 9.58(1H, s) Pr28-20 ESI−: 429 Pr28-21 ESI+: 399 Pr28-22 ESI+: 433 Pr28-23 ESI−: 463 Pr28-24 ESI+: 435 Pr28-25 MS+: 365 Pr28-26 ESI+: 439 Pr28-27 ESI+: 381 Pr29 NMR: 5.00(2H, s), 7.11(1H, s), 7.21-7.28(1H, m), 7.43-7.52(2H, m), 7.77-7.85(4H, m), 9.61(1H, s) Pr29-1 NMR: 4.99(2H, d), 7.04-7.06(1H, m), 7.20(1H, dd), 7.42-7.48(5H, m), 7.55-7.59 (1H, m), 7.65-7.67(1H, m), 9.60(1H, s) Pr29-2 NMR: 3.80(3H, s), 4.98(2H, d), 6.98-7.02(3H, m), 7.16(1H, dd), 7.43(1H, d), 7.51 (2H, d), 7.64-7.66(1H, m), 9.59(1H, s) Pr29-3 NMR: 2.34(3H, s), 4.99(2H, d), 7.01-7.03(1H, m), 7.17(1H, dd), 7.25(2H, d), 7.44 (1H, d), 7.46(2H, d), 7.64-7.66(1H, m), 9.59(1H, s) Pr29-4 NMR: 5.00(2H, d), 7.09-7.11(1H, m), 7.24(1H, dd), 7.48(1H, d), 7.65-7.68(1H, m), 7.76(2H, d), 7.92(2H, d), 9.61(1H, s)

TABLE 102 Pr29-5 NMR: 5.00(2H, d), 7.09-7.11(1H, m), 7.24(1H, dd), 7.47(1H, d), 7.65-7.72(2H, m), 7.81(1H, dm), 7.88(1H, dm), 7.93-7.96(1H, m), 9.61(1H, s) Pr29-6 NMR: 5.00(2H, d), 6.99-7.03(1H, m), 7.18(1H, dd), 7.49(1H, d), 7.61-7.69(2H, m), 7.75(1H, t), 7.84(2H, t), 9.61(1H, s) Pr29-7 NMR: 1.27-1.86(10H, m), 2.58-2.71(1H, m), 4.95(2H, s), 6.83-6.84(1H, m), 7.00 (1H, dd), 7.36(1H, d), 7.61-7.63(1H, m), 9.57(1H, s) Pr29-8 NMR: 1.22-1.36(2H, m), 1.46-1.68(4H, m), 1.73-1.83(2H, m), 2.02-2.15(1H, m), 2.44(2H, d), 4.95(2H, d), 6.83-6.86(1H, m), 7.01(1H, dd), 7.36(1H, d), 7.60-7.63 (1H, m), 9.57(1H, s) Pr29-9 NMR: 1.28(9H, s), 4.95(2H, d), 6.80-6.82(1H, m), 6.98(1H, dd), 7.35(1H, d), 7.61- 7.63(1H, m), 9.57(1H, s) Pr29-10 NMR: 0.90(6H, d), 1.44(2H, q), 1.64-1.77(1H, m), 2.44(2H, t), 4.95(2H, d), 6.82- 6.85(1H, m), 7.00(1H, dd), 7.36(1H, d), 7.60-7.63(1H, m), 9.57(1H, s) Pr29-11 NMR: 4.99(2H, d), 7.04-7.06(1H, m), 7.17-7.23(2H, m), 7.42-7.49(2H, m), 7.65- 7.67(1H, m), 7.69-7.77(1H, m), 9.60(1H, s) Pr29-12 NMR: 5.03(2H, d), 7.02(1H, s), 7.19(1H, dd), 7.76-7.85(5H, m), 9.67(1H, s) Pr29-13 NMR: 2.72(2H, t), 2.85(2H, t), 4.95(2H, d), 6.79(1H, s), 6.97(1H, dd), 7.19-7.26 (1H, m), 7.29-7.32(4H, m), 7.35(1H, d), 7.61(1H, s), 9.57(1H, s) Pr29-14 NMR: 1.79-1.89(2H, m), 2.44(2H, t), 2.72(2H, t), 4.99(2H, d), 6.78(1H, s), 6.95 (1H, dd), 7.16-7.33(5H, m), 7.72-7.75(1H, m), 9.65(1H, s) Pr29-15 NMR: 2.84(2H, t), 3.13(2H, t), 4.95(2H, d), 6.81(1H, s), 6.97(1H, dd), 7.36(1H, d), 7.61-7.64(1H, m), 7.92(1H, d), 8.00(1H, s), 8.09(1H, d), 9.56(1H, s) Pr30 NMR: 0.24(9H, s), 0.88(6H, d), 1.77-1.90(1H, m), 2.46(2H, d), 7.07(2H, d), 7.37 (2H, d) Pr30-1 NMR: 0.27(9H, s), 7.69-7.75(2H, m), 7.88(1H, s) Pr31 NMR: 0.86(6H, d), 1.78-1.92(1H, m), 2.49(2H, d), 5.02(2H, d), 6.93(1H, s), 7.10 (1H, dd), 7.24(2H, d), 7.49(2H, d), 7.76-7.77(1H, m), 9.66(1H, s) Pr31-1 NMR: 5.05(2H, d), 6.96(1H, s), 7.13(1H, dd), 7.78-7.79(1H, m), 8.08(1H, d), 8.16 (1H, s), 8.17(1H, d), 9.68(1H, s) Pr32 NMR: 1.47(3H, d), 4.98-5.05(1H, m), 5.96(1H, d), 7.10(1H, s), 7.35-7.50(5H, m) Pr33 MS−: 287 Pr33-1 NMR: 4.60(1H, d), 4.85(2H, d), 4.90(1H, d), 5.41(1H, t), 7.32(1H, d), 7.38(1H, dd), 7.70(1H, d) Pr33-2 EI+: 226 Pr33-3 EI+: 232 Pr33-4 NMR: 4.60(1H, d), 4.85(2H, d), 4.90(1H, d), 5.41(1H, t), 7.32(1H, d), 7.38(1H, dd), 7.70(1H, d) Pr33-5 EI+: 234 Pr33-6 ESI+: 259 Pr33-7 ESI+: 257 Pr33-8 ESI+: 223 Pr33-9 EI+: 288 Pr33-10 EI+: 240 Pr33-11 EI+: 210 Pr33-12 ESI+: 245 Pr33-13 EI: 244 Pr33-14 EI: 220

TABLE 103 Pr33-15 EI: 244 Pr33-16 ESI+: 260 Pr33-17 ESI+: 259 Pr33-18 NMR: 1.44(3H, d), 4.44(2H, d), 5.17-5.29(2H, m), 7.25(1H, dd), 7.31(1H, d), 7.40 (1H, d) Pr33-19 ESI+: 257 Pr33-20 ESI+: 223 Pr33-21 ESI−: 287 Pr34 MS+: 206 Pr34-1 MS+: 243 Pr34-2 MS+: 198 Pr34-3 NMR: 4.72(2H, d), 5.87(1H, t), 7.13(1H, d), 7.41-7.47(2H, m), 7.52-7.58(2H, m) Pr34-4 NMR: 4.62(2H, d), 5.63(1H, t), 7.03(1H, s), 7.34-7.41(1H, m), 7.43-7.49(2H, m), 7.52-7.57(2H, m) Pr34-5 NMR: 1.20(3H, t), 2.81(2H, q), 4.58(2H, d), 5.39(1H, t), 6.89(1H, s), 7.28-7.46 (5H, m) Pr34-6 MS+: 255 Pr34-7 NMR: 1.18(3H, t), 2.71(2H, q), 4.54(2H, d), 5.50(1H, t), 6.84(1H, s) Pr34-8 MS+: 255 Pr34-9 MS+: 304 Pr34-10 MS−: 267 Pr34-11 NMR: 4.67(2H, d), 5.54(1H, t), 6.29(2H, t), 7.48(2H, t), 7.79-7.81(2H, m), 7.88- 7.91(1H, m) Pr34-12 NMR: 1.86(3H, s), 4.69(2H, d), 5.80(1H, t), 7.22-7.27(2H, m), 7.42-7.50(3H, m) Pr34-13 MS+: 359 Pr34-14 MS+: 361 Pr34-15 MS−: 240 Pr34-16 MS+: 243 Pr34-17 MS+: 439 Pr34-18 EI+: 288 Pr34-19 EI+: 255 Pr34-20 NMR: 0.88(6H, d), 1.85-1.97(1H, m), 2.60(2H, d), 4.54(2H, d), 5.31(1H, t), 7.40 (1H, d), 7.51(1H, d), 7.61(1H, s) Pr34-21 ESI+: 321, 323 Pr34-22 ESI+: 256 Pr34-23 ESI−: 287 Pr34-24 ESI+: 234 Pr34-25 EI+: 270 Pr34-26 EI+: 266 Pr34-27 EI+: 272 Pr34-28 EI+: 274 Pr34-29 NMR: 1.45(3H, d), 4.47(2H, d), 4.95-5.06(1H, m), 5.42(1H, t), 7.44(2H, s) Pr34-30 ESI+: 290 Pr35 MS+: 325 Pr35-1 MS+: 321

TABLE 104 Pr35-2 MS+: 323 Pr35-3 ESI−: 391 Pr36 MS−: 407 Pr36-1 ESI+: 445 Pr36-2 EI: 245 Pr37 MS+: 269 Pr37-1 MS+: 283 Pr37-2 MS+: 283 Pr37-3 MS+: 367 Pr38 MS+: 382 Pr38-1 MS+: 324 Pr38-2 MS+: 356 Pr38-3 MS+: 331 Pr38-4 NMR: 4.94(2H, d), 5.44(2H, s), 6.44(1H, d), 6.74(1H, dd), 7.35-7.51(7H, m), 7.59 (1H, s), 9.52(1H, s) Pr38-5 MS+: 418 Pr38-6 MS+: 453 Pr38-7 MS−: 449 Pr38-8 MS+: 349 Pr38-9 NMR: 3.04(2H, s), 4.93(2H, s), 5.33(2H, s), 6.62(1H, d), 6.72(1H, dd), 7.28-7.43 (3H, m), 7.44-7.50(2H, m), 7.52-7.60(3H, m), 9.52(1H, s) Pr38-10 NMR: 1.21(3H, t), 2.85(2H, q), 4.93(2H, s), 5.29(2H, s), 6.61(1H, d), 6.71(1H, dd), 7.18(1H, s), 7.31-7.48(6H, m), 7.58(1H, s), 9.51(1H, s) Pr38-11 MS−: 433 Pr38-12 MS+: 391 Pr38-13 MS+: 433 Pr38-14 MS−: 445 Pr38-15 MS+: 455 Pr38-16 NMR: 1.19(3H, t), 2.74(2H, q), 4.93(2H, s), 5.27(2H, s), 6.58(1H, d), 6.68(1H, dd), 7.15(1H, s), 7.34(1H, d), 7.57(1H, s), 9.51(1H, s) Pr38-17 MS+: 413 Pr38-18 MS+: 417 Pr38-19 MS−: 385 Pr38-20 NMR: 4.97(2H, s), 5.32(2H, s), 6.54(1H, d), 6.72(1H, dd), 7.30-7.43(2H, m), 7.43- 7.49(4H, m), 7.69-7.72(1H, m), 7.74-7.80(1H, m), 7.90-7.93(1H, m), 9.59(1H, s) Pr38-21 MS+: 441 Pr38-22 MS+: 480 Pr38-23 MS+: 467 Pr38-24 MS−: 447 Pr38-25 NMR: 4.96(2H, s), 5.26(2H, s), 6.32(2H, t), 7.53(2H, t), 7.69-7.71(1H, m), 7.80- 7.83(1H, m), 7.93-7.97(2H, m), 9.59(1H, s) Pr38-26 MS+: 434 Pr38-27 MS−: 416 Pr38-28 MS+: 451

TABLE 105 Pr38-29 MS+: 417 Pr38-30 MS+: 465 Pr38-31 MS+: 435 Pr38-32 MS+: 469 Pr38-33 MS+: 467 Pr38-34 MS+: 421 Pr38-35 ESI+: 487 Pr38-36 ESI+: 369 Pr38-37 ESI+: 435 Pr38-38 ESI+: 413 Pr38-39 ESI+: 399 Pr38-40 ESI+: 395, 397 Pr38-41 ESI+: 479, 481 Pr38-42 ESI+: 436 Pr38-43 ESI+: 447 Pr38-44 ESI+: 392 Pr38-45 ESI+: 429 Pr38-46 ESI+: 425 Pr38-47 ESI+: 431 Pr38-48 ESI+: 403 Pr38-49 ESI+: 433 Pr38-50 ESI+: 379 Pr38-51 ESI+: 447 Pr38-52 ESI+: 393 Pr38-53 ESI+: 385 Pr38-54 ESI+: 391 Pr38-55 ESI+: 447 Pr38-56 ESI+: 418 Pr38-57 ESI+: 451 Pr38-58 ESI+: 447 Pr38-59 ESI+: 369 Pr38-60 ESI+: 448 Pr38-61 ESI+: 414 Pr39 MS+: 413 Pr39-1 MS−: 323 Pr39-2 MS−: 295 Pr39-3 MS+: 321 Pr39-4 MS+: 239 Pr39-5 MS+: 359 Pr39-6 MS+: 357 Pr40 MS+: 437 Pr41 MS−: 142 Pr41-1 MS+: 140 Pr41-2 MS−: 133 Pr41-3 MS+: 134 Pr41-4 MS+: 130 Pr41-5 ESI+: 144

TABLE 106 Pr42 MS+: 262 Pr43 MS+: 256 Pr44 MS−: 193 Pr44-1 NMR: 2.30(3H, s), 4.82(2H, d), 6.13(1H, d), 6.32(1H, dd), 7.71(1H, d), 9.52(1H, s), 10.19(1H, brs) Pr44-2 MS−: 205 Pr44-3 ESI−: 189 Pr44-4 NMR: 4.88(2H, d), 6.28(1H, d), 6.44(1H, dd), 7.22(1H, d), 7.52(1H, s), 9.47(1H, s), 10.24(1H, s) Pr44-5 MS+: 318 Pr44-6 MS+: 318 Pr45 MS−: 203 Pr46 NMR: 2.56(2H, td), 2.87(1H, t), 3.03(2H, t), 7.85(1H, d), 7.98(1H, s), 8.06(1H, d) Pr47 MS+: 191 Pr47-1 MS−: 223 Pr47-2 MS+: 227 Pr48 MS+: 157 Pr48-1 MS−: 127 Pr49 NMR: 3.48(2H, dd), 5.33(2H, s), 5.80-5.89(1H, m), 6.47(1H, d), 6.75(1H, dd), 6.87(1H, d), 7.08(1H, d), 8.00(1H, d), 8.10(1H, s), 8.15(1H, d) Pr50 MS+: 417 Pr51 MS+: 467 Pr51-1 MS+: 443 Pr51-2 MS+: 479 Pr51-3 MS+: 269 Pr51-4 MS+: 467 Pr51-5 MS+: 337 Pr52 MS+: 253 Pr52-1 MS+: 451 Pr52-2 NMR: 0.89(6H, d), 1.91-2.03(1H, m), 2.70(2H, d), 3.89(3H, s), 6.63(1H, d), 7.65 (1H, d), 8.17(1H, s) Pr52-3 EI+: 294 Pr52-4 EI+: 300 Pr53 NMR: 1.46(3H, d), 4.74(2H, s), 5.27-5.38(1H, m), 7.37(1H, d), 7.42(1H, dd), 7.59 (1H, d) Pr53-1 NMR: 1.29(6H, d), 4.64-4.73(3H, m), 7.16(1H, d), 7.35(1H, dd), 7.51(1H, d) Pr53-2 NMR: 1.28(6H, d), 4.74-4.85(3H, m), 7.30(1H, d), 7.65-7.70(2H, m) Pr53-3 NMR: 1.44(3H, d), 4.83(2H, s), 5.42-5.53(1H, m), 7.42(1H, d), 7.46(1H, dd), 7.72 (1H, d) Pr53-4 NMR: 4.74(2H, s), 4.87(1H, d), 4.91(1H, d), 7.28(1H, d), 7.42(1H, dd), 7.59(1H, d) Pr54 NMR: 1.51-1.85(7H, m), 2.00-2.09(2H, m), 3.86(3H, s), 7.57(1H, s), 7.86(1H, dd), 7.91(1H, d) Pr55 ESI+: 545 Pr55-1 ESI+: 552 Pr56 ESI−: 247 Pr56-1 MS−: 257 Pr56-2 ESI−: 235 Pr56-3 ESI+: 241 Pr56-4 EI: 234

TABLE 107 Pr56-5 ESI+: 247 Pr56-6 ESI+: 249 Pr57 EI+: 317 Pr58 ESI+: 170 Pr58-1 ESI+: 156 Pr59 ESI+: 238 Pr60 ESI+: 207 Pr61 ESI+: 184 Pr62 ESI+: 588 Pr62-1 ESI+: 431 Pr62-2 NMR: 1.29(6H, d), 4.75-4.84(1H, m), 4.93(2H, d), 5.12(2H, s), 6.57(1H, d), 6.69(1H, dd), 7.29-7.35(2H, m), 7.57(1H, s), 7.65-7.69(2H, m), 9.51(1H, s) Pr62-3 ESI+: 403 Pr62-4 ESI+: 421 Pr62-5 Pr62-6 ESI+: 574 Pr62-7 ESI+: 536 Pr62-8 ESI+: 536 Pr62-9 ESI+: 588 Pr62-10 ESI+: 570 Pr62-11 ESI+: 447 Pr62-12 ESI+: 395, 397 Pr62-13 ESI+: 532 Pr62-14 ESI+: 532 Pr62-15 ESI+: 544 Pr62-16 ESI+: 544 Pr62-17 ESI+: 574 Pr62-18 ESI+: 545 Pr62-19 ESI+: 545 Pr63 ESI+: 262 Pr64 MS+: 362 Pr64-1 ESI+: 528 Pr64-2 ESI+: 532 Pr64-3 ESI+: 362 Pr64-4 ESI+: 534 Pr64-5 ESI+: 546 Pr64-6 ESI+: 534 Pr64-7 ESI+: 592

TABLE 108 Ex RefEx Data Ex1 Ex1 NMR: 1.93-2.57(2H, m), 3.00-3.75(5H, m), 3.27(3H, s), 3.96(2H, s), 4.90 (2H, d), 5.34(2H, s), 6.42(1H, s), 6.59(1H, dd), 6.88(1H, s), 8.00(1H, d), 8.09-8.19(2H, m), 11.11(1H, brs), 12.06(1H, brs), MS+: 619 Ex2 Ex2 NMR: 1.88-1.99(2H, m), 2.38-2.61(2H, m), 2.65-2.73(1H, m), 2.84-2.96 (1H, m), 3.04-3.14(1H, m), 3.30-3.39(2H, m), 4.69(2H, s), 5.36(2H, s), 6.34(1H, s), 6.50(1H, d), 6.57(1H, dd), 6.99(1H, d), 7.37(1H, s), 7.41-7.52 (5H, m) MS+: 538 Ex3 Ex3 NMR: 2.00-2.40(2H, m), 3.04-3.81(5H, m), 3.99(2H, s), 5.03(2H, s), 6.89 (1H, s), 7.00(1H, s), 7.06(1H, dd), 8.06(1H, d), 8.15(1H, s), 8.16(1H, d), 11.43(1H, brs), 12.89(1H, brs), MS+: 514 Ex4 Ex2 NMR: 0.90(3H, t, J = 7.4 Hz), 1.55-1.65(2H, m), 2.55(2H, t, J = 7.9 Hz), 3.03 (2H, s), 3.09-3.41(5H, m), 3.80(3H, s), 4.60(2H, s), 4.94(2H, s), 6.30(1H, s), 6.37(1H, d, J = 2.2 Hz), 6.75(1H, dd, J = 2.4, 8.3 Hz), 6.77(1H, dd, J = 1.3, 8.8 Hz), 6.87(1H, d, J = 1.3 Hz), 6.94(1H, d, J = 8.3 Hz), 7.23(1H, d, J = 7.6 Hz) MS−: 422 Ex5 Ex2 NMR: 3.04(2H, s), 3.12-3.40(5H, m), 4.61(2H, s), 5.11(2H, s), 6.30(1H, s), 6.44(1H, d, J = 2.3 Hz), 6.54(1H, dd, J = 2.5, 8.2 Hz), 6.96(1H, d, J = 8.2 Hz), 7.34-7.39(1H, m), 7.44-7.53(4H, m), 7.64-7.70(4H, m) MS−: 426 Ex6 Ex2 NMR: 0.90(3H, t, J = 7.3 Hz), 1.34(6H, s), 1.55-1.65(2H, m), 2.55(2H, t, J = 7.6 Hz), 3.06(2H, s), 3.11-3.43(5H, m), 3.80(3H, s), 4.93(2H, s), 6.24(1H, s), 6.37(1H, d, J = 2.2 Hz), 6.46(1H, dd, J = 2.4, 8.3 Hz), 6.77(1H, dd, J = 1.3, 7.6 Hz), 6.87(1H, d, J = 1.3 Hz), 6.98(1H, d, J = 8.3 Hz), 7.24(1H, d, J = 7.6 Hz) MS−: 450 Ex7 Ex2 NMR: 3.04(2H, s), 3.11-3.41(5H, m), 4.62(2H, s), 5.56(2H, s), 6.03(1H, s), 6.51(1H, d), 6.60(1H, dd), 6.99(1H, d), 7.46(1H, ddd), 7.54(1H, ddd), 8.00- 8.03(1H, m), 8.10-8.13(1H, m) MS+: 431 Ex8 Ex2 NMR: 1.92-2.00(2H, m), 2.71(2H, t, J = 7.4 Hz), 3.03(2H, s), 3.10-3.42(5H, m), 3.89(2H, t, J = 6.3 Hz), 4.60(2H, s), 6.30(1H, s), 6.33(1H, d, J = 2.3 Hz), 6.43(1H, dd, J = 2.4, 8.3 Hz), 6.93(1H, d, J = 8.3 Hz), 7.23-7.27(2H, m), 7.31- 7.35(2H, m) MS−: 412 Ex9 Ex2 NMR: 0.90(3H, t), 1.03(2H, d), 1.44-1.65(4H, m), 1.73-1.83(2H, m), 1.86- 1.96(3H, m), 2.11-2.21(1H, m), 2.52-2.58(2H, m), 2.70-2.79(2H, m), 2.96 (2H, brs), 3.79(3H, s), 4.63(2H, s), 4.95(2H, s), 6.37(1H, s), 6.38(1H, d), 6.48(1H, dd), 6.77(1H, d), 6.86(1H, brs), 6.93(1H, d), 7.23(1H, d) MS−: 450 Ex10 Ex2 NMR: 3.03(2H, s), 3.10-3.41(5H, m), 4.62(2H, s), 5.30(2H, s), 6.31(1H, s), 6.42(1H, d, J = 2.4 Hz), 6.50(1H, dd, J = 2.6, 8.3 Hz), 6.98(1H, d, J = 8.3 Hz), 7.98(1H, d, J = 8.3 Hz), 8.09(1H, s), 8.14(1H, d, J = 8.3 Hz) MS−: 486 Ex11 Ex2 NMR: 3.03(2H, s), 3.11-3.40(5H, m), 4.61(2H, s), 5.19(2H, s), 6.30(1H, s), 6.44(1H, d), 6.52(1H, dd), 6.96(1H, d), 7.64(2H, d), 7.76(2H, d) MS+: 442

TABLE 109 Ex12 Ex2 NMR: 3.03(2H, s), 3.11-3.24(3H, m), 3.38(2H, t), 3.81(3H, s), 4.60(2H, s), 5.00(2H, s), 6.30(1H, s), 6.39(1H, d), 6.49(1H, dd), 6.93-6.98(2H, m), 7.04(1H, d), 7.30-7.38(2H, m) MS+: 404 Ex13 Ex2 NMR: 1.34(3H, t), 3.02(2H, s), 3.10-3.24(3H, m), 3.37(2H, t), 4.20(2H, q), 4.59(2H, s), 5.09(2H, s), 6.29(1H, s), 6.38-6.44(2H, m), 6.52(1H, dd), 6.93(1H, d), 7.18(1H, dd), 7.39(1H, d), 7.46(1H, dd), 7.58(1H, s) MS−: 417 Ex14 Ex2 NMR: 0.91(3H, t, J = 7.3 Hz), 1.56-1.66(2H, m), 2.31(2H, t, J = 6.3 Hz), 2.56(2H, t, J = 7.8 Hz), 3.18-3.49(7H, m), 3.81(3H, s), 4.43(2H, t, J = 6.3 Hz), 5.00(2H, s), 6.66(1H, d, J = 2.6 Hz), 7.79(1H, dd, J = 1.2, 7.7 Hz), 6.82(1H, dd, J = 2.6, 8.8 Hz), 6.88(1H, d, J = 1.3 Hz), 7.27(1H, d, J = 7.7 Hz), 7.41(1H, d, J = 8.8 Hz) MS−: 470 Ex15 Ex2 NMR: 3.03(2H, s), 3.11-3.40(5H, m), 4.62(2H, s), 5.19(2H, s), 6.31(1H, s), 6.41 (1H, d), 6.50(1H, dd), 6.97(1H, d), 7.56-7.61(1H, m), 7.69-7.74(2H, m), 7.79 (1H, d) MS−: 418 Ex16 Ex2 NMR: 2.22(3H, s), 3.08(2H, s), 3.11-3.42(5H, m), 4.56(2H, s), 5.28(2H, s), 6.28(1H, d), 6.42-6.44(2H, m), 7.97(1H, d), 8.10(1H, s), 8.14(1H, d) MS−: 500 Ex17 Ex2 NMR: 0.88(3H, t), 1.53-1.62(2H, m), 2.50-2.57(2H, m), 3.02(2H, s), 3.10-3.40 (5H, m), 4.60(2H, s), 5.00(2H, s), 6.29(1H, s), 641(1H, d), 6.50(1H, dd), 6.94 (1H, d), 7.19(2H, d), 7.32(2H, d) MS−: 392 Ex18 Ex2 NMR: 1.98(3H, s), 3.10-3.41(7H, m), 4.55(2H, d, J = 1.3 Hz), 5.32(2H, s), 6.46 (1H, d, J = 2.6 Hz), 6.57(1H, dd, J = 2.6, 8.5 Hz), 7.17(1H, d, J = 8.6 Hz), 7.98(1H, d, J = 8.2 Hz), 8.10(1H, s), 8.14(1H, d, J = 8.2 Hz) MS−: 500 Ex19 Ex2 NMR: 0.90(3H, t, J = 7.3 Hz), 1.55(2H, m), 1.98(3H, s), 2.55(2H, t, J = 7.9 Hz), 3.10-3.41(7H, m), 3.80(3H, s), 4.53(2H, d, J = 1.3 Hz), 4.96(2H, s), 6.40(1H, d, J = 2.6 Hz), 6.54(1H, dd, J = 2.5, 8.5 Hz), 6.77(1H, dd, J = 1.3, 7.5 Hz), 6.87(1H, d, J = 1.3 Hz), 7.13(1H, d, J = 8.5 Hz), 7.24(1H, d, J = 7.5 Hz) MS−: 436 Ex20 Ex2 NMR: 2.32(2H, t, J = 6.0 Hz), 3.15-3.48(7H, m), 4.45(2H, t, J = 6.0 Hz), 5.36(2H, s), 6.73(1H, d, J = 2.6 Hz), 6.87(1H, dd, J = 2.6, 8.8 Hz), 7.46(1H, d, J = 8.8 Hz), 8.02(1H, d, J = 8.1 Hz), 8.11(1H, s), 8.16(1H, d, J = 8.1 Hz) MS+: 536 Ex21 Ex2 NMR: 3.02(2H, s), 3.00-3.25(3H, m), 3.36(2H, t), 4.59(2H, s), 4.99(2H, s), 6.26-6.29(2H, m), 6.36(1H, dd), 6.91(1H, d), 7.42-7.50(5H, m), 7.62(1H, s), 7.75-7.83(2H, m) MS−: 494 Ex22 Ex2 NMR: 2.03(3H, s), 2.12(2H, t, J = 6.0 Hz), 3.15-3.45(7H, m), 4.38(2H, t, J = 6.0 Hz), 5.33(2H, s), 6.65(1H, d, J = 2.6 Hz), 6.79(1H, dd, J = 2.6, 8.6 Hz), 7.25(1H, d, J = 8.6 Hz), 8.02(1H, d, J = 8.2 Hz), 8.10(1H, s), 8.15(1H, d, J = 8.2 Hz) MS−: 514 Ex23 Ex2 NMR: 0.91(3H, t, J = 7.4 Hz), 1.55-1.66(2H, m), 2.02(3H, s), 2.12(2H, t, J = 5.9 Hz), 2.56(2H, t, J = 7.8 Hz), 3.13-3.45(7H, m), 3.81(3H, s), 4.37(2H, t, J = 5.9 Hz), 4.97(2H, s), 4.58(1H, d, J = 2.6 Hz), 6.74(1H, dd, J = 2.6, 8.6 Hz), 6.78(1H, dd, J = 1.0, 7.6 Hz), 6.88(1H, d, J = 1.0 Hz), 7.2(1H, d, J = 8.6 Hz), 7.26(1H, d, J = 7.6 Hz) MS+: 474

TABLE 110 Ex24 Ex2 NMR(CDCl3): 0.95(3H, t, J = 7.3 Hz), 1.58-1.69(2H, m), 2.58(2H, t, J = 7.4 Hz), 3.36-4.37(10H, m), 4.87(2H, s), 5.03(2H, s), 6.49(1H, d, J = 2.3 Hz), 6.61(1H, dd, J = 2.3, 8.7 Hz), 6.71(1H, s), 6.77(1H, d, J = 7.4 Hz), 7.27(1H, d, J = 8.7 Hz), 7.36(1H, d, J = 8.7 Hz) MS−: 456 Ex25 Ex2 NMR: 3.14-3.45(7H, m), 4.76(2H, s), 5.35(2H, s), 6.56(1H, d, J = 2.5 Hz), 6.68 (1H, dd, J = 2.5, 8.6 Hz), 7.33(1H, d, J = 8.6 Hz), 8.00(1H, d, J = 8.2 Hz), 8.10(1H, s), 8.15(1H, d, J = 8.2 Hz) MS−: 520 Ex26 Ex2 NMR: 0.88(3H, t), 1.50-1.60(2H, m), 2.47(2H, t), 3.06(2H, s), 3.12-3.25(3H, m), 3.33-3.42(2H, m), 3.75(3H, s), 4.65(2H, s), 4.93(2H, s), 6.36(1H, s), 6.64 (1H, dd), 6.77-6.82(2H, m), 6.86(1H, d), 6.89(1H, dd), 7.03(1H, d) MS+: 446 Ex27 Ex2 NMR: 2.91(2H, s), 2.95(2H, t, J = 6.8 Hz), 3.05-3.14(1H, m), 3.27(2H, t, J = 7.2 Hz), 4.77(2H, s), 5.30(2H, s), 6.38(1H, d, J = 8.5 Hz), 6.46(1H, dd, J = 2.5, 8.5 Hz), 6.53(1H, d, J = 2.5 Hz), 7.12-7.17(2H, m), 7.38-7.44(1H, m), 7.45-7.50(2H, m), 7.97(1H, d, J = 8.3 Hz), 8.09(1H, s), 8.13(1H, d, J = 8.2 Hz) MS−: 565 Ex28 Ex2 MS−: 450 Ex29 Ex2 NMR: 0.90(3H, t, J = 7.3 Hz), 1.31-1.52(2H, m), 1.53-1.68(4H, m), 1.70-1.80 (1H, m), 1.93-2.17(2H, m), 2.35-2.46(1H, m), 2.55(2H, t, J = 7.8 Hz), 2.94-3.04 (1H, m), 3.80(3H, s), 4.65(2H, s), 4.95(2H, s), 6.32(1H, s), 6.38(1H, d, J = 2.1 Hz), 6.48(1H, dd, J = 2.3, 8.3 Hz), 6.77(1H, d, J = 7.5 Hz), 6.87(1H, s), 6.94(1H, d, J = 8.2 Hz), 7.24(1H, d, J = 7.5 Hz) MS−: 450 Ex30 Ex2 NMR: 0.90(3H, t, J = 7.3 Hz), 1.55-1.65(2H, m), 1.67-1.88(3H, m), 2.03-2.15 (1H, m), 2.43-2.58(3H, m), 3.06-3.13(1H, m), 3.18-3.25(2H, m), 3.45(1H, d, J = 13.5 Hz), 3.80(3H, s), 4.72(2H, s), 4.95(2H, s), 6.38(1H, s), 6.39(1H, d, J = 2.4 Hz), 6.48(1H, dd, J = 2.4, 8.3 Hz), 6.77(1H, dd, J = 1.0, 7.6 Hz), 6.87(1H, s), 6.95 (1H, d, J = 8.3 Hz), 7.24(1H, d, J = 7.6 Hz) MS−: 436 Ex31 Ex2 NMR: 0.90(3H, t, J = 7.3 Hz), 1.55-1.66(2H, m), 1.90-1.99(2H, m), 2.40-3.15 (9H, m), 3.80(3H, s), 4.66(2H, s), 4.95(2H, s), 6.33(1H, s), 6.39(1H, d, J = 2.4 Hz), 6.48(1H, dd, J = 2.4, 8.3 Hz), 6.77(1H, dd, J = 1.3, 7.6 Hz), 6.87(1H, d, J = 1.3 Hz), 6.94(1H, d, J = 8.3 Hz), 7.24(1H, d, J = 7.6 Hz) MS−: 436 Ex32 Ex2 NMR: 3.04(2H, s), 3.10-3..23(3H, m), 3.34-3.43(2H, m), 4.62(2H, s), 5.35(2H, s), 6.31(1H, s), 6.49(1H, d), 6.57(1H, dd), 6.99(1H, d), 7.35-7.39(1H, m), 7.42-7.51(5H, m) MS+: 524 Ex33 Ex2 NMR: 1.52-1.64(6H, m), 3.03(2H, s), 3.10-3.34(9H, m), 4.61(2H, s), 5.01(2H, s), 6.30(1H, s), 6.37(1H, d, J = 2.4 Hz), 6.48(1H, dd, J = 2.4, 8.3 Hz), 6.95(1H, d, J = 8.3 Hz), 7.15-7.21(2H, m), 7.47(1H, d, J = 8.3 Hz) MS−: 501 Ex34 Ex2 NMR: 3.08(2H, s), 3.12-3.42(5H, m), 4.66(2H, s), 5.31(2H, s), 6.32-6.34(1H, m), 6.39(1H, s), 6.50(1H, dd), 7.99(1H, d), 8.09(1H, s), 8.15(1H, d) MS−: 504 Ex35 Ex2 NMR: 3.05(2H, s), 3.10-3.38(5H, m), 3.76(3H, s), 4.56(2H, s), 5.31(2H, s), 6.08(1H, d), 6.24(1H, d), 6.42(1H, s), 8.00(1H, d), 8.09(1H, s), 8.14(1H, d) MS−: 516

TABLE 111 Ex36 Ex2 NMR: 1.65(3H, d), 3.02(2H, s), 3.10-3.23(3H, m), 3.34-3.40(2H, m), 4.61(2H, s), 5.87(1H, q), 6.29(1H, s), 6.46(1H, d), 6.54(1H, dd), 6.95(1H, d), 7.30- 7.38(1H, m), 7.40-7.52(5H, m) MS+: 538 Ex37 Ex2 NMR: 3.04(2H, s), 3.10-3.24(3H, m), 3.32-3.42(2H, m), 4.62(2H, s), 5.35(2H, s), 6.31(1H, s), 6.48(1H, d), 6.57(1H, dd), 6.99(1H, d), 7.35-7.39(1H, m), 7.42-7.48(2H, m), 7.53-7.58(2H, m) MS+: 558 Ex38 Ex2 NMR: 3.05(2H, s), 3.12-3.26(3H, m), 3.32-3.43(2H, m), 4.62(2H, s), 5.27(2H, s), 6.31(1H, s), 6.47(1H, d), 6.55(1H, dd), 6.97(1H, d), 7.21-7.33(1H, m), 7.37-7.45(2H, m), 7.62-7.72(3H, m), 7.86(1H, d) MS+: 456 Ex39 Ex2 NMR: 0.91(3H, t), 1.53-1.66(2H, m), 2.56(2H, t), 3.07(2H, s), 3.13-3.25(3H, m), 3.37-3.45(2H, m), 3.84(3H, s), 4.66(2H, s), 6.37(1H, s), 6.79(1H, d), 6.85 (1H, s), 6.90(1H, s), 7.00-7.10(3H, m), 7.30(1H, d), 7.52(1H, d) MS−: 418 Ex40 Ex2 NMR: 0.89(3H, t), 1.53-1.62(2H, m), 2.51(2H, t), 2.65-2.78(4H, m), 3.05(2H, s), 3.10-3.23(3H, m), 3.35-3.43(2H, m), 3.77(3H, s), 4.61(2H, s), 6.32(1H, s), 6.58(1H, s), 6.63-6.71(2H, m), 6.77(1H, s), 6.91(1H, d), 6.99(1H, d) MS+: 444 Ex41 Ex2 NMR: 3.04(2H, s), 3.10-3.22(3H, m), 3.35-3.42(2H, m), 4.62(2H, s), 5.39(2H, s), 6.31(1H, s), 6.48(1H, d), 6.57(1H, dd), 6.99(1H, d), 7.47-7.59(3H, m), 7.63 (1H, s), 7.70-7.76(2H, m) MS+: 481 Ex42 Ex2 NMR: 1.21(3H, t), 2.84(2H, q), 3.03(2H, s), 3.13-3.24(3H, m), 3.32-3.43(2H, m), 4.61(2H, s), 5.19(2H, s), 6.30(1H, s), 6.45(1H, d), 6.54(1H, dd), 6.96(1H, d), 7.14(1H, s), 7.30-7.47(5H, m) MS−: 460 Ex43 Ex2 NMR: 3.04(2H, s), 3.09-3.25(3H, m), 3.35-3.43(2H, m), 4.62(2H, s), 5.24(2H, s), 6.31(1H, s), 6.46(1H, d), 6.54(1H, dd), 6.97(1H, d), 7.28(1H, s), 7.35-7.43 (1H, m), 7.43-7.51(2H, m), 7.51-7.57(2H, m) MS+: 534, 536 Ex44 Ex2 NMR: 2.01-3.73(7H, m), 3.87(2H, s), 4.86(2H, s), 5.33(2H, s), 6.51(1H, d, J = 2.4 Hz), 6.59(1H, dd, J = 2.4, 8.3 Hz), 6.72(1H, s), 7.09(1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.10(1H, s), 8.15(1H, d, J = 8.1 Hz) MS−: 500 Ex45 Ex2 NMR: 1.96-4.01(9H, m), 4.86(2H, s), 5.34(2H, s), 6.41(1H, brs), 6.59(1H, dd, J = 2.3, 11.3 Hz), 6.85(1H, brs), 8.00(1H, d, J = 8.1 Hz), 8.11(1H, s), 8.16(1H, s, J = 8.1 Hz) MS−: 518

TABLE 112 Ex46 Ex2 NMR: 3.08(2H, s), 3.12-3.25(3H, m), 3.34-3.45(2H, m), 4.67(2H, s), 5.37(2H, s), 6.36-6.40(2H, m), 6.54(1H, dd), 7.36-7.39(1H, m), 7.41-7.52(5H, m) MS−: 518 Ex47 Ex2 NMR: 2.44(3H, s), 3.03(2H, s), 3.09-3.22(3H, m), 3.34-3.43(2H, m), 4.61(2H, s), 5.19(2H, s), 6.30(1H, s), 6.44(1H, d), 6.53(1H, dd), 6.96(1H, d), 7.19(1H, s), 7.29-7.38(1H, m), 7.39-7.48(4H, m) MS+: 470 Ex48 Ex2 NMR: 0.88(3H, t), 1.52-1.65(2H, m), 2.78(2H, t), 3.03(2H, s), 3.11-3.47(5H, m), 4.61(2H, s), 5.19(2H, s), 6.30(1H, s), 6.45(1H, d), 6.53(1H, dd), 6.96(1H, d), 7.13(1H, s), 7.30-7.40(3H, m), 7.41-7.48(2H, m) MS+: 498 Ex49 Ex2 NMR: 0.61-0.68(2H, m), 0.94-1.06(2H, m), 2.10-2.19(1H, m), 2.97-3.09(5H, m), 3.21-3.42(2H, m), 4.60(2H, s), 5.15(2H, s), 6.25(1H, s), 6.42(1H, d), 6.52 (1H, dd), 6.92-6.97(1H, m), 7.19(1H, s), 7.30-7.36(1H, m), 7.42-7.48(2H, m), 7.52-7.60(2H, m) MS−: 472 Ex50 Ex2 NMR: 3.03(2H, s), 3.08-3.24(3H, m), 3.34-3.42(2H, m), 4.61(2H, s), 5.20(2H, s), 6.30(1H, s), 6.45(1H, d), 6.53(1H, dd), 6.96(1H, d), 7.28-7.35(2H, m), 7.40-7.49(4H, m), 7.60-7.66(1H, m), 7.85(1H, d) MS+: 518 Ex51 Ex2 NMR: 1.44(3H, d), 3.02(2H, brs), 3.09-3.40(5H, m), 4.60(2H, s), 5.07(2H, s), 5.42-5.52(1H, m), 6.29(1H, s), 6.43(1H, d), 6.51(1H, dd), 6.95(1H, d), 7.50 (1H, d), 7.70-7.75(2H, m) MS−: 530 Ex52 Ex2 NMR: 2.95-3.64(7H, m), 4.61(2H, s), 4.89(1H, d), 4.94(1H, d), 5.11(2H, s), 6.28(1H, s), 6.39(1H, d), 6.49(1H, dd), 6.96(1H, d), 7.36-7.45(2H, m), 7.68(1H, d) MS+: 540 Ex53 Ex2 NMR: 1.22(6H, d), 3.00(2H, s), 3.06-3.13(1H, m), 3.25-3.42(5H, m) 4.62(2H, s), 5.17(2H, s), 6.28(1H, s), 6.45(1H, d), 6.53(1H, dd), 6.96(1H, d), 7.06(1H, s), 7.32-7.38(3H, m), 7.41-7.48(2H, m) MS−: 474 Ex54 Ex2 NMR: 1.21(3H, t), 2.84(2H, q), 2.95-3.16(5H, m), 3.28-3.42(2H, m), 4.61(2H, s), 5.19(2H, s), 6.28(1H, s), 6.45(1H, d), 6.53(1H, dd), 6.95(1H, d), 7.23(1H, s), 7.60-7.72(4H, m) MS+: 552 Ex55 Ex2 NMR: 1.08(3H, t), 3.00-3.15(5H, m), 3.24-3.51(4H, m), 4.61(2H, s), 5.18(2H, s), 6.29(1H, s), 6.44(1H, d), 6.52(1H, dd), 6.91-6.97(2H, m), 7.37(1H, d), 7.56-7.64(1H, m), 7.66-7.73(1H, m), 7.81-7.87(1H, m) MS−: 528

TABLE 113 Ex56 Ex2 NMR: 1.21(3H, t), 1.90-1.99(2H, m), 2.40-2.62(3H, m), 2.63-2.73(1H, m), 2.80- 2.96(3H, m), 3.13(2H, q), 4.71(2H, s), 5.22(2H, s), 6.38(1H, d), 6.43(1H, s), 6.51(1H, dd), 7.16(1H, s), 7.30-7.40(3H, m), 7.40-7.48(2H, m) MS+: 516 Ex57 Ex2 NMR: 1.16(3H, t), 2.06(3H, s), 2.67(2H, q), 3.02(2H, s), 3.09-3.20(3H, m), 3.32-3.43(2H, m), 4.60(2H, s), 5.09(2H, s), 6.29(1H, s), 6.40(1H, d), 6.49(1H, dd), 6.85(1H, s), 6.94(1H, d) MS+: 422 Ex58 Ex2 NMR: 1.29-1.53(2H, m), 1.55-1.80(2H, m), 1.94-2.21(2H, m), 2.33-2.44(1H, m), 2.52-2.62(1H, m), 2.74(1H, d), 3.07(2H, dd), 4.72(2H, s), 5.31(2H, s), 6.33 (1H, m), 6.42(1H, s), 6.51(1H, dd), 7.98(1H, d), 8.01(1H, s), 8.15(1H, d) MS+: 534 Ex59 Ex2 NMR: 1.90-2.00(2H, m), 2.41-2.54(2H, m), 2.56(3H, s), 2.56-2.61(1H, m), 2.69 (1H, t), 2.85-2.96(1H, m), 3.13(2H, dd), 4.71(2H, s), 5.38(2H, s), 6.41(1H, m), 6.43(1H, s), 6.55(1H, dd), 7.35-7.41(1H, m), 7.44-7.49(2H, m), 7.65-7.68 (2H, m) MS+: 503 Ex60 Ex2 NMR: 1.80-1.94(2H, m), 2.41-2.62(2H, m), 2.65-2.73(1H, m), 2.84-2.89(1H, m), 3.08-3.41(3H, m), 4.72(2H, s), 5.37(2H, s), 6.38-6.45(2H, m), 6.55(1H, dd), 7.38(1H, s), 7.40-7.53(5H, m) MS+: 556 Ex61 Ex2 NMR: 1.88-1.99(2H, m), 2.41-2.64(3H, m), 2.65-2.73(1H, m), 2.85-2.95(1H, m), 3.04-3.21(2H, m), 4.72(2H, s), 5.25(2H, s), 6.35(1H, d), 6.43(1H, s), 6.52 (1H, dd), 7.40-7.57(3H, m), 7.72-7.86(3H, m), 7.98-8.04(2H, m) MS+: 550 Ex62 Ex2 NMR: 1.87-1.97(2H, m), 2.41-3.24(7H, m), 4.72(2H, s), 5.23(2H, s), 6.39(1H, d), 6.43(1H, s), 6.54(1H, dd), 7.30-7.34(2H, m), 7.42-7.47(4H, m), 7.74-7.77 (1H, m), 7.86-7.89(1H, m) MS−: 526 Ex63 Ex2 NMR: 1.79-2.00(2H, m), 2.30-2.41(1H, m), 2.43-2.79(4H, m), 3.09(2H, s), 4.71 (2H, s), 5.20(2H, s), 6.33(1H, d), 6.40(1H, s), 6.48(1H, dd), 6.60-6.63(1H, m), 7.80-7.87(2H, m), 8.12-8.25(2H, m), 8.69(1H, d) MS−: 516 Ex64 Ex2 NMR: 1.78-2.04(2H, m), 2.30-2.79(7H, m), 3.09(2H, s), 3.55(2H, t), 3.78(2H, t), 4.70(2H, s), 5.02(2H, s), 6.28(1H, s), 6.38-6.45(2H, m), 6.84-6.89(2H, m), 7.45-7.52(1H, m) MS−: 555 Ex65 Ex2 NMR: 1.78-2.02(2H, m), 1.95(3H, s), 2.30-2.81(5H, m), 3.08-3.19(2H, m), 4.72 (2H, s), 5.32(2H, s), 6.40-6.44(2H, m), 6.55(1H, dd), 7.24-7.30(2H, m), 7.42-7.51(3H, m) MS+: 570

TABLE 114 Ex66 Ex2 NMR: 1.20(3H, s), 1.41-1.52(1H, m), 2.24(1H, d), 2.22-2.36(1H, m), 2.43-2.60 (2H, m), 2.86(1H, d), 3.11(2H, s), 4.72(2H, s), 5.37(2H, s), 6.38-6.42(2H, m), 6.54(1H, dd), 7.38(1H, s), 7.41-7.52(5H, m) MS+: 570 Ex67 Ex2 NMR: 1.18(3H, t), 1.70-2.01(2H, m), 2.31-3.51(13H, m), 4.67(2H, s), 6.34(1H, s), 6.67(1H, s), 6.72-6.81(2H, m), 6.94(1H, s), 7.31-7.38(3H, m), 7.39-7.44 (2H, m) MS+: 496 Ex68 Ex2 NMR: 1.24(3H, t), 1.91-2.04(2H, m), 2.42-2.75(4H, m), 2.85(2H, q), 2.85-3.60 (3H, m), 4.72(2H, s), 6.41(1H, s), 6.79(1H, d), 6.97(1H, s), 7.00-7.09(2H, m), 7.14(1H, s), 7.30-7.50(6H, m) MS−: 470 Ex69 Ex2 NMR: 1.02(3H, d), 2.04-2.09(1H, m), 2.21-2.38(2H, m), 2.56-2.79(3H, m), 3.01- 3.16(2H, m), 4.72(2H, s), 5.36(2H, s), 6.37-6.44(2H, m), 6.53(1H, dd), 7.38(1H, s), 7.40-7.53(5H, m) MS−: 546 Ex70 Ex2 NMR: 1.94-2.49(3H, m), 2.95-3.72(4H, m), 3.90(2H, brs), 4.94(2H, s), 5.21(2H, s), 6.34(2H, t), 6.41(1H, brs), 6.57(1H, dd), 6.86(1H, brs), 7.54(2H, t), 7.80 (1H, d), 7.94-7.99(2H, m) Ex71 Ex2 NMR: 1.19(3H, s), 1.38-1.52(1H, m), 2.23(1H, d), 2.24-2.34(1H, m), 2.43-2.58 (2H, m), 2.85(1H, d), 3.10(2H, s), 4.72(2H, s), 5.31(2H, s), 6.33(1H, s), 6.40 (1H, d), 6.49(1H, dd), 7.99(1H, d), 8.09(1H, s), 8.14(1H, d) MS+: 556 Ex72 Ex2 NMR: 1.20(3H, s), 1.38-1.53(1H, m), 1.95(3H, s), 2.24(1H, d), 2.25-2.35(1H, m), 2.40-2.62(2H, m), 2.86(1H, d), 3.11(2H, s), 4.73(2H, s), 5.32(2H, s), 6.39- 6.41(2H, m), 6.56(1H, d), 7.25-7.32(2H, m), 7.42-7.55(3H, m) MS+: 584 Ex73 Ex2 NMR: 2.01-2.23(2H, m), 2.46-2.79(3H, m), 2.92-3.00(1H, m), 3.12-3.27(2H, m), 3.43-3.57(1H, m), 4.75(2H, s), 5.37(2H, s), 6.40(1H, d), 6.45(1H, s), 6.55 (1H, dd), 7.35-7.42(1H, m), 7.42-7.54(5H, m) MS+: 558 Ex74 Ex2 NMR: 1.72-1.93(1H, m), 2.21-2.48(2H, m), 2.63-2.89(3H, m), 3.16(2H, s), 4.74 (2H, s), 5.37(2H, s), 6.40(1H, d), 6.43(1H, s), 6.54(1H, dd), 7.34-7.40(1H, m), 7.41-7.53(5H, m) MS+: 574 Ex75 Ex2 NMR: 1.18(3H, s), 1.38-1.48(1H, m), 2.22(1H, d), 2.26-2.68(3H, m), 2.85(1H, d), 3.05(2H, s), 4.68(2H, s), 4.92(2H, q), 5.11(2H, s), 6.31(1H, s), 6.39(1H, d), 6.48(1H, dd), 6.95(1H, d), 7.35-7.45(2H, m), 7.69(1H, d) MS+: 568 Ex76 Ex2 NMR: 1.19(3H, s), 1.44(3H, d), 2.18-2.23(3H, m), 2.39-2.65(2H, m), 2.80-2.88 (1H, m), 3.02(2H, s), 4.68(2H, s), 5.06(2H, s), 5.43-5.50(1H, m), 6.37(1H, brs), 6.43(1H, d), 6.51(1H, dd), 6.94(1H, d), 7.49(1H, d), 7.69-7.75(2H, m) MS+ 582 Ex77 Ex2 NMR: 0.92-1.06(2H, m), 1.52-1.63(1H, m), 2.27-2.35(1H, m), 2.53-2.64(1H, m), 2.78-2.85(2H, m), 3.12(2H, s), 4.67(2H, s), 5.37(2H, s), 6.37-6.43(2H, m), 6.54(1H, dd), 7.35-7.40(1H, m), 7.41-7.53(5H, m) MS−: 544

TABLE 115 Ex78 Ex2 NMR: 1.70-1.82(1H, m), 2.38-2.70(3H, m), 3.04-3.14(2H, m), 3.23-3.43(2H, m), 4.71(2H, s), 5.37(2H, s), 6.39(1H, d), 6.43(1H, s), 6.55(1H, dd), 7.35-7.39 (1H, m), 7.41-7.56(5H, m) MS−: 600 Ex79 Ex2 NMR: 2.17-2.27(2H, m), 2.39-2.47(2H, m), 2.92-2.99(2H, m), 3.10(2H, s), 4.72 (2H, s), 5.31(2H, s), 6.35(1H, s), 6.42-6.56(3H, m), 7.99(1H, d), 8.09(1H, s), 8.14(1H, d), MS−: 530 Ex80 Ex2 NMR: 1.09-1.24(2H, m), 1.56-1.68(3H, m), 1.87(2H, t), 2.12(2H, d), 2.77(2H, dm), 3.01(2H, s), 4.70(2H, s), 5.32(2H, s), 6.33-6.35(1H, m), 6.40(1H, s), 6.50 (1H, dd), 7.99(1H, d), 8.10(1H, s), 8.15(1H, d), MS−: 546 Ex81 Ex2 NMR: 1.38(3H, s), 2.96(2H, d), 3.07(2H, s), 3.31(2H, d), 4.46(2H, s), 5.36(2H, s), 6.32-6.42(2H, m), 6.54(1H, dd), 7.34-7.40(1H, m), 7.40-7.52(5H, m) MS+: 556 Ex82 Ex2 NMR: 1.84-1.95(2H, m), 2.32(2H, t), 2.59(3H, s), 2.82-3.08(2H, m), 3.73(2H, brs), 4.89(2H, s), 5.34(2H, s), 6.40-6.43(1H, m), 6.57(1H, dd), 6.77-6.85(1H, m), 8.00(1H, d), 8.11(1H, s), 8.16(1H, d), 11.11(1H, brs), 11.99(1H, brs), MS−: 520 Ex83 Ex2 NMR: 1.76-2.02(2H, m), 2.31-2.85(5H, m), 3.12(2H, s), 3.43(2H, s), 5.32(2H, s), 6.37(1H, s), 6.73(1H, s), 6.87(1H, d), 7.07(1H, d), 8.02(1H, d), 8.05-8.15 (2H, m) MS+: 518 Ex84 Ex2 NMR: 1.21-1.78(5H, m), 1.77-2.00(1H, m), 2.20-2.38(2H, m), 2.37-2.51(1H, m), 2.64-2.78(2H, m), 3.02(2H, s), 4.72(2H, s), 5.37(2H, s), 6.34-6.58(3H, m), 7.38(1H, s), 7.41-7.53(5H, m) MS+: 574 Ex85 Ex2 NMR: 2.10-2.21(2H, m), 2.35-2.43(2H, m), 2.99(2H, s), 3.13(2H, s), 4.72(2H, s), 5.31(2H, s), 6.33-6.36(1H, m), 6.44(1H, s), 6.47-6.58(2H, m), 7.99(1H, d), 8.09(1H, s), 8.14(1H, d), MS−: 530 Ex86 Ex2 NMR: 1.89-1.97(2H, m), 2.01(3H, s), 2.18-2.28(2H, m), 2.43-3.20(9H, m), 5.26(2H, s), 6.24(2H, dd), 6.83-6.89(2H, m), 6.90-6.95(2H, m), 7.17-7.25(1H, m), 7.53(1H, d), 7.84(1H, d), 7.96(1H, d) MS+: 533 Ex87 Ex2 NMR: 1.20(3H, s), 1.40-1.53(1H, m), 2.01(3H, s), 2.19-2.35(4H, m), 2.42- 2.70(4H, m), 2.84(1H, d), 3.18(2H, s), 5.26(2H, s), 6.24(2H, dd), 6.83-6.89(2H, m), 6.91-6.96(2H, m), 7.19(1H, d), 7.53(1H, d), 7.83(1H, d), 7.95(1H, s) MS+: 525 Ex88 Ex2 NMR: 1.20(3H, s), 1.40-1.54(1H, m), 2.01(3H, s), 2.20-2.38(4H, m), 2.40- 2.69(4H, m), 2.85(1H, d), 3.18(2H, s), 5.38(2H, s), 6.83-6.90(2H, m), 7.20(1H, d), 7.38(1H, s), 7.43-7.52(5H, m) MS+: 542 Ex89 Ex2 NMR: 1.18(3H, s), 1.38-1.48(1H, m), 2.23(1H, d), 2.25-2.35(1H, m), 2.38- 2.53(2H, m), 2.84(1H, d), 3.09(2H, s), 4.72(2H, s), 5.24(2H, s), 6.23(2H, dd), 6.36-6.43(2H, d), 6.52(1H, dd), 6.93(2H, s), 7.53(1H, d), 7.82(1H, d), 7.94(1H, s) MS+: 553

TABLE 116 Ex90 Ex2 NMR: 1.19(3H, s), 1.38-1.51(1H, m), 2.23(1H, d), 2.24-2.36(1H, m), 2.42- 2.57(2H, m), 2.84(1H, d), 3.11(2H, s), 4.72(2H, s), 5.24(2H, s), 6.37-6.43(2H, m), 6.53(1H, dd), 7.30-7.37(2H, m), 7.41-7.48(4H, m), 7.76(1H, d), 7.89(1H, s) MS+: 542 Ex91 Ex2 NMR: 1.38(3H, s), 2.01(3H, s), 2.18(2H, t), 2.16(2H, t), 2.97(2H, d), 3.19(2H, s), 3.33(2H, d), 5.38(2H, s), 6.84-6.90(2H, m), 7.19(1H, d), 7.38(1H, s), 7.41- 7.54(5H, m) MS+: 550 Ex92 Ex2 NMR: 1.40(3H, s), 2.02(3H, s), 2.18(2H, t), 2.61(2H, t), 3.00(2H, d), 3.21(2H, s), 3.34(2H, d), 5.26(2H, s), 6.24(2H, dd), 6.82-6.89(2H, m), 6.91-6.95(2H, m), 7.19(1H, d), 7.53(1H, d), 7.83(1H, dd), 7.96(1H, d) MS+: 533 Ex93 Ex2 NMR: 1.34(3H, s), 2.91(2H, d), 3.05(2H, s), 3.27(2H, d), 4.66(2H, s), 5.22(2H, s), 6.34-6.39(2H, m), 6.52(1H, d), 7.28-7.35(2H, m), 7.40-7.48(4H, m), 7.75(1H, d), 7.88(1H, s) MS+: 550 Ex94 Ex2 NMR: 1.34(3H, s), 2.91(2H, d), 3.05(2H, s), 3.29(2H, d), 4.66(2H, s), 5.23(2H, s), 6.23(2H, dd), 6.33-6.39(2H, m), 6.51(1H, d), 6.91-6.95(2H, m), 7.52(1H, d), 7.81(1H, d), 7.93(1H, d) MS+: 539 Ex95 Ex2 NMR: 1.35(3H, s), 1.97(3H, s), 2.02(3H, s), 2.19(2H, t), 2.62(2H, t), 2.90- 2.95(2H, m), 3.18(2H, s), 3.26-3.36(2H, m), 5.33(2H, s), 6.85-6.93(2H, m), 7.20 (1H, d), 7.25-7.32(2H, m), 7.41-7.54(3H, m) MS+: 564 Ex96 Ex2 NMR: 1.68-2.01(2H, m), 2.31-2.42(1H, m), 2.46-2.62(2H, m), 2.63-2.78(2H, m), 3.04-3.18(2H, m), 4.72(2H, s), 5.23(2H, s), 6.40(2H, d), 6.53(1H, dd), 7.26-7.36(2H, m), 7.40-7.49(4H, m), 7.75(1H, d), 7.88(1H, s) MS+: 550 Ex97 Ex2 NMR: 1.35(3H, s), 2.88-2.94(2H, m), 3.06(2H, s), 3.25-3.36(2H, m), 4.66(2H, s), 5.14(2H, s), 6.54(2H, d), 6.51(1H, dd), 7.38-7.50(7H, m), 7.62(1H, s) MS+: 516 Ex98 Ex2 NMR: 2.23-2.30(2H, m), 2.42-2.53(2H, m), 3.03(2H, s), 3.18(2H, s), 4.72(2H, s), 5.24(2H, s), 6.41(1H, d), 6.48(1H, s), 6.55(1H, dd), 6.82-6.88(1H, m), 7.28-7.35(2H, m), 7.40-7.48(4H, m), 7.76(1H, d), 7.89(1H, s) MS+: 562 Ex99 Ex2 NMR: 1.70-2.01(2H, m), 2.32-2.42(1H, m), 2.47-2.62(2H, m), 2.63-2.70(1H, m), 2.71-2.87(1H, m), 3.04-3.18(2H, m), 4.72(2H, s), 5.23(2H, s), 6.41(2H, d), 6.53(1H, dd), 7.26-7.36(2H, m), 7.40-7.48(4H, m), 7.75(1H, d), 7.88 (1H, s) MS+: 550 Ex100 Ex2 NMR: 2.03(3H, s), 2.18(2H, t), 2.61(2H, t), 3.11-3.19(2H, m), 3.24(2H, s), 3.31-3.37(2H, m), 4.64(2H, d), 5.26(2H, s), 6.24(2H, dd), 6.82-6.88(2H, m), 6.91-6.95(2H, m), 7.17-7.23(1H, m), 7.53(1H, d), 7.80-7.86(1H, m), 7.93-7.97 (1H, m) MS+: 551 Ex101 Ex2 NMR: 2.02(3H, s), 2.18(2H, t), 2.61(2H, t), 3.12-3.20(2H, m), 3.24(2H, s), 3.28-3.38(2H, m), 4.65(2H, d), 5.38(2H, s), 6.83-6.91(2H, m), 7.20(1H, d), 7.38 (1H, s), 7.40-7.53(5H, m) MS−: 544

TABLE 117 Ex102 Ex2 NMR: 0.79(3H, t), 1.81(2H, q), 2.02(3H, s), 2.17(2H, t), 2.61(2H, t), 3.00-3.08 (2H, m), 3.20(2H, s), 3.26-3.35(2H, m), 5.38(2H, s), 6.83-6.88(2H, m), 7.20 (1H, d), 7.38(1H, d), 7.40-7.54(5H, m) MS+: 564 Ex103 Ex2 NMR: 0.80(3H, t), 1.80(2H, q), 2.97-3.05(2H, m), 3.08(2H, s), 3.34-3.32(2H, m), 4.66(2H, s), 5.24(2H, s), 6.24(2H, dd), 6.35-6.41(2H, m), 6.53(1H, dd), 6.91-6.96(2H, m), 7.53(1H, d), 7.82(1H, d), 7.94(1H, s) MS+: 553 Ex104 Ex2 NMR: 1.20(3H, s), 1.42-1.53(1H, m), 2.01(3H, s), 2.18-2.38(4H, m), 2.41-2.70 (4H, m), 2.80-2.88(1H, m), 3.19(2H, s), 5.29(2H, s), 6.52(1H, dd), 6.84-6.90 (2H, m), 7.17-7.24(1H, m), 7.60-7.66(1H, d), 7.75(1H, d), 7.85-7.92(1H, m), 7.99(1H, d), 8.05(1H, d) MS+: 548 Ex105 Ex2 NMR: 1.81-2.02(2H, m), 2.01(3H, s), 2.19-2.27(2H, m), 2.41-2.85(7H, m), 3.18(2H, s), 5.29(2H, s), 6.52(1H, dd), 6.82-6.90(2H, m), 7.17-7.24(1H, m), 7.63(1H, d), 7.75(1H, d), 7.85-7.90(1H, m), 7.96-8.01(1H, m), 8.05(1H, d) MS+: 534 Ex106 Ex2 NMR: 1.37(3H, s), 2.01(3H, s), 2.18(2H, t), 2.61(2H, t), 2.93-3.01(2H, m), 3.19 (2H, s), 3.28-3.35(2H, m), 5.28(2H, s), 6.52(1H, dd), 6.80-6.88(2H, m), 7.14- 7.24(1H, m), 7.60-7.67(1H, m), 7.75(1H, d), 7.85-7.92(1H, m), 7.97-8.02 (1H, d), 8.04(1H, d) MS+: 534 Ex107 Ex2 NMR: 1.70-2.01(2H, m), 2.30-2.73(5H, m), 3.09(2H, s), 4.72(2H, s), 5.24(2H, s), 6.36-6.46(2H, m), 6.53(1H, dd), 7.24-7.37(3H, m), 7.42-7.56(2H, m), 7.78(1H, d), 7.91(1H, s) MS+: 568 Ex108 Ex2 NMR: 1.70-2.01(2H, m), 2.30-2.73(5H, m), 3.09(2H, s), 4.72(2H, s), 5.24(2H, s), 6.36-6.46(2H, m), 6.53(1H, dd), 7.24-7.37(3H, m), 7.42-7.56(2H, m), 7.78(1H, d), 7.91(1H, s) MS+: 568 Ex109 Ex2 NMR: 1.76-2.00(2H, m), 2.28-2.58(3H, m), 2.60-2.80(2H, m), 3.07-3.17(2H, m), 4.72(2H, s), 5.24(2H, s), 6.20-6.26(2H, m), 6.37-6.45(2H, m), 6.53(1H, dd), 6.89-6.97(2H, m), 7.53(1H, d), 7.76-7.85(1H, m), 7.90-7.97(1H, m) MS+: 539 Ex110 Ex2 NMR: 1.80-2.01(2H, m), 2.01(3H, s), 2.23(2H, t), 2.35-2.96(7H, m), 3.17(2H, s), 5.26(2H, s), 6.21-6.27(2H, m), 6.83-6.90(2H, m), 6.90-6.98(2H, m), 7.15- 7.25(1H, m), 7.53(1H, d), 7.81-7.88(1H, m), 7.92-7.97(1H, m) MS+: 533 Ex111 Ex2 NMR: 1.76-2.00(2H, m), 2.28-2.58(3H, m), 2.60-2.80(2H, m), 3.07-3.17(2H, m), 4.72(2H, s), 5.24(2H, s), 6.20-6.26(2H, m), 6.37-6.45(2H, m), 6.53 (1H, dd), 6.89-6.97(2H, m), 7.53(1H, d), 7.76-7.85(1H, m), 7.90-7.97(1H, m) MS+: 539

TABLE 118 Ex112 Ex2 NMR: 2.10-2.24(2H, m), 2.32-2.43(2H, m), 2.99(2H, s), 3.13(2H, s), 4.72(2H, s), 5.37(2H, s), 6.37-6.47(2H, m), 6.55(1H, dd), 7.38(1H, s), 7.40-7.54(6H, m) MS−: 544 Ex113 Ex2 NMR: 2.13-2.25(2H, m), 2.31-2.50(2H, m), 2.97-3.04(2H, m), 3.16(2H, s), 4.72 (2H, s), 5.25(2H, s), 6.21-6.28(2H, m), 6.38-6.42(1H, m), 6.43-6.46(2H, m), 6.54(1H, dd), 6.90-6.98(2H, m), 7.53(1H, d), 7.80-7.85(1H, m), 7.92-7.97(1H, m) MS+: 551 Ex114 Ex2 NMR: 1.22(3H, s), 1.46-1.54(1H, m), 2.41-2.48(4H, m), 2.47-2.61(1H, m), 2.67 (2H, t), 2.83-2.89(1H, m), 3.05-3.10(2H, m), 3.23-3.27(1H, m), 5.35(2H, s), 6.37(1H, s), 7.02(1H, s), 7.24-7.47(8H, m) MS+: 528 Ex115 Ex2 NMR: 1.80-2.01(2H, m), 2.01(3H, s), 2.23(2H, t), 2.35-2.96(7H, m), 3.17(2H, s), 5.26(2H, s), 6.21-6.27(2H, m), 6.83-6.90(2H, m), 6.90-6.98(2H, m), 7.15- 7.25(1H, m), 7.53(1H, d), 7.81-7.88(1H, m), 7.92-7.97(1H, m) MS+: 533 Ex116 Ex2 NMR: 1.35(3H, s), 2.87-2.95(2H, m), 3.02(2H, s), 3.20-3.32(2H, s), 4.62(2H, s), 5.23(2H, s), 6.20-6.26(2H, m), 6.24-6.30(1H, m), 6.46(1H, d), 6.55(1H, dd), 6.90-7.00(3H, m), 7.52(1H, d), 7.76-7.85(1H, m), 7.90-7.97(1H, m) MS+: 521 Ex117 Ex2 NMR: 0.89(3H, d), 1.40(3H, s), 2.07-2.18(1H, m), 2.47(1H, dd), 2.76(1H, dd), 2.99(2H, d), 3.08(2H, s), 3.32(2H, d), 3.71-3.80(2H, m), 4.64(2H, s), 6.21- 6.23(1H, m), 6.33-6.39(2H, m), 7.21(2H, d), 7.33(2H, d) ESI−: 458 Ex118 Ex2 NMR: 2.16-2.22(2H, m), 2.39-2.46(2H, m), 2.91-2.97(2H, m), 3.08-3.13(2H, m), 4.61-4.84(6H, m), 4.92-5.08(3H, m), 6.32-6.40(2H, m), 6.43(1H, s), 6.47(1H, dd), 7.31(1H, d), 7.37(1H, dd), 7.53(1H, d) ESI−: 522 Ex119 Ex3 NMR: 3.53-3.70(1H, m), 3.80-4.41(5H, m), 4.79(2H, s), 6.72(1H, brs), 7.01 (1H, s), 7.16(1H, dd, J = 1.4, 7.8 Hz), 7.20(1H, d, J = 7.8 Hz), 7.76(2H, d, J = 8.6 Hz), 7.80(4H, d, J = 8.6 Hz) MS−: 412 Ex120 Ex3 NMR: 3.57-3.71(1H, m), 3.87-3.99(2H, m), 4.08-4.32(4H, m), 4.83(2H, s), 6.74- 6.78(1H, m), 6.94-6.97(1H, m), 7.11(1H, dd), 7.12(1H, d), 7.40-7.45(3H, m), 7.52-7.57(2H, m), 11.31(1H, brs), 13.14(1H, brs) MS−: 344 Ex121 Ex3 NMR: 3.59-3.69(1H, m), 3.79(3H, s), 3.89-3.97(2H, m), 4.07-4.31(4H, m), 4.82 (2H, s), 6.73-6.77(1H, m), 6.90-6.92(1H, m), 6.99(2H, d), 7.07(1H, dd), 7.15 (1H, d), 7.48(2H, d), 11.28(1H, brs), 13.06(1H, brs) MS−: 374

TABLE 119 Ex122 Ex3 NMR: 2.34(3H, s), 3.59-3.71(1H, m), 3.87-4.00(2H, m), 4.06-4.34(4H, m), 4.82 (2H, s), 6.71-6.79(1H, m), 6.92-6.94(1H, m), 7.09(1H, dd), 7.16(1H, d), 7.24 (2H, d), 7.43(2H, d), 11.13(1H, brs), 13.11(1H, brs) MS−: 358 Ex123 Ex3 NMR: 1.24-1.56(6H, m), 1.57-1.73(2H, m), 1.75-1.86(2H, m), 2.57-2.70(1H, m), 3.55-3.70(1H, m), 3.83-3.98(2H, m), 4.02-4.34(4H, m), 4.76(2H, s), 6.68- 6.76(2H, m), 6.91(1H, dd), 7.08(1H, d), 10.94(1H, brs), 13.08(1H, brs) MS−: 350 Ex124 Ex3 NMR: 3.57-3.72(1H, m), 3.85-4.01(2H, m), 4.04-4.38(4H, m), 4.85(2H, s), 6.74- 6.79(1H, m), 7.00-7.02(1H, m), 7.15(1H, dd), 7.20(1H, d), 7.68(1H, t), 7.79 (1H, d), 7.86(1H, d), 7.91(1H, s), 11.31(1H, brs), 13.13(1H, brs) MS−: 412 Ex125 Ex3 NMR: 3.57-3.70(1H, m), 3.89-4.02(2H, m), 4.09-4.35(4H, m), 4.84(2H, s), 6.74- 6.79(1H, m), 6.91-6.94(1H, m), 7.1(1H, dd), 7.21(1H, d), 7.63(1H, t), 7.73 (1H, t), 7.80(1H, d), 7.84(1H, d), 11.13(1H, brs), 1311(1H, brs) MS−: 412 Ex126 Ex3 NMR: 1.24-1.56(6H, m), 1.57-1.73(2H, m), 1.75-1.86(2H, m), 2.57-2.70(1H, m), 3.55-3.70(1H, m), 3.83-3.98(2H, m), 4.02-4.34(4H, m), 4.76(2H, s), 6.68-6.76(2H, m), 6.91(1H, dd), 7.08(1H, d), 10.94(1H, brs), 13.08(1H, brs) MS−: 350 Ex127 Ex3 NMR: 1.27(9H, s), 3.56-3.68(1H, m), 3.84-3.96(2H, m), 4.06-4.33(4H, m), 4.77 (2H, s), 6.68-6.74(2H, m), 6.89(1H, dd), 7.07(1H, d), 11.04(1H, brs), 13.11 (1H, brs) MS−: 324 Ex128 Ex3 NMR: 1.23-1.34(2H, m), 1.46-1.67(4H, m), 1.72-1.82(2H, m), 2.00-2.13(1H, m), 2.41(2H, d), 3.57-3.68(1H, m), 3.86-3.96(2H, m), 4.04-4.32(4H, m), 4.78 (2H, s), 6.70-6.72(1H, m), 6.74-6.76(1H, m), 6.92(1H, dd), 7.08(1H, d), 11.13 (1H, brs), 13.09(1H, brs) MS−: 350 Ex129 Ex3 NMR: 0.89(6H, d), 1.43(2H, q), 1.62-1.76(1H, m), 2.41(2H, t), 3.57-3.69(1H, m), 3.86-3.96(2H, m), 4.06-4.33(4H, m), 4.78(2H, s), 6.69-6.78(2H, m), 6.91 (1H, dd), 7.08(1H, d), 11.13(1H, brs), 13.11(1H, brs) MS−: 338 Ex130 Ex3 NMR: 3.57-3.69(1H, m), 3.86-4.00(2H, m), 4.06-4.35(4H, m), 4.82(2H, s), 6.73- 6.78(1H, m), 6.94-6.97(1H, m), 7.12(1H, d), 7.18(1H, d), 7.19(1H, dt), 7.44 (1H, dt), 7.67-7.74(1H, m), 11.13(1H, brs), 13.09(1H, brs) MS−: 380 Ex131 Ex3 NMR: 3.56-3.68(1H, m), 3.88-4.33(6H, m), 4.86(2H, s), 6.89(1H, s), 6.93(1H, s), 7.10(1H, dd), 7.77(2H, d), 7.82(2H, d), 10.94(1H, brs), 13.09(1H, brs): MS−: 430 Ex132 Ex3 NMR: 2.69(2H, t), 2.84(2H, t), 3.57-3.68(1H, m), 3.91(2H, s), 4.04-4.30(4H, m), 4.78(2H, s), 6.69-6.72(2H, m), 6.88(1H, dd), 7.07(1H, dd), 7.19-7.25(1H, m), 7.28-7.32(4H, m), 11.11(1H, brs), 13.13(1H, brs), MS−: 372

TABLE 120 Ex133 Ex3 NMR: 0.86(6H, d), 1.79-1.90(1H, m), 2.48(2H, d), 3.57-3.69(1H, m), 3.97(2H, s), 4.08-4.31(4H, m), 4.86(2H, s), 6.84(1H, s), 6.90(1H, s), 7.01(1H, dd), 7.23(2H, d), 7.46(2H, d), 11.13(1H, brs), 13.11(1H, brs), MS−: 418 Ex134 Ex3 NMR: 3.53-3.66(1H, m), 3.90(2H, s), 3.99-4.25(4H, m), 4.89(2H, s), 6.84-6.90 (2H, m), 7.05(1H, dd), 8.06(1H, d), 8.15(1H, s), 8.17(1H, d), 11.31(1H, brs), 12.89(1H, brs), MS−: 498 Ex135 Ex3 NMR: 2.03-2.38(2H, m), 2.95-4.05(7H, m), 4.86(2H, s), 5.16(2H, s), 6.39(1H, s), 6.55(1H, dd), 6.85(1H, s), 7.12-7.17(2H, m), 7.21-7.32(2H, m), 7.38(1H, d), 7.43-7.49(2H, m), 7.74(1H, d), 10.85(1H, brs), 12.95(1H, brs) MS+: 566 Ex136 Ex3 NMR: 1.79-1.88(2H, m), 2.02-2.30(2H, m), 2.42(2H, t), 2.71(2H, t), 3.03-3.76 (5H, m), 3.95(2H, s), 4.93(2H, s), 6.72(1H, s), 6.86(1H, dd), 6.93(1H, s), 7.16- 7.33(5H, m), 11.06(1H, brs), 12.94(1H, brs), MS+: 420 Ex137 Ex3 NMR: 2.04(3H, s), 2.09-2.35(2H, m), 2.92-3.73(5H, m), 3.83(2H, s), 4.89(2H, s), 5.35(2H, s), 6.59(1H, d), 6.70(1H, s), 6.96(1H, d), 8.02(1H, d), 8.11(1H, s), 8.16(1H, d), 11.33(1H, brs), 12.89(1H, brs), MS−: 514 Ex138 Ex3 NMR: 2.00-2.34(2H, m), 2.99-3.72(5H, m), 3.87(2H, brs), 4.91(2H, s), 5.20 (2H, s), 6.77(1H, s), 6.94(1H, s), 7.04(1H, dd), 7.17(1H, d), 7.22-7.51(7H, m), 11.23(1H, brs), 12.89(1H, brs), MS−: 526 Ex139 Ex3 NMR: 2.80(2H, t), 3.12(2H, t), 2.96-3.66(5H, m), 3.74(2H, brs), 4.72(2H, s), 6.52(1H, brs), 6.68(1H, s), 6.85(1H, dd), 7.03(1H, d), 7.91(1H, d), 8.00(1H, s), 8.09(1H, d) Ex140 Ex3 NMR: 0.90(3H, d), 2.08-2.19(1H, m), 2.48(1H, dd), 2.76(1H, dd), 3.51-3.65 (1H, m), 3.72-3.89(4H, m), 3.96-4.19(4H, m), 4.78(2H, m), 6.27(1H, s), 6.42 (1H, dd), 6.74-6.82(1H, m), 7.21(2H, d), 7.33(2H, d) ESI−: 444 Ex141 Ex3 NMR: 1.45(3H, d), 2.50-2.61(1H, m), 2.65-2.83(1H, m), 2.94-3.11(1H, m), 3.43-3.57(1H, m), 3.63-3.77(1H, m), 3.82-4.04(3H, m), 4.87-5.06(2H, m), 5.13(2H, s), 5.44-5.55(1H, m), 6.43(1H, s), 6.57(1H, d), 6.86-6.95(1H, m), 6.99- 7.06(1H, m), 7.52(1H, d), 7.71-7.77(2H, m), 11.31(1H, brs), 12.97(1H, brs) ESI−: 574 Ex142 Ex3 NMR: 1.93-2.02(2H, m), 2.51-2.62(1H, m), 2.65-2.81(3H, m), 2.96-3.09(1H, m), 3.44-3.55(1H, m), 3.64-3.77(1H, m), NMR: 3.84-4.03(5H, m), 4.84-5.04 (2H, m), 6.32(1H, s), 6.45(1H, dd), 6.86-6.93(1H, m), 6.99-7.06(1H, m), 7.25(2H, d), 7.34(2H, d), 11.21(1H, brs), 12.99(1H, brs) ESI−: 456 Ex143 Ex3 NMR: 2.43-2.76(2H, m), 2.97-3.10(1H, m), 3.46-3.55(1H, m), 3.65-3.77(1H, m), 3.88-4.04(3H, m), 4.59-5.11(9H, m), 6.41(1H, s), 6.56(1H, d), 6.87- 6.93(1H, m), 6.99-7.06(1H, m), 7.31(1H, d), 7.37(1H, dd), 7.54(1H, d), 10.84(1H, brs), 13.00(1H, brs) ESI−: 522

TABLE 121 Ex144 Ex3 NMR: 1.45(3H, d), 2.43-2.82(2H, m), 2.95-3.09(1H, m), 3.44-3.58(1H, m), 3.62-3.78(1H, m), 3.83-4.07(3H, m), 4.34-5.02(2H, m), 5.06(2H, s), 5.26-5.37(1H, m), 6.41(1H, s), 6.55(1H, d), 6.83-7.08(2H, m), 7.36- 7.43(2H, m), 7.56-7.57(1H, m), 11.03(1H, brs), 13.00(1H, brs) ESI−: 540 Ex145 Ex3 NMR: 1.45(3H, d), 2.51-2.60(1H, m), 2.66-2.82(1H, m), 2.97-3.12(1H, m), 3.43-3.54(1H, m), 3.64-3.76(1H, m), 3.83-4.00(3H, m), 4.83-5.00 (2H, m), 5.11(2H, s), 5.44-5.55(1H, m), 6.52(1H, d), 6.60(1H, dd), 6.71- 6.81(1H, m), 6.99-7.06(1H, m), 7.09(1H, d), 7.52(1H, d), 7.71-7.76(2H, m), 11.20(1H, brs), 12.99(1H, brs) ESI−: 556 Ex146 Ex3 NMR: 1.29(6H, d), 2.52-2.61(1H, m), 2.63-2.77(1H, m), 2.95-3.10(1H, m), 3.46-3.55(1H, m), 3.65-3.77(1H, m), 3.86-4.04(3H, m), 4.62-4.72 (1H, m), 4.85-4.96(2H, m), 5.02(2H, s), 6.41(1H, s), 6.55(1H, d), 6.86- 6.94(1H, m), 6.98-7.07(1H, m), 7.18(1H, d), 7.34(1H, dd), 7.49(1H, d), 10.89(1H, brs), 13.00(1H, brs) ESI−: 486 Ex147 Ex3 NMR: 1.29(6H, d), 2.53-2.62(1H, m), 2.64-2.80(1H, m), 2.96-3.10(1H, m), 3.44-3.57(1H, m), 3.65-3.79(1H, m), 3.84-4.06(3H, m), 4.75-4.85 (1H, m), 4.87-5.01(2H, m), 5.09(2H, s), 6.42(1H, s), 6.56(1H, dd), 6.85- 6.95(1H, m), 6.99-7.07(1H, m), 7.32(1H, d), 7.63-7.68(2H, m), 11.04(1H, brs), 13.00(1H, brs) ESI−: 520 Ex148 Ex3 NMR: 1.44(3H, d), 2.52-2.61(1H, m), 2.66-2.81(1H, m), 2.96-3.09(1H, m), 3.46-3.55(1H, m), 3.65-3.77(1H, m), 3.85-4.04(3H, m), 4.86-5.05 (2H, m), 5.15(2H, s), 5.42-5.55(1H, m), 6.41(1H, s), 6.56(1H, dd), 6.88- 6.94(1H, m), 7.00-7.06(1H, m), 7.43-7.48(2H, m), 7.71(1H, d), 11.19(1H, brs), 13.01(1H, brs) ESI−: 574 Ex149 Ex3 NMR: 1.45(3H, d), 2.50-2.61(1H, m), 2.61-2.77(1H, m), 2.94-3.13(1H, m), 3.42-3.57(1H, m), 3.64-3.77(1H, m), 3.84-4.02(3H, m), 4.78-4.95 (2H, m), 5.05(2H, s), 5.25-5.36(1H, m), 6.51(1H, d), 6.59(1H, dd), 6.72- 6.79(1H, m), 7.00-7.06(1H, m), 7.09(1H, d), 7.36-7.42(2H, m), 7.56(1H, d), 10.75(1H, brs), 13.02(1H, brs) ESI−: 522 Ex150 Ex3 NMR: 2.53-2.61(1H, m), 2.63-2.77(1H, m), 2.95-3.10(1H, m), 3.46-3.55 (1H, m), 3.65-3.77(1H, m), 3.88-4.04(3H, m), 4.85-4.99(4H, m), 5.07 (2H, s), 6.39-6.45(1H, m), 6.56(1H, dd), 6.84-6.94(1H, m), 6.99-7.07(1H, m), 7.23(1H, d), 7.42(1H, dd), 7.57(1H, d), 10.80(1H, brs), 13.03(1H, brs) ESI−: 526 Ex151 Ex3 NMR: 1.29(6H, d), 2.53-2.61(1H, m), 2.63-2.77(1H, m), 2.97-3.11(1H, m), 3.45-3.55(1H, m), 3.65-3.77(1H, m), 3.84-4.01(3H, m), 4.62-4.72 (1H, m), 4.81-4.95(2H, m), 5.01(2H, s), 6.51(1H, d), 6.58(1H, dd), 6.72- 6.79(1H, m), 7.00-7.06(1H, m), 7.08(1H, d), 7.17(1H, d), 7.34(1H, dd), 7.49(1H, d), 10.80(1H, brs), 13.01(1H, brs) ESI−: 468

TABLE 122 Ex152 Ex1 NMR: 1.34-1.51(1H, m), 1.79-1.96(2H, m), 2.00-2.10(1H, m), 2.73-3.10 (3H, m), 3.24(3H, s), 3.30-3.54(2H, m), 3.79-3.96(2H, m), 4.59-4.85 (4H, m), 4.85-4.99(2H, m), 5.09-5.25(1H, m), 5.11(2H, s), 6.42(1H, s), 6.56(1H, dd), 6.85(1H, s), 7.44(1H, d), 7.67-7.74(2H, m), 10.72(1H, brs), 12.06(1H, brs) ESI+: 637 Ex153 Ex1 NMR: 1.36-1.51(1H, m), 1.80-1.94(2H, m), 1.98-2.12(1H, m), 2.73-2.86 (1H, m), 2.79(6H, s), 2.87-3.07(2H, m), 3.28-3.52(2H, m), 3.85(2H, s), 4.59-4.85(4H, m), 4.86-4.97(2H, m), 5.10-5.25(1H, m), 5.12(2H, s), 6.42 (1H, s), 6.56(1H, dd), 6.84(1H, s), 7.44(1H, d), 7.67-7.73(2H, m), 10.65 (1H, brs), 11.72(1H, brs) ESI+: 666 EX154 — NMR: 4.67(2H, s), 4.93(2H, s), 5.32(2H, s), 6.37(1H, s), 6.44(1H, s), 6.54 (1H, dd), 7.85(1H, s), 7.99(1H, d), 8.09(1H, s), 8.14(1H, d), 8.31(1H, s), 12.41(1H, brs) ESI+: 517 Ex155 Ex154 NMR: 4.64(2H, s), 4.71(2H, s), 5.31(2H, s), 6.36(2H, s), 6.41(1H, dd), 6.53 (1H, dd), 6.84(1H, t), 7.42(1H, t), 7.99(1H, d), 8.09(1H, s), 8.14(1H, d), 11.77(1H, brs) ESI+: 538 Ex156 — NMR: 1.35-1.52(4H, m), 1.65-2.02(3H, m), 2.72-3.08(3H, m), 3.20-3.60 (2H, m), 3.72-3.95(2H, m), 4.79-4.96(2H, m), 5.11(2H, s), 5.42-5.55(1H, m), 6.52(1H, d, J = 2.4 Hz), 6.59(1H, dd, J = 2.4, 8.4 Hz), 6.71(1H, s), 7.09(1H, d, J = 8.4 Hz), 7.51(1H, d, J = 9.3 Hz), 7.69-7.78(2H, m), 10.71(1H, bs), 12.85(1H, bs) ESI+: 560 Ex157 Ex156 NMR: 1.28(6H, d), 1.38-1.44(2H, m), 1.58-1.65(2H, m), 3.79(2H, brs), 4.74-4.83(1H, m), 4.82(2H, s), 5.06(2H, s), 6.49(1H, d), 6.57(1H, dd), 6.62(1H, s), 7.05(1H, d), 7.31(1H, d), 7.63-7.68(2H, m), 9.88(1H, brs) FAB−: 476 Ex158 Ex156 NMR: 1.28(6H, d), 2.12(3H, s), 2.40-2.56(1H, m), 2.62-2.76(1H, m), 2.97-3.12(1H, m), 3.40-3.51(1H, m), 3.62-3.74(1H, m), 3.84-3.99(3H, m), 4.75-4.83(1H, m), 4.86(2H, d), 5.07(2H, s), 6.51(1H, d), 6.59(1H, dd), 6.74(1H, s), 7.09(1H, d), 7.31(1H, d), 7.62-7.68(2H, m), 10.59(1H, brs), 12.97(1H, brs) ESI+: 518 Ex159 Ex156 NMR: 1.28(6H, d), 1.50-1.71(2H, m), 1.81-1.95(3H, m), 2.20(1.6H, d), 2.38(0.4H, d), 2.82-2.97(2H, m), 3.40(2H, d), 3.76(1.6H, d), 3.87(0.4H, d), 4.74-4.84(1H, m), 4.85(2H, s), 5.07(2H, s), 6.51(1H, d), 6.58(1H, dd), 6.69(0.8H, s), 6.73(0.2H, s), 7.07(1H, d), 7.31(1H, d), 7.63-7.67(2H, m), 10.17(0.8H, brs), 10.35(0.2H, brs), 12.21(1H, brs); two rotamers (4:1) ESI+: 520 Ex160 Ex156 NMR: 1.35-1.53(2H, m), 1.65-2.12(3H, m), 2.70-3.06(2H, m), 3.25-3.60 (2H, m), 3.72-3.94(2H, m), 4.88(2H, bs), 4.95(2H, q, J = 8.8 Hz), 5.12(2H, s), 6.52(1H, d, J = 2.2 Hz), 6.59(1H, dd, J = 2.4, 8.4 Hz), 6.71(1H, s), 7.08(1H, d, J = 8.4 Hz), 7.41(1H, d, J = 9.2 Hz), 7.68-7.81(2H, m), 10.62(1H, bs), 12.83(1H, bs) ESI+: 546

TABLE 123 Ex161 Ex156 NMR: 1.35-1.56(1H, m), 1.60-2.14(3H, m), 2.70-3.12(3H, m), 3.25-3.60 (2H, m), 3.66-4.00(2H, m), 4.59-5.16(9H, m), 6.50(1H, d, J = 2.3 Hz), 6.58 (1H, dd, J = 2.4, 8.4 Hz), 6.71(1H, s), 7.08(1H, d, J = 8.4 Hz), 7.31(1H, d, J = 8.6 Hz), 7.37(1H, dd, J = 2.0, 8.5 Hz), 7.53(1H, d, J = 2.0 Hz), 10.69(1H, bs), 12.84(1H, bs) ESI+: 508 Ex162 Ex156 NMR: 1.28(6H, d), 2.25-2.35(1H, m), 2.44-2.60(1H, m), 3.00-3.14(3H, m), 3.44-3.53(1H, m), 3.53-3.64(1H, m), 3.69-3.79(1H, m), 3.81-3.91 (2H, m), 4.74-4.85(1H, m), 4.84(2H, brs), 5.07(2H, s), 5.58(1H, brs), 6.51 (1H, d), 6.59(1H, dd), 6.71(1H, s), 7.07(1H, d), 7.31(1H, d), 7.63-7.68 (2H, m), 10.35(1H, brs), 12.40(1H, brs) ESI+: 518 Ex163 Ex156 NMR: 1.88-2.15(4H, m), 2.44-2.56(0.8H, m), 2.72-2.81(0.2H, m), 2.82- 3.00(2H, m), 3.38-3.50(2H, m), 3.68-3.86(2H, m), 4.60-4.85(4H, m), 4.90(2H, s), 4.92-5.09(3H, m), 6.50(1H, d), 6.57(1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.01-7.09(1H, m), 7.31(1H, d), 7.37(1H, dd), 7.53(1H, d), 10.78(0.8H, brs), 10.87(0.2H, brs), 12.54(1H, brs); two rotamers(4:1) ESI+: 508 Ex164 Ex156 NMR: 1.44(3H, d), 1.83-1.99(2H, m), 1.99-2.13(2H, m), 2.43-2.53(0.8H, m), 2.73-2.82(0.2H, m), 2.83-3.00(2H, m), 3.23-3.38(0.4H, m), 3.39- 3.50(1.6H, m), 3.68-3.87(2H, m), 4.88(2H, s), 5.11(2H, s), 5.42-5.54 (1H, m), 6.51(1H, d), 6.59(1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.03- 7.10(1H, m), 7.51(1H, d), 7.71-7.77(2H, m), 10.49(0.8H, brs), 10.59(0.2H, brs), 12.54(1H, brs); two rotamers(4:1) ESI+: 560 Ex165 Ex156 NMR: 1.84-1.99(2H, m), 1.99-2.13(2H, m), 2.45-2.54(0.8H, m), 2.74- 2.81(0.2H, m), 2.82-3.00(2H, m), 3.25-3.37(0.4H, m), 3.38-3.49(1.6H, m), 3.70-3.86(2H, m), 4.58-4.66(1H, m), 4.66-4.77(2H, m), 4.78-4.85 (1H, m), 4.88(2H, s), 5.10(2H, s), 5.10-5.24(1H, m), 6.51(1H, d), 6.59(1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.02-7.10(1H, m), 7.43(1H, d), 7.65- 7.73(2H, m), 10.53(0.8H, brs), 10.62(0.2H, brs), 12.54(1H, brs); two rotamers(4:1) ESI+: 542 Ex166 Ex156 NMR: 3.60(2H, m), 3.69-3.92(2H, m), 4.01-4.08(1H, m), 4.89(2H, s), 5.09 (2H, s), 6.51(1H, d, J = 2.3 Hz), 6.59(1H, dd, J = 2.4, 8.4 Hz), 6.71(1H, s), 7.08(1H, d, J = 8.4 Hz), 7.55(1H, d, J = 8.6 Hz), 7.67(1H, d, J = 1.8 Hz), 7.72(1H, dd, J = 1.8, 8.6 Hz), 10.71(1H, bs), 12.84(1H, bs) ESI+: 504 Ex167 Ex156 NMR: 0.64-0.70(2H, m), 0.81-0.88(2H, m), 1.85-2.13(4H, m), 2.41-2.57 (0.8H, m), 2.73-2.80(0.2H, m), 3.21-3.50(4H, m), 3.71-3.87(2H, m), 4.01-4.08(1H, m), 4.88(2H, s), 5.09(2H, s), 6.51(1H, d), 6.59(1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.02-7.10(1H, m), 7.55(1H, d), 7.67(1H, d), 7.72(1H, dd), 10.50-10.75(1H, m), 12.55(1H, brs); two rotamers(4:1) ESI+: 504 Ex168 Ex156 NMR: 1.38-1.55(1H, m), 1.54-1.73(4H, m), 1.77-2.15(7H, m), 2.72-3.08 (2H, m), 3.18-3.58(4H, m), 3.81(2H, s), 4.90(2H, s), 5.15(2H, s), 6.52 (1H, d), 6.60(1H, dd), 6.71(1H, s), 7.08(1H, d), 7.60-7.72(3H, m), 10.82 (1H, brs), 12.84(1H, brs) ESI+: 516

TABLE 124 EX169 Ex156 NMR: 1.54-1.75(4H, m), 1.77-2.13(8H, m), 2.83-2.98(2H, m), 3.19-3.49 (4H, m), 3.72-3.86(2H, m), 4.89(2H, s), 5.15(2H, s), 6.51(1H, d), 6.59 (1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.02-7.10(1H, m), 7.61-7.72(3H, m), 10.61-10.81(1H, m), 12.54(1H, brs); two rotamers(4:1) ESI+: 516 Ex170 Ex156 NMR: 1.45(3H, d), 1.51-1.71(2H, m), 1.80-1.96(3H, m), 2.20(2H, d), 2.82-2.96(2H, m), 3.35-3.44(2H, m), 3.72-3.78(1.6H, m), 3.84-3.89(0.4H, m), 4.87(2H, s), 5.11(2H, s), 5.43-5.54(1H, m), 6.51(1H, d), 6.59(1H, dd), 6.69(0.8H, s), 6.73(0.2H, s), 7.07(1H, d), 7.51(1H, d), 7.71-7.75(2H, m), 10.36(0.8H, brs), 10.53(0.2H, brs), 12.20(1H, brs); two rotamers(4:1) ESI+: 574 Ex171 Ex156 NMR: 1.80-2.12(4H, m), 2.83-2.99(2H, m), 3.26-3.49(3H, m), 3.73-3.86 (2H, m), 4.87(2H, s), 4.95(2H, q), 5.12(2H, s), 6.51(1H, d), 6.59(1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.03-7.10(1H, m), 7.41(1H, d), 7.72-7.78 (2H, m), 10.38-10.57(1H, m), 12.54(1H, brs); two rotamers(4:1) ESI+: 546 Ex172 Ex156 NMR: 1.49(3H, d), 1.78-1.99(2H, m), 2.00-2.12(1H, m), 2.70-3.15(3H, m), 3.30-3.47(2H, m), 3.49-3.57(1H, m), 3.82(2H, s), 4.89(2H, s), 5.07 (2H, s), 5.43-5.54(1H, m), 6.52(1H, d), 6.59(1H, dd), 6.71(1H, s), 7.09(1H, d), 7.51(1H, d), 7.77(1H, dd), 7.86(1H, d), 10.69(1H, brs), 12.84(1H, brs) ESI+: 517 Ex173 Ex156 NMR: 1.49(3H, d), 1.85-2.12(4H, m), 2.82-3.00(2H, m), 3.25-3.50(3H, m), 3.72-3.86(2H, m), 4.88(2H, s), 5.07(2H, s), 5.43-5.54(1H, m), 6.51 (1H, d), 6.59(1H, dd), 6.70(0.8H, s), 6.74(0.2H, s), 7.03-7.09(1H, m), 7.51(1H, d), 7.77(1H, dd), 7.86(1H, d), 10.45-10.70(1H, m), 12.55(1H, brs); two rotamers(4:1) ESI+: 517 Ex174 Ex156 NMR: 1.45(3H, d), 2.81(3H, s), 3.87(2H, s), 4.06(2H, s), 4.83(2H, s), 5.11 (2H, s), 5.43-5.55(1H, m), 6.51(1H, d), 6.59(1H, dd), 6.71(1H, s), 7.08 (1H, d), 7.52(1H, d), 7.68-7.77(2H, m) ESI+: 520 Ex175 Ex2 NMR: 1.20-1.31(1H, m), 1.28(6H, d), 1.34-1.47(1H, m), 1.54-1.64(1H, m), 1.71-1.81(1H, m), 1.81-2.01(2H, m), 2.10-2.22(1H, m), 2.58-2.65 (1H, m), 2.75-2.83(1H, m), 2.95(2H, s), 4.66(2H, s), 4.74-4.83(1H, m), 5.03(2H, s), 6.31(1H, s), 6.43(1H, d), 6.51(1H, dd), 6.95(1H, d), 7.30 (1H, d), 7.61-7.67(2H, m); (CO2H too broad to be seen) ESI+: 528(M + Na)+ Ex176 Ex2 NMR: 1.17-1.30(1H, m), 1.28(6H, d), 1.33-1.47(1H, m), 1.53-1.63(1H, m), 1.71-1.96(3H, m), 2.04-2.19(1H, m), 2.57-2.68(1H, m), 2.76-2.83 (1H, m), 2.95(2H, s), 4.66(2H, s), 4.74-4.83(1H, m), 5.03(2H, s), 6.31(1H, s), 6.43(1H, d), 6.51(1H, dd), 6.95(1H, d), 7.30(1H, d), 7.62-7.67(2H, m); (CO2H too broad to be seen) ESI+: 528 Ex177 Ex3 NMR: 0.89(6H, d), 1.84-1.99(1H, m), 2.46-2.78(2H, m), 2.63(2H, d), 2.96- 3.10(1H, m), 3.43-3.56(1H, m), 3.64-3.77(1H, m), 3.84-4.04(3H, m), 4.91(1H, d), 4.99(1H, d), 5.17(1H, s), 6.44(1H, s), 6.58(1H, dd), 6.91 (1H, s), 7.03(1H, s), 7.49(1H, d), 7.66(1H, d), 7.74(1H, s), 11.09(1H, brs), 13.01(1H, brs) ESI−: 518

TABLE 125 Ex178 Ex3 NMR: 1.28(6H, d), 2.50-2.60(1H, m), 2.65-2.83(1H, m), 2.97-3.10(1H, m), 3.43-3.54(1H, m), 3.64-3.75(1H, m), 3.85-3.98(3H, m), 4.74-4.83 (1H, m), 4.86(1H, d), 4.93(1H, d), 5.07(2H, s), 6.52(1H, d), 6.59(1H, d), 6.76(1H, s), 7.03(1H, s), 7.09(1H, d), 7.31(1H, d), 7.63-7.69(2H, m), 10.96(1H, brs), 12.99(1H, brs) ESI−: 502 Ex179 Ex3 NMR: 2.53-2.62(1H, m), 2.62-2.77(1H, m), 2.98-3.11(1H, m), 3.45-3.55 (1H, m), 3.66-3.77(1H, m), 3.87-4.00(3H, m), 4.79-4.93(4H, m), 5.05 (2H, s), 6.51(1H, s), 6.59(1H, d), 6.75(1H, s), 7.03(1H, s), 7.09(1H, d), 7.29(1H, d), 7.41(1H, dd), 7.56(1H, d), 10.53(1H, brs), 13.04(1H, brs) ESI−: 508 Ex180 Ex3 NMR: 2.55-2.61(1H, m), 2.64-2.77(1H, m), 2.98-3.10(1H, m), 3.45-3.55 (1H, m), 3.65-3.77(1H, m), 3.85-3.98(3H, m), 4.42(2H, dt), 4.85(1H, d), 4.91(1H, d), 5.04(2H, s), 6.42(1H, tt), 6.51(1H, d), 6.59(1H, dd), 6.75 (1H, s), 7.00-7.05(1H, m), 7.08(1H, d), 7.24(1H, d), 7.38(1H, dd), 7.54(1H, d), 10.77(1H, brs), 13.01(1H, brs) ESI−: 490 Ex181 Ex3 NMR: 2.53-2.63(2H, m), 3.03-3.13(1H, m), 3.49-3.58(1H, m), 3.72-3.83 (1H, m), 3.86-4.00(3H, m), 4.60-4.88(6H, m), 4.93-5.08(1H, m), 5.04 (2H, s), 6.50(1H, s), 6.59(1H, d), 6.74(1H, s), 6.77(1H, s), 7.07(1H, d), 7.31(1H, d), 7.37(1H, dd), 7.53(1H, d), 10.50(1H, brs), 12.82(1H, brs) ESI+: 528 Ex182 Ex3 NMR: 1.45(3H, d), 2.42-2.65(2H, m), 2.98-3.14(1H, m), 3.47-3.58(1H, m), 3.66-3.78(1H, m), 3.88-4.02(3H, m), 4.80(1H, d), 4.86(1H, d), 5.05 (2H, s), 5.26-5.36(1H, m), 6.51(1H, s), 6.59(1H, d), 6.75(1H, s), 7.04 (1H, s), 7.10(1H, d), 7.35(1H, d), 7.44(1H, dd), 7.70(1H, d), 10.17(1H, brs), 13.02(1H, brs) ESI−: 566 Ex183 Ex3 NMR: 1.49(3H, d), 2.53-2.72(2H, m), 2.98-3.13(1H, m), 3.46-3.56(1H, m), 3.65-3.78(1H, m), 3.88-4.02(3H, m), 4.81(1H, d), 4.88(1H, d), 5.09 (2H, s), 5.87-5.98(1H, m), 6.54(1H, s), 6.62(1H, d), 6.76(1H, s), 7.04(1H, s), 7.11(1H, d), 8.10(1H, d), 8.27(1H, d), 10.26(1H, brs), 13.02(1H, brs) ESI+: 547 Ex184 Ex3 NMR: 1.21-1.34(1H, m), 1.29(6H, d), 1.35-1.48(1H, m), 1.56-1.64(1H, m), 1.72-1.81(1H, m), 1.84-2.05(2H, m), 2.17-2.29(1H, m), 2.57-2.65 (1H, m), 2.73-2.85(1H, m), 2.96(2H, s), 4.60-4.71(1H, m), 4.65(2H, s), 4.97(2H, s), 6.31(1H, s), 6.41(1H, d), 6.50(1H, dd), 6.95(1H, d), 7.16 (1H, d), 7.33(1H, dd), 7.48(1H, d); (CO2H too broad to be seen) ESI+: 494(M + Na)+ Ex185 Ex3 NMR: 1.20-1.34(1H, m), 1.29(6H, d), 1.33-1.47(1H, m), 1.53-1.65(1H, m), 1.71-1.81(1H, m), 1.83-2.03(2H, m), 2.14-2.27(1H, m), 2.57-2.65 (1H, m), 2.74-2.83(1H, m), 2.96(2H, s), 4.60-4.72(1H, m), 4.65(2H, s), 4.97(2H, s), 6.31(1H, s), 6.42(1H, d), 6.50(1H, dd), 6.94(1H, d), 7.16 (1H, d), 7.33(1H, dd), 7.47(1H, d); (CO2H too broad to be seen) ESI+: 494 Ex186 Ex3 NMR: 1.45(3H, d), 2.46-2.76(2H, m), 2.99-3.11(1H, m), 3.45-3.55(1H, m), 3.66-3.77(1H, m), 3.87-3.99(3H, m), 4.84(1H, d), 4.91(1H, d), 5.18 (2H, s), 5.43-5.54(1H, m), 6.54(1H, d), 6.62(1H, dd), 6.76(1H, s), 7.04(1H, s), 7.11(1H, d), 7.24(1H, d), 7.57(1H, s), 7.68(1H, d), 10.61(1H, brs), 13.02(1H, brs) ESI−: 556

TABLE 126 Ex187 Ex3 NMR: 1.19-1.31(1H, m), 1.33-1.48(1H, m), 1.45(3H, d), 1.54-1.64(1H, m), 1.72-1.99(3H, m), 2.12-2.23(1H, m), 2.58-2.67(1H, m), 2.77-2.86 (1H, m), 2.96(2H, m), 4.66(2H, s), 5.00(2H, s), 5.23-5.34(1H, m), 6.30 (1H, s), 6.42(1H, d), 6.50(1H, dd), 6.94(1H, d), 7.34-7.41(2H, m), 7.54 (1H, s); (CO2H too broad to be seen) ESI+: 526 Ex188 Ex3 NMR: 1.29(6H, d), 2.45-2.72(2H, m), 3.01-3.15(1H, m), 3.48-3.58(1H, m), 3.70-3.83(1H, m), 3.83-3.99(3H, m), 4.61-4.72(1H, m), 4.86(1H, d), 4.92(1H, d), 5.01(2H, s), 6.50(1H, d), 6.58(1H, dd), 6.72-6.79(2H, m), 7.06(1H, d), 7.17(1H, d), 7.34(1H, dd), 7.48(1H, d), 10.95(1H, brs), 12.79(1H, brs) FAB+: 470 Ex189 Ex3 NMR: 1.19-1.30(1H, m), 1.33-1.47(1H, m), 1.45(3H, d), 1.53-1.64(1H, m), 1.72-1.99(3H, m), 2.10-2.21(1H, m), 2.58-2.69(1H, m), 2.76-2.85 (1H, m), 2.95(2H, s), 4.66(2H, s), 5.00(2H, s), 5.23-5.34(1H, m), 6.30 (1H, s), 6.42(1H, d), 6.50(1H, dd), 6.95(1H, d), 7.34-7.41(2H, m), 7.54 (1H, s); (CO2H too broad to be seen) ESI+: 526 Ex190 Ex3 NMR: 1.19(6H, d), 2.08-2.15(2H, m), 2.32-2.39(2H, m), 2.93-2.99(2H, m), 3.07(2H, s), 3.70-3.81(1H, m), 4.57(1H, d), 4.66(2H, s), 4.93(2H, s), 6.23-6.39(2H, m), 6.42(1H, d), 6.50(1H, dd), 6.89(1H, d), 6.96(1H, d), 7.44-7.50(2H, m); ( CO2H too broad to be seen) ESI+: 503 Ex191 Ex3 NMR: 2.53-2.72(2H, m), 3.00-3.15(1H, m), 3.46-3.59(1H, m), 3.70-3.84 (1H, m), 3.83-3.98(3H, m), 4.59-4.96(6H, m), 5.07-5.25(1H, m), 5.10 (2H, s), 6.51(1H, d), 6.59(1H, dd), 6.71-6.81(2H, m), 7.06(1H, d), 7.44 (1H, d), 7.66-7.74(2H, m), 11.05(1H, brs), 12.67(1H, brs) ESI+: 540 Ex192 Ex3 NMR: 1.45(3H, d), 1.85-2.14(4H, m), 2.73-3.01(3H, m), 3.37-3.49(2H, m), 3.65-3.87(2H, m), 4.89(2H, s), 5.05(2H, s), 5.24-5.36(1H, m), 6.50 (1H, d), 6.58(1H, dd), 6.66-6.77(1H, m), 7.01-7.10(1H, m), 7.36-7.43 (2H, m), 7.55(1H, s), 10.76(1H, brs), 12.51(1H, brs) ESI+: 526 Ex193 Ex3 NMR: 1.28(6H, d), 2.77-3.17(1H, m), 3.2-3.63(4H, m), 3.68-4.13(3H, m), 4.49-4.69(1H, m), 4.73-4.83(1H, m), 4.83-4.98(2H, m), 5.06(2H, s), 6.50(1H, d), 6.58(1H, dd), 6.69(1H, brs), 7.06(1H, d), 7.31(1H, d), 7.63-7.68(2H, m), 11.90(1H, brs), 13.31(1H, brs) ESI+: 508 Ex194 Ex3 NMR: 1.36-1.53(2H, m), 1.73-1.93(2H, m), 1.99-2.09(1H, m), 2.73-3.05 (3H, m), 3.49-3.59(1H, m), 3.81(2H, s), 4.58-4.85(4H, m), 4.88(2H, s), 5.06-5.25(1H, m), 5.10(2H, s), 6.51(1H, d), 6.59(1H, dd), 6.71(1H, s), 7.08(1H, d), 7.44(1H, d), 7.66-7.74(2H, m), 10.60(1H, brs), 12.83(1H, brs) ESI+: 542 Ex195 Ex3 NMR: 1.97(3H, s), 2.55-2.62(1H, m), 2.65-2.78(1H, m), 2.99-3.13(1H, m), 3.46-3.55(1H, m), 3.66-3.77(1H, m), 3.87-4.00(3H, m), 4.87(1H, d), 4.94(1H, d), 5.26(2H, s), 6.58(1H, d), 6.66(1H, dd), 6.78(1H, s), 7.03 (1H, s), 7.10(1H, d), 7.12(1H, d), 7.20-7.26(1H, m), 7.28-7.33(2H, m), 7.35(1H, d), 7.76(1H, d), 7.90(1H, s), 10.86(1H, brs), 13.00(1H, brs) ESI+: 536

TABLE 127 Ex196 Ex3 NMR: 1.93(3H, s), 2.56-2.76(2H, m), 2.98-3.13(1H, m), 3.46-3.57(1H, m), 3.66-3.78(1H, m), 3.87-4.01(3H, m), 4.84(1H, d), 4.91(1H, d), 5.25 (2H, s), 6.57(1H, d), 6.65(1H, d), 6.77(1H, s), 7.04(1H, s), 7.13(1H, d), 7.25-7.27(1H, m), 7.36(1H, d), 7.39(1H, d), 7.75(1H, d), 7.88(1H, s), 10.59(1H, brs), 13.00(1H, brs) ESI+: 542 Ex197 Ex3 NMR: 1.45(3H, d), 1.55-1.75(2H, m), 2.10-2.24(2H, m), 2.55-2.76(2H, m), 2.99-3.23(2H, m), 3.73-3.94(3H, m), 4.86(2H, s), 5.04(2H, s), 5.24- 5.35(1H, m), 6.49(1H, d), 6.57(1H, dd), 6.69(1H, s), 7.04(1H, d), 7.35- 7.42(2H, m), 7.55(1H, s), 10.95(1H, brs), 12.29(1H, brs) ESI+: 526 Ex198 Ex3 NMR: 1.51-1.73(5H, m), 1.78-1.90(2H, m), 1.93-2.08(2H, m), 2.52-2.59 (1H, m), 2.61-2.74(1H, m), 3.01-3.14(1H, m), 3.20-3.32(1H, m), 3.48- 3.56(1H, m), 3.71-3.83(1H, m), 3.84-3.96(2H, m), 4.89(1H, d), 4.95(1H, d), 5.15(2H, s), 6.52(1H, d), 6.60(1H, dd), 6.73-6.79(2H, m), 7.07 (1H, d), 7.61-7.71(3H, m), 11.21(1H, brs), 12.79(1H, brs) ESI+: 514 Ex199 Ex3 NMR: 1.34(3H, t), 2.52-2.62(1H, m), 2.64-2.83(1H, m), 2.94-3.12(1H, m), 3.43-3.56(1H, m), 3.63-3.78(1H, m), 3.81-4.00(3H, m), 4.18(2H, q), 4.81-4.98(2H, m), 5.08(2H, s), 6.51(1H, s), 6.58(1H, d), 6.69-6.79 (1H, brs), 7.01(1H, s), 7.07(1H, d), 7.27(1H, d), 7.64-7.70(2H, m), 11.21 (1H, brs), 12.90(1H, brs) ESI+: 490 Ex200 Ex3 NMR: 2.54-2.75(2H, m), 2.98-3.11(1H, m), 3.43-3.56(1H, m), 3.65-3.77 (1H, m), 3.86-4.00(3H, m), 4.83(1H, d), 4.90(1H, d), 4.93(1H, d), 4.98 (1H, d), 5.12(2H, s), 6.52(1H, d), 6.60(1H, dd), 6.75(1H, s), 7.03(1H, s), 7.09(1H, d), 7.41(1H, d), 7.72-7.77(2H, m), 10.61(1H, brs), 13.01(1H, brs) ESI+: 544 Ex201 Ex3 NMR: 1.46(3H, d), 2.55-2.76(2H, m), 2.99-3.11(1H, m), 3.45-3.56(1H, m), 3.65-3.77(1H, m), 3.86-4.00(3H, m), 4.85(1H, d), 4.92(1H, d), 4.99- 5.11(1H, m), 5.09(2H, s), 6.53(1H, d), 6.61(1H, dd), 6.76(1H, s), 7.03 (1H, s), 7.10(1H, d), 7.61(2H, s), 10.75(1H, brs), 13.01(1H, brs) ESI+: 558 Ex202 Ex3 NMR: 2.26-2.45(4H, m), 2.82-2.94(1H, m), 3.53-3.63(2H, m), 4.27-4.39 (1H, m), 4.82(2H, s), 5.33(2H, s), 6.40(1H, s), 6.57(1H, dd), 6.76(1H, s), 8.00(1H, d), 8.10(1H, s), 8.16(1H, d), 10.07(1H, brs) ESI+: 520 Ex203 Ex3 NMR: 1.37-1.51(1H, m), 1.49(3H, d), 1.77-2.10(4H, m), 2.73-3.05(3H, m), 3.46-3.56(1H, m), 3.81(2H, s), 4.89(2H, s), 5.09(2H, s), 5.85-5.98 (1H, m), 6.53(1H, d), 6.60(1H, dd), 6.71(1H, s), 7.08(1H, d), 8.10(1H, d), 8.26(1H, d), 10.78(1H, brs), 12.83(1H, brs) ESI+: 527 Ex204 Ex3 NMR: 2.53-2.78(2H, m), 2.99-3.12(1H, m), 3.44-3.56(1H, m), 3.66-3.77 (1H, m), 3.87-3.99(3H, m), 4.85(1H, d), 4.92(1H, d), 5.10(2H, s), 6.54 (1H, d), 6.61(1H, dd), 6.76(1H, s), 6.97(2H, d), 7.03(1H, s), 7.11(2H, d), 7.15(1H, t), 7.36-7.44(3H, m), 7.67(1H, d), 10.67(1H, brs), 12.99(1H, brs) ESI+: 504

TABLE 128 Ex205 Ex3 NMR: 1.28(6H, d), 2.50-2.59(1H, m), 2.62-2.73(1H, m), 2.75-2.84(1H, m), 2.97-3.14(1H, m), 3.15-3.38(4H, m), 4.19-4.25(1H, m), 4.69(2H, s), 4.74-4.84(1H, m), 5.04(2H, s), 6.41-6.47(2H, m), 6.54(1H, dd), 6.98 (1H, d), 7.31(1H, d), 7.62-7.67(2H, m) ESI+: 507 Ex206 Ex3 NMR: 1.47-1.98(8H, m), 2.53-2.78(2H, m), 2.97-3.11(1H, m), 3.44-3.55 (1H, m), 3.64-3.76(1H, m), 3.84-3.99(3H, m), 4.81-4.95(3H, m), 5.01 (2H, s), 6.50(1H, d), 6.58(1H, dd), 6.75(1H, s), 7.03(1H, s), 7.08(1H, d), 7.15(1H, d), 7.34(1H, dd), 7.48(1H, d), 10.86(1H, brs), 12.95(1H, brs) ESI+: 496 Ex207 Ex3 NMR: 2.54-2.63(2H, m), 3.04-3.14(1H, m), 3.50-3.59(1H, m), 3.73-3.83 (1H, m), 3.86-4.00(3H, m), 4.86(2H, d), 4.93(1H, d), 4.98(1H, d), 5.12 (2H, s), 6.52(1H, d), 6.60(1H, dd), 6.74(1H, s), 6.77(1H, s), 7.08(1H, d), 7.41(1H, d), 7.71-7.78(2H, m), 10.57(1H, brs), 12.81(1H, brs) ESI+: 544 Ex208 Ex3 NMR: 0.64-0.70(2H, m), 0.81-0.88(2H, m), 2.56-2.76(2H, m), 2.99-3.12 (1H, m), 3.45-3.56(1H, m), 3.65-3.78(1H, m), 3.87-4.00(3H, m), 4.01- 4.08(1H, m), 4.83(1H, d), 4.90(1H, d), 5.10(2H, s), 6.52(1H, d), 6.60 (1H, dd), 6.76(1H, s), 7.03(1H, s), 7.09(1H, d), 7.56(1H, d), 7.67(1H, d), 7.73(1H, dd), 10.61(1H, brs), 13.00(1H, brs) ESI+: 502 Ex209 Ex3 NMR: 2.41-2.61(1H, m), 2.63-2.84(1H, m), 2.90-3.14(1H, m), 3.35-3.58 (1H, m), 3.61-3.80(1H, m), 3.77-4.07(3H, m), 4.85-5.06(2H, m), 5.35 (2H, s), 6.45(1H, s), 6.51(1H, s), 6.60(1H, d), 7.01(1H, s), 7.96(1H, d), 8.06-8.13(2H, m), 11.43(1H, brs), 12.97(1H, brs) ESI+: 532 Ex210 Ex3 NMR: 1.29(6H, d), 1.82-2.12(4H, m), 2.73-3.01(3H, m), 3.39-3.49(2H, m), 3.72-3.80(1.6H, m), 3.80-3.86(0.4H, m), 4.61-4.72(1H, m), 4.85(2H, s), 5.01(2H, s), 6.46-6.51(1H, m), 6.54-6.60(1H, m), 6.70(0.8H, s), 6.73 (0.2H, s), 7.01-7.08(1H, m), 7.17(1H, d), 7.33(1H, dd), 7.48(1H, d), 10.27(0.8H, brs), 10.37(0.2H, brs), 12.52(1H, brs); two rotaners(4:1) ESI+: 472 Ex211 Ex3 NMR: 1.56(3H, s), 3.76-3.93(4H, m), 4.10-4.27(2H, m), 4.59-4.85(6H, m), 4.92-5.08(1H, m), 5.02(2H, s), 6.47(1H, d), 6.56(1H, dd), 6.67(1H, s), 7.03(1H, d), 7.31(1H, d), 7.36(1H, dd), 7.53(1H, d); (CO2H too broad to be seen) ESI+: 494 Ex212 Ex3 NMR: 1.36-1.52(2H, m), 1.76-2.12(3H, m), 2.70-3.08(3H, m), 3.45-3.62 (1H, m), 3.76-3.96(2H, m), 4.59-4.85(4H, m), 4.92(2H, s), 5.09-5.25 (1H, m), 5.11(2H, s), 6.41(1H, s), 6.55(1H, dd), 6.84(1H, s), 7.44(1H, s), 7.67-7.73(2H, m), 10.86(1H, brs), 12.81(1H, brs) ESI+: 560 Ex213 Ex3 NMR: 2.45-2.62(1H, m), 2.65-2.82(1H, m), 2.96-3.10(1H, m), 3.42-3.56 (1H, m), 3.64-3.78(1H, m), 3.83-4.05(3H, m), 4.94(1H, d), 5.01(1H, d), 5.32(2H, s), 6.48(1H, s), 6.62(1H, d), 6.91(1H, s), 7.03(1H, s), 8.11(1H, s), 8.16(2H, s), 11.27(1H, brs), 12.99(1H, brs) ESI+: 532

TABLE 129 Ex214 Ex3 NMR: 1.46-1.66(6H, m), 2.55-2.72(2H, m), 2.76-2.84(4H, m), 2.98-3.10 (1H, m), 3.45-3.55(1H, m), 3.65-3.78(1H, m), 3.87-4.02(3H, m), 4.82 (1H, d), 4.88(1H, d), 5.13(2H, s), 6.53(1H, d), 6.61(1H, dd), 6.76(1H, s), 7.04(1H, s), 7.10(1H, d), 7.52(1H, d), 7.66-7.75(2H, m), 10.42(1H, brs), 13.01(1H, brs) ESI+: 529 Ex215 Ex3 NMR: 2.54-2.78(2H, m), 2.96-3.08(1H, m), 3.45-3.55(1H, m), 3.65-3.77 (1H, m), 3.85-4.05(3H, m), 4.85-5.01(4H, m), 5.14(2H, s), 6.43(1H, s), 6.57(1H, dd), 6.90(1H, s), 7.03(1H, s), 7.42(1H, d), 7.73-7.79(2H, m), 10.96(1H, brs), 13.00(1H, brs) ESI+: 562 Ex216 Ex3 NMR: 1.51-2.09(9H, m), 2.53-2.62(1H, m), 2.62-2.76(1H, m), 2.97-3.12 (1H, m), 3.45-3.56(1H, m), 3.64-3.77(1H, m), 3.85-4.00(3H, m), 4.84 (1H, d), 4.90(1H, d), 5.15(2H, s), 6.52(1H, s), 6.60(1H, d), 6.75(1H, s), 7.03(1H, s), 7.10(1H, d), 7.61-7.72(3H, m), 10.67(1H, brs), 12.96(1H, brs) ESI+: 514 Ex217 Ex3 NMR: 1.44(3H, d), 2.54-2.68(2H, m), 3.02-3.15(1H, m), 3.49-3.59(1H, m), 3.71-3.84(1H, m), 3.84-4.00(3H, m), 4.86(1H, d), 4.91(1H, d), 5.14 (2H, s), 5.41-5.52(1H, m), 6.49(1H, s), 6.57(1H, d), 6.73-6.80(2H, m), 7.08(1H, d), 7.42-7.49(2H, m), 7.69(1H, d), 10.79(1H, brs), 12.82(1H, brs) ESI+: 558 Ex218 Ex3 NMR: 0.64-0.70(2H, m), 0.81-0.88(2H, m), 2.54-2.63(2H, m), 3.04-3.14 (1H, m), 3.50-3.59(1H, m), 3.72-3.83(1H, m), 3.86-3.99(3H, m), 4.01- 4.07(1H, m), 4.83(1H, d), 4.89(1H, d), 5.09(2H, s), 6.52(1H, s), 6.60(1H, d), 6.74(1H, s), 6.77(1H, s), 7.08(1H, d), 7.55(1H, d), 7.67(1H, d), 7.72 (1H, dd), 10.52(1H, brs), 12.83(1H, brs) ESI+: 502 Ex219 Ex3 NMR: 1.48-1.84(7H, m), 1.96-2.06(2H, m), 2.48-2.68(2H, m), 3.02-3.14 (1H, m), 3.48-3.58(1H, m), 3.69-3.83(1H, m), 3.84-3.98(3H, m), 4.84 (1H, d), 4.90(1H, d), 5.07(2H, s), 6.50(1H, d), 6.58(1H, dd), 6.74(1H, s), 6.77(1H, s), 7.07(1H, d), 7.34(1H, dd), 7.42(1H, d), 7.46(1H, d), 10.74 (1H, brs), 12.83(1H, brs) ESI+: 480 Ex220 Ex3 NMR: 1.54-1.73(2H, m), 2.07-2.23(2H, m), 2.54-2.70(1H, m), 2.92-3.60 (4H, m), 3.83(2H, s), 4.87(2H, s), 5.33(2H, s), 6.50(1H, d), 6.58(1H, dd), 6.70(1H, s), 7.08(1H, d), 7.99(1H, d), 8.10(1H, s), 8.14(1H, d), 10.93 (1H, brs), 12.29(1H, brs) ESI+: 516 Ex221 Ex3 NMR: 2.54-2.72(2H, m), 3.01-3.13(1H, m), 3.47-3.57(1H, m), 3.70-3.82 (1H, m), 3.83-3.91(3H, m), 4.83-4.95(4H, m), 5.05(2H, s), 6.50(1H, d), 6.58(1H, dd), 6.74(1H, s), 6.77(1H, s), 7.06(1H, d), 7.29(1H, d), 7.41 (1H, dd), 7.56(1H, d), 10.98(1H, brs), 12.77(1H, brs) ESI+: 510 Ex222 Ex3 NMR: 2.53-2.66(2H, m), 3.01-3.12(1H, m), 3.49-3.58(1H, m), 3.71-3.85 (1H, m), 3.86-4.01(3H, m), 4.58-4.85(4H, m), 4.89(1H, d), 4.96(1H, d), 5.08-5.25(1H, m), 5.11(2H, s), 6.47(1H, s), 6.56(1H, dd), 6.76(1H, s), 6.89 (1H, s), 7.44(1H, d), 7.67-7.74(2H, m), 10.86(1H, brs), 12.79(1H, brs) ESI+: 558

TABLE 130 Ex223 Ex3 NMR: 1.36-1.53(1H, m), 1.79-1.95(2H, m), 2.00-2.09(1H, m), 2.72-3.04 (3H, m), 3.32-3.44(1H, m), 3.49-3.58(1H, m), 3.86(2H, s), 4.60-4.84 (4H, m), 4.93(2H, s), 4.93-5.09(1H, m), 5.05(2H, s), 6.40(1H, d), 6.54(1H, dd), 6.84(1H, s), 7.31(1H, d), 7.37(1H, dd), 7.54(1H, d), 10.80(1H, brs), 12.83(1H, brs) ESI+: 526 Ex224 Ex3 NMR: 1.45(3H, d), 2.39-2.68(2H, m), 3.01-3.14(1H, m), 3.46-3.59(1H, m), 3.69-3.99(2H, m), 3.89(2H, s), 4.85(1H, d), 4.91(1H, d), 5.05(2H, s), 5.24-5.36(1H, m), 6.51(1H, d), 6.59(1H, dd), 6.72-6.80(2H, m), 7.07(1H, d), 7.35-7.43(2H, m), 7.54-7.57(1H, m), 10.84(1H, brs), 12.82(1H, brs) ESI+: 524 Ex225 Ex3 NMR: 1.50(3H, d), 2.39-2.76(2H, m), 2.96-3.12(1H, m), 3.44-3.57(1H, m), 3.64-3.78(1H, m), 3.84-4.00(3H, m), 4.88(2H, s), 5.14(2H, s), 5.94- 6.09(1H, m), 6.47-6.66(2H, m), 6.77(1H, s), 6.97-7.14(2H, m), 8.29(1H, d), 8.58(1H, d), 10.73(1H, brs), 12.91(1H, brs) ESI+: 559 Ex226 Ex3 NMR: 1.38-1.54(1H, m), 1.50(3H, d), 1.78-2.11(3H, m), 2.72-3.09(3H, m), 3.30-3.44(1H, m), 3.46-3.57(1H, m), 3.81(2H, s), 4.91(2H, s), 5.16 (2H, s), 5.96-6.08(1H, m), 6.52-6.57(1H, m), 6.61(1H, dd), 6.72(1H, s), 7.09(1H, d), 8.30(1H, d), 8.58(1H, d), 10.93(1H, brs), 12.73(1H, brs) ESI+: 561 Ex227 Ex3 NMR: 1.44(3H, d), 1.51-1.71(2H, m), 2.06-2.20(2H, m), 2.38-2.64(2H, m), 2.95-3.46(3H, m), 3.56-3.92(2H, m), 4.80(2H, s), 5.10(2H, s), 5.42- 5.53(1H, m), 6.49(1H, d), 6.57(1H, dd), 6.57-6.67(1H, m), 7.04(1H, d), 7.51(1H, d), 7.70-7.76(2H, m), 10.61(1H, brs), 12.27(1H, brs) ESI+: 560 Ex228 Ex3 NMR: 2.27-2.49(4H, m), 2.82-2.97(1H, m), 3.56(2H, s), 3.57-3.70(1H, m), 4.59-4.85(4H, m), 4.75(2H, s), 4.91-5.08(1H, m), 5.03(2H, s), 6.49 (1H, d), 6.57(1H, dd), 6.62(1H, s), 7.04(1H, d), 7.31(1H, d), 7.37(1H, dd), 7.53(1H, d), 8.85-9.21(2H, m), 12.38(1H, brs) ESI+: 494 Ex229 Ex3 NMR: 1.36-1.52(1H, m), 1.59-1.96(3H, m), 1.99-2.11(1H, m), 2.72-2.96 (2H, m), 3.36-3.46(1H, m), 3.50-3.60(1H, m), 3.88(2H, s), 4.67-4.86 (4H, m), 4.90(2H, s), 5.09(2H, s), 5.61-5.78(1H, m), 6.44(1H, d), 6.58(1H, dd), 6.82(1H, s), 8.06(1H, d), 8.23(1H, d), 10.29(1H, brs), 12.84(1H, brs) ESI+: 527 Ex230 Ex3 NMR: 1.37-1.52(1H, m), 1.62-1.93(3H, m), 1.99-2.10(1H, m), 2.71-2.97 (2H, m), 3.36-3.45(1H, m), 3.49-3.62(1H, m), 3.88(2H, s), 4.58-4.86 (4H, m), 4.89(2H, s), 5.08-5.25(1H, m), 5.11(2H, s), 6.42(1H, s), 6.56(1H, dd), 6.84(1H, s), 7.44(1H, d), 7.65-7.73(2H, m), 10.37(1H, brs), 12.83 (1H, brs) ESI+: 560 Ex231 Ex3 NMR: 1.74-1.94(2H, m), 1.95-2.14(3H, m), 2.81-3.01(2H, m), 3.40-3.51 (2H, m), 3.84(1.4H, d), 3.89(0.6H, d), 4.58-4.86(4H, m), 4.88(2H, s), 5.08-5.25(1H, m), 5.11(2H, s), 6.42(1H, s), 6.53-6.60(1H, m), 6.84(0.7H, s), 6.89(0.3H, s), 7.44(1H, d), 7.66-7.74(2H, m), 10.08(0.7H, brs), 10.18(0.3H, brs), 12.52(1H, brs); two rotamers(7:3) ESI+: 560

TABLE 131 Ex232 Ex3 NMR: 1.45(3H, d), 2.30-2.47(4H, m), 2.83-2.97(1H, m), 3.54(2H, s), 3.56- 3.67(1H, m), 4.79(2H, s), 5.10(2H, s), 5.44-5.54(1H, m), 6.50(1H, d), 6.58(1H, dd), 6.64(1H, s), 7.04(1H, d), 7.52(1H, d), 7.70-7.76(2H, m), 9.16-9.55(2H, brs), 12.38(1H, brs) ESI+: 546 Ex233 Ex3 NMR: 1.17(2.1H, s), 1.26(0.9H, s), 1.71-1.90(2H, m), 2.05-2.22(2H, m), 2.72-2.90(1.4H, m), 2.99-3.14(0.6H, m), 3.21-3.45(2H, m), 3.70-3.90 (2H, m), 4.60-4.90(6H, m), 4.92-5.08(3H, m), 6.49(1H, d), 6.57(1H, dd), 6.71(1H, s), 7.01-7.08(1H, m), 7.31(1H, d), 7.36(1H, dd), 7.53(1H, d), 10.26-10.50(1H, m), 12.73(1H, brs); two rotamers(7:3) ESI+: 522 Ex234 Ex3 NMR: 1.86-2.03(2H, m), 2.08-2.20(2H, m), 2.85-3.13(3H, m), 3.14-3.30 (1H, m), 3.46-3.57(1H, m), 3.73-3.90(2H, m), 4.60-4.83(4H, m), 4.84 (2H, s), 4.92-5.09(1H, m), 5.04(2H, s), 6.50(1H, d), 6.58(1H, dd), 6.71 (1H, s), 7.07(1H, d), 7.31(1H, d), 7.37(1H, dd), 7.53(1H, d), 10.10-10.43 (1H, m), 12.44(1H, brs) ESI+: 548 Ex235 Ex3 NMR: 1.37-1.52(1H, m), 1.81-1.93(2H, m), 1.99-2.10(1H, m), 2.72-3.04 (3H, m), 3.31-3.44(1H, m), 3.49-3.59(1H, m), 3.87(2H, s), 4.61-4.85 (4H, m), 4.92(2H, s), 4.94-5.09(1H, m), 5.05(2H, s), 6.41(1H, s), 6.55 (1H, dd), 6.85(1H, s), 7.31(1H, d), 7.37(1H, dd), 7.54(1H, d), 10.67(1H, brs), 12.80(1H, brs) ESI+: 526 Ex236 Ex156 NMR: 1.36-1.52(1H, m), 1.79-2.10(3H, m), 2.72-3.06(3H, m), 3.31-3.44 (1H, m), 3.48-3.59(1H, m), 3.86(2H, s), 4.88-5.01(4H, m), 5.13(2H, s), 6.42(1H, d), 6.56(1H, dd), 6.85(1H, s), 7.42(1H, d), 7.72-7.78(2H, m), 10.89(1H, brs), 12.84(1H, brs) ESI+: 564

INDUSTRIAL APPLICABILITY

The compound of the present invention has an S1P1 agonist action and can be used for prevention or treatment of diseases induced by undesirable lymphocyte infiltration, for example, autoimmune diseases or inflammatory diseases such as graft rejection or graft-versus-host diseases during organ, bone marrow, or tissue transplantation, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, lung disorders, asthma, atopic dermatitis, inflammatory bowel disease, arteriosclerosis, ischemic reperfusion disorder, and diseases induced by abnormal proliferation or accumulation of cells, for example, cancer, leukemia, and the like.

Claims

1. A method for preventing or treating a disease induced by undesirable lymphocyte infiltration associated with S1P1, comprising administering to a patient an effective amount of a 2H-chromene compound represented by the following formula (1):

(wherein A represents lower alkyl, cycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl may respectively be substituted with one to five R1s which are the same as or different from each other, other;
R1 represents halogen, —CN, —NO2, lower alkyl, lower alkenyl, lower alkynyl, halogeno-lower alkyl, aryl, heteroaryl, cycloalkyl, —OH, —O-(lower alkyl), —O-(halogeno-lower alkyl), —O-(aryl), —O-(cycloalkyl), —O-(heteroaryl), —NH2, —NH(lower alkyl), —NH(halogeno-lower alkyl), —N(lower alkyl)2, or cyclic amino, wherein aryl, heteroaryl, cycloalkyl, and cyclic amino may respectively be substituted with one to five substituents which are the same as or different from each other and selected from the group consisting of halogen, —CN, lower alkyl and halogeno-lower alkyl;
L represents lower alkylene, lower alkenylene, lower alkynylene, -(lower alkylene)-O—, —O-(lower alkylene)-, or -(lower alkylene)-O-(lower alkylene)-;
Q represents S or —C(R2B)═C(R2C)—;
R2A, R2B, and R2C independently represent —H, halogen, lower alkyl, halogeno-lower alkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl);
Y represents O, S, or —CH2—, provided that wherein Y is —CH2—, Q is S;
m represents 0 or 1;
R3 represents —H, halogen, lower alkyl, halogeno-lower alkyl, or aryl;
R4A represents —H or lower alkyl;
R4B represents lower alkyl substituted with a group selected from Group G or cycloalkyl substituted with a group selected from Group G;
or R4A and R4B are combined with N to which they bind to form cyclic amino substituted with a group selected from Group G, in which the cyclic amino may further contain one to four substituents which are the same as or different from each other and selected from the group consisting of halogen, lower alkyl, and halogeno-lower alkyl; and
Group G represents, —C(═O)OH, tetrazolyl, —C(═O)NHS(═O)2(lower alkyl), -(lower alkylene)-C(═O)OH, or
or a salt thereof.

2. The method as described in claim 1, wherein Y is O, Q is —C(R2B)═C(R2C)—, and m is 0.

3. The method as described in claim 2, wherein R4A and R4B are combined with N to which they bind to form azetidinyl, pyrrolidinyl, piperidinyl or tetrahydropyridyl, which is substituted with a group selected from Group G, and which may further be substituted with lower alkyl or halogen.

4. The method as described in claim 3, wherein the group represented by Group G is —C(═O)OH or —C(═O)NHS(═O)2CH3.

5. The method as described in claim 4, wherein A is phenyl, pyridyl, or thienyl, substituted with one to three R1s which are the same as or different from each other.

6. The method as described in claim 5, wherein L is -(lower alkylene)-O—, lower alkenylene, or lower alkynylene.

7. The method as described in claim 6, wherein R2A is —H or lower alkyl; R2B is —H; R2C is —H or halogen; R3 is —H or halogen; R1 is halogen, lower alkyl, halogeno-lower alkyl, phenyl, pyrrolyl, cycloalkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl); and L is —CH2—O—, —CH═CH—, or 3-butynylene.

8. The method as described in claim 7, wherein R4A and R4B are combined with N to which they bind to form piperidinyl or tetrahydropyridyl, which is substituted with —C(═O)OH; L is —CH2—O—; R2A and R2B are —H; R2C is —H or halogen; R3 is —H; and A is phenyl or pyridyl, which is substituted with two R1s which are independently halogen, halogeno-lower alkyl, —O-(lower alkyl) or —O-(halogeno-lower alkyl).

9. The method as described in claim 8, wherein R4A and R4B are combined with N to which they bind to form piperidinyl which is substituted with —C(═O)OH; and A is phenyl which is substituted with two R1s which are the same as or different from each other.

10. The method as described in claim 8, wherein R4A and R4B are combined with N to which they bind to form tetrahydropyridyl which is substituted with —C(═O)OH; and A is pyridyl which is substituted with two R1s which are the same as or different from each other.

11. The method of claim 1, wherein said 2H-chromene compound is:

1-{[7-({3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-({7-[(3-chloro-4-isopropylbenzyl)oxy]-2H-chromen-3-yl}methyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-[(7-{[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-{[7-({3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,3,6-tetrahydropyridine-4-carboxylic acid,
1-{[7-({5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-yl}methoxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
(3R)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
1-[(7-{[4-cyclopentyl-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
(3R)-1-{[7-({3-chloro-4-[(1,3-difluoropropan-2-yl)oxy]benzyl)oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
(3S)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
(3R)-1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
(3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
(3S)-1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
(3R)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}-N-(methylsulfonyl)piperidine-3-carboxamide, or
1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-4-carboxylic acid,
or a pharmaceutically acceptable salt thereof.

12-14. (canceled)

15. The method as described in claim 1, wherein the disease is autoimmune or inflammatory disease in human or an animal.

16. The method as described in claim 15, wherein the disease is rejection or graft-versus-host diseases from organ, bone marrow, or tissue transplantation in human or an animal.

17. The method as described in claim 15, wherein the disease is multiple sclerosis.

18-20. (canceled)

21. A method for preventing or treating a disease induced by undesirable lymphocyte infiltration associated with S1P1, comprising administering to a patient an effective amount of compound of the formula

or a pharmaceutically acceptable salt thereof.

22. The method as described in claim 21, wherein the disease is autoimmune or inflammatory disease in human or an animal.

23. The method as described in claim 22, wherein the disease is rejection or graft-versus-host diseases from organ, bone marrow, or tissue transplantation in human or an animal.

24. The method as described in claim 22, wherein the disease is multiple sclerosis.

Patent History
Publication number: 20120178735
Type: Application
Filed: Feb 15, 2012
Publication Date: Jul 12, 2012
Applicant: ASTELLAS PHARMA INC. (Tokyo)
Inventors: Hironori Harada (Tokyo), Kazuyuki Hattori (Tokyo), Kazuya Fujita (Tokyo), Sunao Imada (Tokyo), Tatsuaki Morokata (Tokyo)
Application Number: 13/396,861