5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS

5- and 6-membered heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described as are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Also described is the treatment of neurological, neurodegenerative and psychiatric disorders including but not limited to those comparing cognitive deficits or schizophrenic symptoms.

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Description

The disclosure relates to 5- and 6-membered heterocyclic compounds which are inhibitors of phosphodiesterase 10. The disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. The disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.

BACKGROUND

Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G-protein coupled receptors. In neurons, PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis. To date, eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.

The discovery of a new PDE family, PDE10, was reported simultaneously by three groups in 1999 (Soderling et al. “Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A” Proc. Natl. Sci. 1999, 96, 7071-7076; Loughney et al. “Isolation and characterization of PDE10A, a novel human 3′,5′-cyclic nucleotide phosphodiesterase” Gene 1999, 234, 109-117; Fujishige et al. “Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)” J. Biol. Chem. 1999, 274, 18438-18445). The human PDE10 sequence is highly homologous to both the rat and mouse variants with 95% amino acid identity overall, and 98% identity conserved in the catalytic region.

PDE10 is primarily expressed in the brain (caudate nucleus and putamen) and is highly localized in the medium spiny neurons of the striatum, which is one of the principal inputs to the basal ganglia. This localization of PDE10 has led to speculation that it may influence the dopaminergic and glutamatergic pathways both which play roles in the pathology of various psychotic and neurodegenerative disorders.

PDE10 hydrolyzes both cAMP (Km=0.05 uM) and cGMP (Km=3 uM) (Soderling et al. “Isolation and Characterization of a dual-substrate phosphodiesterase gene family: PDE10.” Proc. Natl Sci. USA 1999, 96(12), 7071-7076). In addition, PDE10 has a five-fold greater Vmax for cGMP than for cAMP and these in vitro kinetic data have lead to the speculation that PDE10 may act as a cAMP-inhibited cGMP phosphodiesterase in vive (Soderling and Beavo “Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions,” Curr. Opin. Cell Biol., 2000, 12, 174-179).

PDE10 is also one of five phosphodiesterase members to contain a tandem GAF domain at their N-terminus. It is differentiated by the fact that the other GAF containing PDEs (PDE2, 5, 6, and 11) bind cGMP while recent data points to the tight binding of cAMP to the GAF domain of PDE10 (Handa et al. “Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP” J. Biol. Chem. 2008, May 13th, ePub).

PDE10 inhibitors have been disclosed for the treatment of a variety of neurological and psychiatric disorders including Parkinson's disease, schizophrenia, Huntington's disease, delusional disorders, drug-induced psychoses, obsessive compulsive and panic disorders (US Patent Application 2003/0032579). Studies in rats (Kostowski et. al “Papaverine drug induced stereotypy and catalepsy and biogenic amines in the brain of the rat” Pharmacol. Biochem. Behav. 1976, 5, 15-17) have showed that papaverine, a selective PDE10 inhibitor, reduces apomorphine induced stereotypies and rat brain dopamine levels and increases haloperidol induced catalepsy. This experiment lends support to the use of a PDE10 inhibitor as an antipsychotic since similar trends are seen with known, marketed antipsychotics.

Antipsychotic medications are the mainstay of current treatment for schizophrenia. Conventional or classic antipsychotics, typified by haloperidol, were introduced in the mid-1950s and have a proven track record over the last half century in the treatment of schizophrenia. While these drugs are effective against the positive, psychotic symptoms of schizophrenia, they show little benefit in alleviating negative symptoms or the cognitive impairment associated with the disease. In addition, drugs such as haloperidol have extreme side effects such as extrapyramidal symptoms (EPS) due to their specific dopamine D2 receptor interaction. An even more severe condition characterized by significant, prolonged, abnormal motor movements known as tardive dyskinesia also may emerge with prolonged classic antipsychotic treatment.

The 1990s saw the development of several new drugs for schizophrenia, referred to as atypical antipsychotics, typified by risperidone and olanzapine and most effectively, clozapine. These atypical antipsychotics are generally characterized by effectiveness against both the positive and negative symptoms associated with schizophrenia, but have little effectiveness against cognitive deficiencies and persisting cognitive impairment remain a serious public health concern (Davis, J. M et al. “Dose response and dose equivalence of antipsychotics.” Journal of Clinical Psychopharmacology, 2004, 24 (2), 192-208; Friedman, J. H. et al “Treatment of psychosis in Parkinson's disease: Safety considerations.” Drug Safety, 2003, 26 (9), 643-659). In addition, the atypical antipsychotic agents, while effective in treating the positive and, to some degree, negative symptoms of schizophrenia, have significant side effects. For example, clozapine which is one of the most clinically effective antipsychotic drugs shows agranulocytosis in approximately 1.5% of patients with fatalities due to this side effect being observed. Other atypical antipsychotic drugs have significant side effects including metabolic side effects (type 2 diabetes, significant weight gain, and dyslipidemia), sexual dysfunction, sedation, and potential cardiovascular side effects that compromise their clinically effectiveness. In the large, recently published NIH sponsored CATIE study, (Lieberman et al “The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome.” Schizophrenia Research, 2005, 80 (1), 9-43) 74% of patients discontinued use of their antipsychotic medication within 18 months due to a number of factors including poor tolerability or incomplete efficacy. Therefore, a substantial clinical need still exists for more effective and better tolerated antipsychotic mediations possibly through the use of PDE10 inhibitors.

BRIEF SUMMARY

Described herein are 5- and 6-membered heterocyclic compounds of Formulas (I), (II) or (III) which are inhibitors of at least one phosphodiesterase 10 (e.g., PDE-10A):

Wherein:

HET is a heterocyclic ring selected from Formulas A1-A2, A6-A8, A10-A32 and A38 below

and the left most radical is connected to the X group;

W is selected from halogen, cyano, nitro, alkoxy, amino, alkylamino, dialkylamino, carboxy, amido, alkylamido, and dialkylamido;

X is selected from C3-C8 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

Y is a bond or a divalent linker group selected from —CH2—, —O—, —SO2—, —CH2O—, —OCH2— and —CH2CH2— with the rightmost radical of the Y group connected to the Z substituent;
Z is optionally substituted heteroaryl;
R1a is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl with the proviso that when R1a is not hydrogen, R1b is hydrogen or that when R1b is absent, R1a must be hydrogen;
R1b is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl with the proviso that when R1b is not hydrogen, R1a is hydrogen;
Each R2 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl with the proviso that when two R2 are present, at least one R2 is hydrogen;
R3 and R4 are independently selected from hydrogen, C1-C4 alkyl, CF3 and optionally substituted cycloalkyl with the proviso that at least one R3 or R4 group must be hydrogen;
R5 is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
R7 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl; and
n is independently selected from 1 and 2.

In some embodiments, alkyl groups are fully saturated whether present on their own or as part of another group (e.g., alkylamino).

In certain embodiments, substituent groups are not further substituted.

In various embodiments, any group that is defined as being optionally substituted is independently singly or multiply substituted.

In various embodiments, any group that is defined as being optionally substituted not substituted.

In one embodiment, a compound of Formula (I) is selected.

In another embodiment, a compound of Formula (II) is selected.

In another embodiment, a compound of Formula (III) is selected.

In one embodiment, alkyl groups are fully saturated whether present on their own or on another group.

In a further embodiment, HET is selected from Formulas A7, A8, A14, A15, A19, A25, A29, A30, A31, A32, and A38.

In a further embodiment, HET is selected from Formulas A7, A8, A25, A29, A30, A31, A32, and A38.

In another embodiment, HET is selected from Formulas A7, A8, A25, A29, A30 and A38.

In another embodiment, HET is selected from Formulas A7, A8, A17 A18, A25, A29, and A30.

In one embodiment, HET is selected from Formulas A1, A2, A7, A8, A14, A15 and A19.

In another embodiment, HET is selected from Formulas A6, A9 A10, A20 and A24.

In an additional embodiment, HET is selected from Formulas A1, A2, A7 and A8.

In another embodiment, HET is selected from Formulas A22, A23, A25 and A26.

In another embodiment, HET is selected from Formulas A29, A30, A31 and A32.

In another embodiment, HET is selected from Formulas A7, A8, A29 and A30.

In a further embodiment, HET is selected from Formulas A7, A8, A29 and A31.

In another embodiment, HET is selected from Formulas A29, A31 and A38.

In another embodiment, HET is selected from Formulas A25, A29 and A38.

In another embodiment, HET is selected from Formulas A25, A29 and A30.

In another embodiment, HET is selected from Formulas A25 and A38.

In another embodiment, HET is selected from Formulas A7 and A8.

In another embodiment, HET is selected from Formulas A25 and A26.

In another embodiment, HET is selected from Formulas A29 and A30.

In another embodiment, HET is selected from Formulas A29 and A31.

In a further embodiment, HET is selected from Formulas A31 and A32.

In another embodiment, HET is Formula A1.

In another embodiment, HET is Formula A2.

In another embodiment, HET is Formula A6.

In another embodiment, HET is Formula A7.

In another embodiment, HET is Formula A8.

In another embodiment, HET is Formula A 10.

In another embodiment, HET is Formula A11.

In another embodiment, HET is Formula A12.

In another embodiment, HET is Formula A 13.

In another embodiment, HET is Formula A14.

In another embodiment, HET is Formula A 15.

In another embodiment, HET is Formula A16.

In another embodiment, HET is Formula A17.

In another embodiment, HET is Formula A 18.

In another embodiment, HET is Formula A19.

In another embodiment, HET is Formula A20.

In another embodiment, HET is Formula A21.

In another embodiment, HET is Formula A22.

In another embodiment, HET is Formula A23.

In another embodiment, HET is Formula A24.

In another embodiment, HET is Formula A25.

In another embodiment, HET is Formula A26.

In another embodiment, HET is Formula A29.

In another embodiment, HET is Formula A30.

In another embodiment, HET is Formula A31.

In another embodiment, HET is Formula A32.

In another embodiment, HET is Formula A38.

In one embodiment, W is selected from nitro, carboxy, amido, alkylamido, and dialkylamido.

In another embodiment, W is selected from amino, alkylamino and dialkylamino.

In a further embodiment, W is selected from halogen, cyano and alkoxy.

In another embodiment, W is selected from halogen and cyano.

In another embodiment, W is halogen.

In another embodiment, W is cyano.

In another embodiment, W is alkoxy.

In one embodiment, X is selected from C3-C8 alkyl, cycloalkyl and cycloalkylalkyl.

In a further embodiment X is selected from cycloalkyl and cycloalkylalkyl. Examples include, but are not limited to, cyclohexyl and cyclohexylmethyl.

In another embodiment X is C3-C8 alkyl. Examples include, but are not limited to, isopropyl, t-butyl and isopentyl.

In an additional embodiment, X is heterocycloalkyl.

In a further embodiment X is heterocycloalkyl having only 6 ring atoms. Examples include, but are not limited to, morpholinyl, piperidinyl, piperazinyl N-Me-piperazinyl and pyranyl.

In another embodiment X is heterocycloalkyl having only 5 ring atoms. Examples include, but are not limited to, tetrahydrofuranyl and pyrrolidinyl.

In another embodiment, X is a heterocycloalkyl group selected from Formulas B1-B16 depicted below:

wherein R6 is selected from hydrogen and C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylalkyl, all of which can be optionally substituted.

In another embodiment X is selected from morpholinyl, pyranyl and tetrahydrofuranyl.

In another embodiment X is selected from morpholinyl (having formula B1) and 4-pyranyl (having Formula B2).

In another embodiment X is heteroaryl.

In another embodiment, X is selected from a monocyclic aromatic ring having 5 ring atoms selected from C, O, S and N provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur, and a monocyclic aromatic ring having 6 atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxyl, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include but are not limited to 1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.

In a further embodiment, X is a monocyclic aromatic ring having 6 ring atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxyl, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include but are not limited to 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.

In a further embodiment, X is a monocyclic aromatic ring having 5 ring atoms selected from C, O, S, and N, provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxyl, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include but are not limited to 1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl.

In a further embodiment, X is selected from 2-pyridinyl, 3-pyridinyl and 4-pyridinyl optionally substituted with one group selected from C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen or cyano.

In a further embodiment, X is 3-pyridinyl optionally substituted with one group selected from C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen or cyano.

In a further embodiment, X is 4-pyridinyl optionally substituted with one group selected from C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen or cyano.

In a further embodiment, X is selected from 3-pyridinyl and 4-pyridinyl.

In a further embodiment, X is 3-pyridinyl.

In another embodiment, X is 2-methoxy-5-pyridinyl.

In a further embodiment, X is 4-pyridinyl.

In another embodiment, X is 2-methoxy-4-pyridinyl.

In another embodiment X is a heterobicyclic ring system.

In another embodiment X is a heterobicyclic ring system where one ring is aromatic.

In a further embodiment, X is a heterobicyclic ring system where both rings are aromatic.

In another embodiment, X is a heterobicyclic ring system containing exactly 9 ring atoms.

In another embodiment, X is a heterobicyclic ring system containing exactly 10 ring atoms.

In another embodiment X is selected from benzo[d]oxazoyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, 1H-benzo[d]imidazoyl, benzo[d]thiazoyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, imidazo[1,2-a]pyridinyl and imidazo[1,5-a]pyridinyl

In another embodiment X is selected from benzo[c][1,2,5]oxadiazyl and benzo[c][1,2,5]thiadiazolyl.

In a further embodiment, X is selected from benzo[d]oxazoyl, 1H-benzo[d]imidazoyl and benzo[d]thiazoyl.

In a further embodiment, X is benzo[d]oxazoyl.

In a further embodiment, X is 1H-benzo[d]imidazoyl.

In a further embodiment, X is benzo[d]thiazoyl.

In another embodiment X is benzo[c][1,2,5]oxadiazoyl.

In a further embodiment X is benzo[c][1,2,5]thiadiazolyl

In a further embodiment, X is benzo[d]isoxazolyl.

In another embodiment, X is benzo[d]isothiazolyl.

In another embodiment, X is benzo[c]isothiazolyl.

In another embodiment, X is benzo[c]isoxazolyl.

In another embodiment, X is imidazo[1,2-a]pyridinyl.

In another embodiment, X is imidazo[1,5-a]pyridinyl.

In an additional embodiment, X is aryl.

In another embodiment, X is selected from phenyl and pyridinyl.

In a further embodiment, X is phenyl.

In another embodiment, X is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, NO2, CF3, OCF3, OCHF2, CH2CF3 and OMe.

In another embodiment, X is restricted phenyl.

In a further embodiment, X is selected from a 3,4-disubstituted phenyl, 3-substituted phenyl and 4-substituted phenyl.

In another embodiment, X is selected from 3,4-disubstituted phenyl and 4-substituted phenyl.

In another embodiment, X is 3-chloro-4-methoxyphenyl

In another embodiment, X is 3-cyano-4-methoxyphenyl

In a further embodiment, X is 3-chloro-4-difluoromethoxyphenyl

In a further embodiment, X is 3-cyano-4-difluoromethoxyphenyl

In an additional embodiment, X is 4-substituted phenyl.

In a further embodiment, X is 4-methoxyphenyl.

In another embodiment, X is 4-nitrophenyl.

In another embodiment, X is 4-chlorophenyl.

In another embodiment, X is 4-cyanophenyl.

In another embodiment, X is 4-trifluoroethylphenyl.

In a further embodiment, X is 4-trifluoromethoxyphenyl.

In a further embodiment, X is 3-substituted phenyl.

In another embodiment, X is 3-nitrophenyl.

In another embodiment, X is 3-trifluoromethoxyphenyl.

In a further embodiment, X is 3-methoxyphenyl.

In another embodiment, X is 3-chlorophenyl.

In another embodiment, X is 3-cyanophenyl.

In another embodiment, X is 3-trifluoroethylphenyl.

In a further embodiment, X is 3-trifluoromethoxyphenyl.

In one embodiment, Y is —CH2O— or —OCH2— with the rightmost radical connected to the Z substituent.

In another embodiment, Y is —CH2CH2— with the rightmost radical connected to the Z substituent.

In an additional embodiment, Y is —CH2O— with the rightmost radical connected to the Z substituent.

In a further embodiment, Y is —OCH2— with the rightmost radical connected to the Z substituent.

In one embodiment, Z is selected from heteroaryl having only 6 ring atoms and a heterobicyclic ring system.

In another embodiment, Z is a heterobicyclic ring system.

In another embodiment, Z is a heterobicyclic ring system where one ring is aromatic.

In a further embodiment, Z is a heterobicyclic ring system where both rings are aromatic.

In another embodiment, Z is a heterobicyclic ring system containing exactly 9 ring atoms.

In another embodiment, Z is a heterobicyclic ring system containing exactly 10 ring atoms.

In an additional embodiment, Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, imidazo[1,2-a]pyridin-2-yl, tetrahydroisoquinolyl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 6-fluoroquinolyl and isoquinolinyl, all for which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In an additional embodiment, Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and isoquinolinyl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In an additional embodiment, Z is selected from quinolinyl, imidazo[1,2-a]pyridin-2-yl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl and 6-fluoroquinolin-2-yl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In an additional embodiment, Z is selected from quinolinyl and isoquinolinyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.

In a further embodiment, Z is selected from 2-quinolinyl and 2-benzimidazolyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In a further embodiment, Z is 2-quinolinyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In a further embodiment, Z is 6-fluoroquinolin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In a further embodiment, Z is 3,5-dimethylpyridin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In a further embodiment, Z is 5-methylpyridin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In an additional embodiment, Z is selected from 2-quinolinyl and 2-benzimidazolyl.

In an additional embodiment, Z is selected from 2-quinolinyl and 5-methylpyridin-2-yl.

In an additional embodiment, Z is selected from 2-quinolinyl and 3,5-dimethylpyridin-2-yl.

In an additional embodiment, Z is selected from 2-quinolinyl and 6-fluoroquinolin-2-yl.

In an additional embodiment, Z is 2-quinolinyl.

In another embodiment, Z is heteroaryl consisting of 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two; said ring is optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In another embodiment, Z is heteroaryl consisting of 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two.

In a further embodiment, Z is pyridinyl optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.

In a further embodiment, Z is 2-pyridinyl optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.

In a further embodiment, any Z is substituent may be unsubstituted.

In one embodiment, R1a is selected from cycloalkyl and alkyl with the proviso that R1b is hydrogen.

In another embodiment, R1a is selected from hydrogen and alkyl with the proviso that R1b is hydrogen when R1a is alkyl.

In an additional embodiment, R1a is cycloalkyl with the proviso that R1b is hydrogen.

In another embodiment, R1a is alkyl with the proviso that R1b is hydrogen In another embodiment, R1a is fully saturated C1-C4 alkyl with the proviso that R1b is hydrogen

In another embodiment, R1a is hydrogen.

In one embodiment, R1b is selected from cycloalkyl and alkyl with the proviso that R1a is hydrogen.

In one embodiment, R1b is selected from hydrogen and alkyl with the proviso that R1a is hydrogen when R1b is alkyl.

In one embodiment, R1b is selected from hydrogen and fully saturated C1-C4 alkyl with the proviso that R1a is hydrogen when R1b is alkyl.

In another embodiment, R1b is cycloalkyl with the proviso that R1a is hydrogen.

In a further embodiment, R1b is alkyl with the proviso that R1a is hydrogen.

In another embodiment, R1b is hydrogen.

In one embodiment, each R2 is independently selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl with the proviso that at least one R2 is hydrogen;

In another embodiment, each R2 is independently selected from hydrogen, alkyl and cycloalkyl with the proviso that at least one R2 is hydrogen;

In another embodiment, each R2 is independently selected from hydrogen and alkyl with the proviso that at least one R2 is hydrogen.

In another embodiment, each R2 is independently selected from hydrogen and fully saturated C1-C4 alkyl with the proviso that at least one R2 is hydrogen.

In an additional embodiment, each R2 is hydrogen.

In one embodiment, R3 and R4 are independently selected from hydrogen and cycloalkyl with the proviso that at least one R3 or R4 group must be hydrogen;

In a further embodiment, R3 and R4 are independently selected from hydrogen and C1-C4 alkyl with the proviso that at least one R3 or R4 group must be hydrogen;

In a further embodiment, R3 and R4 are hydrogen.

In one embodiment, R5 is selected from cycloalkylalkyl and alkoxyalkyl.

In an additional embodiment, R5 is selected from cycloalkyl and alkyl.

In another embodiment, R5 is cycloalkyl.

In another embodiment, R5 is alkyl.

In one embodiment n is 1.

In another embodiment n is 2.

In one embodiment, R7 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.

In another embodiment, R7 is selected from alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.

In another embodiment, R7 is selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl.

In another embodiment, R7 is selected from alkyl, cycloalkyl and cycloalkylalkyl.

In another embodiment, R7 is selected from cycloalkyl and cycloalkylalkyl.

In another embodiment, R7 is selected from alkyl and cycloalkyl.

In another embodiment, R7 is alkyl.

In another embodiment, R7 is cycloalkyl.

In another embodiment, R7 is cycloalkylalkyl.

In a further embodiment, R7 is hydrogen.

Compounds of the disclosure may contain asymmetric centers and exist as different enantiomers or diastereomers or a combination of these therein. All enantiomeric, diastereomeric forms of Formulas (I), (II) and (III) are embodied herein.

Compounds in the disclosure may be in the form of pharmaceutically acceptable salts.

The phrase “pharmaceutically acceptable” refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids. Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc. Salts derived from organic bases include ammonia, primary, secondary and tertiary amines, and amino acids. Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, hydrobromic. Salts derived from organic acids include C1-6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, proprionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as para-tolouene sulfonic acid and benzene sulfonic acid.

Compounds in the disclosure may be in the form of a solvate. This occurs when a compound of Formulas (I) or (II) or (III) has an energetically favorable interaction with a solvent, crystallizes in a manner that it incorporates solvent molecules into the crystal lattice or a complex is formed with solvent molecules in the solid or liquid state. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.

Compounds in the disclosure may exist in different crystal forms known as polymorphs. Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice.

Compounds in the disclosure may exist as isotopically labeled compounds of Formulas (I) or (II) or (III) where one or more atoms are replaced by atoms having the same atomic number but a different atomic mass from the atomic mass which is predominantly seen in nature. Examples of isotopes include, but are not limited to hydrogen isotopes (deuterium, tritium), carbon isotopes (11C, 13C, 14C) and nitrogen isotopes (13N, 15N). For example, substitution with heavier isotopes such as deuterium (2H) may offer certain therapeutic advantages resulting from greater metabolic stability which could be preferable and lead to longer in vivo half-life or dose reduction in a mammal or human.

Prodrugs of compounds embodied by Formulas (I) or (II) or (III) are also within the scope of this disclosure. Particular derivatives of compounds of Formulas (I) or (II) or (III) which may have little to negligible pharmacological activity themselves, can, when administered to a mammal or human, be converted into compounds of Formulas (I) or (II) or (III) having the desired biological activity.

Compounds in the disclosure and their pharmaceutically acceptable salts, prodrugs, as well as metabolites of the compounds, may also be used to treat certain eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome, neurodegenerative disorders and CNS disorders/conditions as well as in smoking cessation treatment.

In one embodiment the treatment of CNS disorders and conditions by the compounds of the disclosure can include Huntington's disease, schizophrenia and schizo-affective conditions, delusional disorders, drug-induced psychoses, panic and obsessive compulsive disorders, post-traumatic stress disorders, age-related cognitive decline, attention deficit/hyperactivity disorder, bipolar disorders, personality disorders of the paranoid type, personality disorders of the schizoid type, psychosis induced by alcohol, amphetamines, phencyclidine, opioids hallucinogens or other drug-induced psychosis, dyskinesia or choreiform conditions including dyskinesia induced by dopamine agonists, dopaminergic therapies, psychosis associated with Parkinson's disease, psychotic symptoms associated with other neurodegenerative disorders including Alzheimer's disease, dystonic conditions such as idiopathic dystonia, drug-induced dystonia, torsion dystonia, and tardive dyskinesia, mood disorders including major depressive episodes, post-stroke depression, minor depressive disorder, premenstrual dysphoric disorder, dementia including but not limited to multi-infarct dementia, AIDS-related dementia, and neurodegenerative dementia,

In another embodiment, compounds of the disclosure may be used for the treatment of eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders as well as in smoking cessation treatment.

In a further embodiment, compounds of the disclosure may be used for the treatment of obesity, schizophrenia, schizo-affective conditions, Huntington's disease, dystonic conditions and tardive dyskinesia.

In another embodiment, compounds of the disclosure may be used for the treatment of schizophrenia, schizo-affective conditions, Huntington's disease and obesity.

In a further embodiment, compounds of the disclosure may be used for the treatment of schizophrenia and schizo-affective conditions.

In an additional embodiment, compounds of the disclosure may be used for the treatment of Huntington's disease.

In another embodiment, compounds of the disclosure may be used for the treatment of obesity and metabolic syndrome.

Compounds of the disclosure may also be used in mammals and humans in conjuction with conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine. The combination of a compound of Formula (I) or (II) or (III) with a subtherapeutic dose of an aforementioned conventional antipsychotic medication may afford certain treatment advantages including improved side effect profiles and lower dosing requirements.

DEFINITIONS

Alkyl is a linear or branched saturated or unsaturated aliphatic C1-C8 hydrocarbon which can be optionally substituted with up to 3 fluorine atoms. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and in the case of a double bond both cis and trans isomers are included. Examples of alkyl groups include but are not limited to methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans-2-butenyl, isobutenyl, propargyl. C1-C4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms.

In each case in which a size range for the number of atoms in a ring or chain is disclosed, all subsets are disclosed. Thus, Cx-Cy includes all subsets, e.g., C1-C4 includes C1-C2, C2-C4, C1-C3 etc.

Acyl is an alkyl-C(O)— group wherein alkyl is as defined above. Examples of acyl groups include acetyl and proprionyl.

Alkoxy is an alkyl-O— group wherein alkyl is as defined above. C1-C4 alkoxy is the subset of alkyl-O— where the subset of alkyl is limited to a total of up to 4 carbon atoms. Examples of alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy

Alkoxyalkyl is an alkyl-O—(C1-C4 alkyl)- group wherein alkyl is as defined above. Examples of alkoxyalkyl groups include methoxymethyl and ethoxymethyl.

Alkoxyalkyloxy is an alkoxy-alkyl-O— group wherein alkoxy and alkyl are as defined above. Examples of alkoxyalkyloxy groups include methoxymethyloxy (CH3OCH2O—) and methoxyethyloxy (CH3OCH2CH2O—) groups.

Alkylthio is alkyl-S— group wherein alkyl is as defined above.

Alkylsulfonyl is alkyl-SO2— wherein alkyl is as defined above.

Alkylamino is alkyl-NH— wherein alkyl is as defined above.

Dialkylamino is (alkyl)2-N— wherein alkyl is as defined above.

Amido is H2NC(O)—

Alkylamido is alkyl-NHC(O)— wherein alkyl is as defined above.

Dialkylamido is (alkyl)2-NC(O)— wherein alkyl is as defined above.

Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are as defined below.

Aryl is a phenyl or napthyl group. Aryl groups may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)NHRa, —OC(O)N(Ra), —SRa, —S(O)Ra, —NH2, —NHRa, —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NH(Rb), —N(Ra)C(O)NH(Rb)2, —C(O)NH2, —C(O)NHRa, —C(O)N(Ra)(Rb), —CO2H, —CO2Ra, —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.

Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as defined above.

Aryloxy is an aryl-O— group wherein aryl is as defined above.

Arylalkoxy is an aryl-(C1-C4 alkyl)-O— group wherein aryl is as defined above.

Carboxy is a CO2H or CO2Rc group wherein Rc is independently chosen from, alkyl, C1-C4 alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, CF3, and alkoxyalkyl, wherein alkyl is as defined above.

Cycloalkyl is a C3-C7 cyclic non-aromatic hydrocarbon which may contain a single double bond and is optionally and independently substituted with up to three groups selected from alkyl, alkoxy, hydroxyl and oxo. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.

Cycloalkyloxy is a cycloalkyl-O— group wherein cycloalkyl is as defined above. Examples include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. C3-C5 cycloalkyloxy is the subset of cycloalkyl-O— where cycloalkyl contains 3-6 carbon atoms.

Cycloalkylalkyl is a cycloalkyl-(C1-C4 alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.

Cycloalkylalkoxy is a cycloalkyl-(C1-C4 alkyl)-O— group wherein cycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.

Halogen is F, Cl, Br or I.

Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C. Examples of heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and benzimidazolyl. Heteroaryl groups may be optionally and independently substituted with up to 3 substituents independently selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)NHRa, —OC(O)N(Ra), —SRa, —S(O)Ra, —NH2, —NHRa, —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NH(Rb), —N(Ra)C(O)NH(Rb)2, —C(O)NH2, —C(O)NHRa, —C(O)N(Ra)(Rb), —CO2H, —CO2Ra, —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.

Heteroarylalkyl is a heteroaryl-(C1-C4 alkyl)- group wherein heteroaryl and alkyl are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethyl and 4-pyridinylethyl.

Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is as defined above.

Heteroarylalkoxy is a heteroaryl-(C1-C4 alkyl)-O— group wherein heteroaryl and alkoxy are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethoxy and 4-pyridinylethoxy.

Heterobicyclic ring system is a ring system having 8-10 atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic; said bicyclic ring may be optionally and independently substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano. Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, 1,2,3,4-tetrahydro-1,5-naphthyridyl 1,6-naphthyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridyl 1,7-naphthyridyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl 1,8-naphthyridyl, 1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl, 2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazolinyl, quinolyl, tetrahydroquinolinyl, quinoxalyl, tetrahydroquinoxalinyl, benzo[d][1,2,3]triazyl, benzo[e][1,2,4]triazyl, pyrido[2,3-b]pyrazyl, pyrido[2,3-c]pyridazyl, pyrido[2,3-d]pyrimidyl, pyrido[3,2-b]pyrazyl, pyrido[3,2-c]pyridazyl, pyrido[3,2-d]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[3,4-c]pyridazyl, pyrido[3,4-d]pyrimidyl, pyrido[4,3-b]pyrazyl, pyrido[4,3-c]pyridazyl, pyrido[4,3-d]pyrimidyl, quinazolyl, 1H-benzo[d][1,2,3]triazoyl, 1H-benzo[d]imidazoyl, 1H-indazoyl, 1H-indoyl, 2H-benzo[d][1,2,3]triazoyl, 2H-pyrazolo[3,4-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, benzo[b]thienyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isothiazoyl, benzo[d]isoxazoyl, benzo[d]oxazoyl, benzo[d]thiazoyl, benzofuryl, imidazo[1,2-a]pyrazyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidyl, imidazo[1,2-b]pyridazyl, imidazo[1,2-c]pyrimidyl, imidazo[1,5-a]pyrazyl, imidazo[1,5-a]pyridinyl, imidazo[1,5-a]pyrimidyl, imidazo[1,5-b]pyridazyl, imidazo[1,5-c]pyrimidyl, indolizyl, pyrazolo[1,5-a]pyrazyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidyl, pyrazolo[1,5-b]pyridazine, pyrazolo[1,5-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidyl, pyrrolo[1,2-b]pyridazyl, pyrrolo[1,2-c]pyrimidyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 2H-indazoyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, benzo[c]isothiazyl, benzo[c]isoxazyl, furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridiyl, isothiazolo[4,5-b]pyridinyl, isothiazolo[4,5-c]pyridinyl, isothiazolo[5,4-b]pyridinyl, isothiazolo[5,4-c]pyridinyl, isoxazolo[4,5-b]pyridinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[5,4-b]pyridinyl, isoxazolo[5,4-c]pyridinyl, oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, oxazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridiyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl and thieno[3,2-c]pyridinyl.

Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C. In the case where the heterocycloalkyl group contains a nitrogen atom the nitrogen may be substituted with an alkyl, acyl, —C(O)O-alkyl, —C(O)NH(alkyl) or a —C(O)N(alkyl)2 group. Heterocycloalkyl groups may be optionally and independently substituted with hydroxy, alkyl, cycloalkyl, cycloalkylalkyl and alkoxy groups and may contain up to two oxo groups. Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms. Examples of heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydro-1H-pyrido[1,2-a]pyrazine, 3-thia-6-azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl Heterocycloalkylalkyl is a heterocycloalkyl-(C1-C4 alkyl)- group wherein heterocycloalkyl is as defined above.

Heterocycloalkyloxy is a heterocycloalkyl-O— group wherein heterocycloalkyl is as defined above.

Heterocycloalkylalkoxy is a heterocycloalkyl-(C1-C4 alkyl)-O— group wherein heterocycloalkyl is as defined above.

Oxo is a —C(O)— group.

Phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)NHRa, —OC(O)N(Ra), —SRa, —S(O)Ra, —NH2, —NHRa, —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NH(Rb), —N(Ra)C(O)NH(Rb)2, —C(O)NH2, —C(O)NHRa, —C(O)N(Ra)(Rb), —CO2H, —CO2Ra, —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.

Restricted phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)N(Ra), —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —C(O)N(Ra)(Rb), —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, EL, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.

Abbreviations used in the following examples and preparations include:

    • Ac Acyl (Me-C(O)—)
    • AcN Acetonitrile
    • BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
    • Bn Benzyl
    • Celite® Diatomaceous earth
    • DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
    • DCC N,N′, Dicyclohexylcarbodiimide
    • DCM Dichloromethane
    • DIEA Di-isopropylethyl amine
    • DIPEA Di-isopropylethyl amine
    • DMAP 4-Dimethylaminopyridine
    • DMF Dimethylformamide
    • DMP Dess Martin Periodinane
    • DMSO Dimethyl sulfoxide
    • Dppf 1,4-Bis(diphenylphosphino) ferrocene
    • EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
    • Et3N Triethylamine
    • g gram(s)
    • h Hour(s)
    • hr Hour(s)
    • HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
    • HMDS Hexamethyldisilazide
    • HOBt 1-Hydroxybenzotriazole
    • HPLC High Pressure Liquid Chromatography
    • HRMS High resolution mass spectrometry
    • i.v. Intravenous
    • KHMDS Potassium Hexamethydisilazide
    • LDA Lithium Di-isopropylamide
    • m Multiplet
    • m- meta
    • mCPBA meta-chloroperbenzoic acid
    • MEM Methoxyethoxymethyl
    • MeOH Methyl Alcohol or Methanol
    • min Minute(s)
    • mmol millimoles
    • mmole millimoles
    • Ms Mesylate
    • MS Mass Spectrometry
    • MW Molecular Weight
    • NBS N-Bromosuccinamide
    • NCS N-Chlorosuccinamide
    • NIS N-Iodosuccinamide
    • NMR Nuclear Magnetic Resonance
    • NMM N-Methyl Morpholine
    • NMP N-Methyl-2-pyrrolidone
    • o ortho
    • o/n overnight
    • p para
    • PCC Pyridinium Chlorochromate
    • PEPPSI 1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridinyl)palladium(II) dichloride
    • PhNTf2 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
    • POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp) palladate (2-)
    • p.s.i. Pounds per square inch
    • PPA Polyphosphoric acid
    • PPAA 1-Propanephosphonic Acid Cyclic Anhydride
    • PTSA p-Toluenesulfonic acid
    • PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
    • RT (or rt) room temperature (about 20-25° C.)
    • s Singlet
    • sat. Saturated
    • t Triplet
    • TBAF Tetra-butyl ammonium fluoride
    • TEA Triethylamine
    • TFA Trifluoroacetic Acid
    • THF Tetrahydrofuran
    • TLC Thin layer chromatography
    • TMS Trimethylsilyl
    • Tf Triflate
    • Tof-MS Time of Flight Mass Spectrometry
    • Ts Tosylate
    • v/v volume/volume
    • wt/v weight/volume

DETAILED DESCRIPTION OF THE DISCLOSURE

The 5- and 6-membered heterocyclic compounds of Formula (I), (II) or (III) may be prepared from multi-step organic synthesis routes from commercially available starting materials by one skilled in the art of organic synthesis using established organic synthesis procedures.

Compounds of the disclosure of Formula (I), (II) or (III) in which X=phenyl, heteroaryl or heterocycloalkyl are as described previously and thus having general Formula XIII may be prepared generally as depicted in Scheme 1.

Compounds of the disclosure of Formula (I), (II) or (III) in which X=phenyl, heteroaryl or heterocycloalkyl are as described previously and thus having general Formula XXIII may be prepared generally as depicted in Scheme 2

Compounds of the disclosure of Formulas (I), (II) or (II) in which X— aryl, phenyl or heteroaryl are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 3.

Compounds of the disclosure of Formulas (I), (II) or (III) in which X=heterocycloalkyl are as described previously and thus having general Formula XLIII may be prepared generally as depicted in Scheme 4:

Compounds of the disclosure of Formulas (I), (II) or (III) in which X=aryl, phenyl, heteroaryl or heterocycloalkyl are as described previously and thus having general Formula LI may be prepared generally as depicted in Scheme 5.

Compounds of the disclosure of Formulas (I), (II) or (III) in which X=phenyl or heteroaryl are as described previously and thus having general Formula LXIII may be prepared generally as depicted in Scheme 6.

Reactive groups not involved in the above processes can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley-Interscience) known to those of ordinary skill in the art. Presently preferred protecting groups include methyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, Cbz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety

Experimental Procedures HPLC Conditions Condition-A: Column: Hypersil BDS C8 250×4.6 mm, 5 um (SHCL06E001) Mobile Phase AcN (A): 0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-B: Column: Zobrax SB-C18 250×4.6 mm, Sum Mobile Phase AcN (A): 0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-C: Column: Targa C-18 250×4.6 mm, Sum Mobile Phase AcN (A): 0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-D: Column: Targa C18 250×4.6 mm, Sum (SHCL-12) Mobile Phase AcN (A): 5M Ammonium Acetate in Water (B).

Flow rate: 1.0 ml/min (Gradient

Condition-E: Column: Higgins-C18 250×4.6 mm, 5 um Mobile Phase AcN (A): 0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-F: Column: Chiralpak AD

Mobile Phase: n-Hexane:Ethanol (50:50)
Flow rate: 0.6 ml/min (Gradient)

Condition-G: Column: Venusil C8, 250×4.6 mm, 5 um. Mobile Phase: AcN (A): 0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-H: Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water (A): AcN (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-I: Column: Acquity BEH-C18, (50×2.1 mm, 1.7 um.) Mobile Phase AcN (B)

Flow rate: 0.5 ml/min (Gradient)

Condition-J: Column: Zobrax C18, (150×4.6 mm, 5 um.) Mobile Phase AcN (A): 0.1% TFA in Water (B).

Flow rate: 11.0 ml/min (Gradient)

Synthesis of 3-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H-one (Example 1094) Methyl 3-hydroxy-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate

To a 0° C. stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (1.0 g, 3.1 mmol) in methanol (10 mL). NaOMe (0.185 g, 3.42 mmol) was added slowly. After stirring for 10 minutes, isonicotinaldehyde (0.367 g, 3.42 mmol) was then added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then quenched with cold water; volatiles were concentrated in vacuo and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-hydroxy-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate (1.02 g, 85%) as a solid.

Methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate

To a stirred solution of 3-hydroxy-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate (0.5 g, 1.2 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.024 g, 2.4 mmol) at 0° C. The reaction mixture was stirred at RT for 3 h, quenched with a saturated NaHCO3 solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate (0.4 g, 80%) as a solid.

3-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H)-one (Example 1094)

To a stirred solution of methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate (100 mg, 0.24 mmol) in ethanol (0.5 mL), NH2OH—HCl (0.083 g, 1.2 mmol) and TEA (0.101 mL, 0.72 mmol) were added to the mixture dropwise. The reaction mixture was then refluxed for 16 h and then concentrated in vacuo to obtain the crude product. The crude material was washed with water and EtOAc to afford 3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H)-one (30 mg, 31%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.68-8.61 (m, 2H), 8.42-8.38 (m, 1H), 8.02-7.94 (m, 2H), 7.79-7.74 (m, 1H), 7.69-7.64 (m, 1H), 7.62-7.58 (m, 1H), 7.42-7.38 (m, 2H), 7.19-7.14 (m, 2H), 7.01-6.92 (m, 2H), 5.38 (s, 2H), 3.59 (s, 1H). MS: M+H: m/z=396.1. HPLC: 91%, (Condition-B).

Synthesis of 5-(Pyridin-4-yl)-4-(4-quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one (Example 1096) 5-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one (Example 1096

To a stirred solution of methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate (0.2 g, 0.48 mmol) in ethanol (5 mL), NH2N1—H2.H2O (0.12 g, 2.42 mmol) and TEA (0.146 g, 1.45 mmol) were added dropwise at RT. The reaction mixture was then refluxed for 16 h and then concentrated in vacuo to obtain crude product. The crude material was washed with water (5 mL) and ether (5 mL) to afford 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one (70 mg, 37%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 9.12 (bs, 1H), 8.38 (d, J=7.2 Hz, 2H), 8.02-7.96 (m, 3H), 7.76 (t, J=7.6 Hz, 2H), 7.64-7.56 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.21 (s, 1H). MS: M+H: m/z=395.1 and HPLC: 80%, (Condition-C).

Synthesis of 2-methyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one (Example 1097) 2-Methyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2)-one (Example 1097)

Following the procedure for the preparation of 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one using methyl hydrazine provided the title compound. Yield: 15%. 1H NMR (500 MHz, d6-DMSO): δ 8.44-8.36 (m, 2H), 8.04-7.96 (m, 2H), 7.82-7.74 (m, 2H), 7.72-7.56 (m, 2H), 7.38-7.22 (m, 1H), 7.18-7.12 (m, 2H), 7.10-7.06 (m, 1H), 7.01-6.98 (m, 2H), 5.36 (s, 2H), 3.69 (s, 1H), 3.59 (s, 3H). MS: M+H: m/z=409.1.

Synthesis of 4-(Pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 1098) 2-Bromo-1-(pyridin-4-yl)ethanone hydrobromide

To a stirred solution of 1-(pyridin-4-yl)ethanone (10 g, 0.08 mol) in CCl4 (150 mL) Br2 (3.99 mL, 0.02 mol) was added dropwise at 0° C. The reaction mixture was then refluxed for 1 h, filtered and dried in vacuo to afford 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (22 g, 94%) as a solid.

Ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (150 mL) were added K2CO3 (23 g, 0.16 mol) and 2-(chloromethyl)quinoline (14.2 g, 0.06 mol) under an inert atmosphere. The reaction mixture was then heated at 80° C. for 16 h, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (19 g, 95%) as an oil.

2-(4-(Quinolin-2-ylmethoxy)phenyl)acetic acid

To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (20 g, 0.05 mol) in MeOH (200 mL), a solution of KOH (12.6 g, 0.22 mol) in water (50 mL) was added dropwise and the reaction mixture was stirred for 1 h at RT. The methanolw as then removed and the reaction mixture was washed with EtOAc (2×100 mL) and acidified to pH˜3 with 1 N HCl at 0° C. The precipitated solid was then filtered and dried to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (15 g, 92%) as a white solid.

2-Oxo-2-(pyridin-3-yl)ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 0.006 mol) in acetonitrile (200 mL) were added TEA (1.74 mL, 0.01 mol), and 2-bromo-1-(pyridin-3-yl)ethanone (3.42 g, 0.017 mol) under an inert atmosphere. The reaction mixture was then stirred at RT for 16 h, concentrated in vacuo and the residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2-oxo-2-(pyridin-3-yl)ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 54%) as a solid.

4-(Pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(51)-one (Example 1098)

To a 0° C. solution of 2-oxo-2-(pyridin-3-yl)ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl) acetate (200 mg, 0.48 mmol) in DMF (5 mL) was added NaH (58 mg, 1.21 mmol). The reaction mixture was then stirred at RT for 1 h, quenched with ice, and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (10 mg, 5%) as a solid.

1H NMR (500 MHz, d6-DMSO): δ 8.41 (d, J=7.2 Hz, 1H), 8.04-7.96 (m, 2H), 7.82-7.76 (m, 2H), 7.70-7.58 (m, 3H), 7.20-7.12 (m, 3H), 7.02-6.96 (m, 3H), 5.35 (s, 2H), 3.52 (s, 2H). MS: M+H: m/z=395.2 and HPLC: 89%, (Condition-C).

Synthesis of 4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 37), Route A 2-(4-(Benzyloxy)phenyl)acetic acid

To a stirred solution of ethyl 2-(4-(benzyloxy)phenyl)acetate (20 g, 0.07 mol) in EtOH (300 mL) was added a solution of KOH (20.7 g, 0.37 mol) in water (100 mL) at RT. The reaction mixture was then stirred for additional 1 h at RT and then concentrated in vacuo. The residue was acidified to pH˜2 using 2 N HCl and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-(4-(benzyloxy)phenyl)acetic acid (19 g, 98%) as a solid.

2-Bromo-1-(pyridin-4-yl)ethanone hydrobromide

To a stirred solution of 1-(pyridin-4-yl)ethanone (10 g, 0.08 mol) in CCl4 (150 mL), Br2 (3.99 mL, 0.02 mol) was added dropwise at 0° C. The reaction mixture was then refluxed for 1 h, filtered, and dried in vacuo to afford 2-bromo-1-(pyridin-4-yl)ethanone hydro bromide (22 g, 94%) as a solid.

2-Oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate

To a 10° C. stirred solution of 2-(4-(benzyloxy)phenyl)acetic acid (5.0 g, 0.02 mol) in MeOH (50 mL) was added a solution of potassium tert-butoxide (2.43 g, 0.02 mol) in MeOH (50 mL) under an inert atmosphere. The reaction mixture was stirred for 1 h, concentrated in vacuo and the residue was dissolved in DMF (30 mL). Potassium tert-butoxide (3.6 g, 0.03 mmol) was then added followed by 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (10.3 g, 0.05 mol), and the reaction mixture at RT. The reaction mixture was then stirred for an additional 16 h at RT, quenched with water, stirred for an additional 10 min and the precipitated solid was filtered. The crude solid was dissolved in EtOAc (200 mL) and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to afford 2-oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate (3.6 g, 48%) as a solid.

3-(4-(Benzyloxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one

To a stirred solution of 2-oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate (1.8 g, 0.004 mol) in acetonitrile (50 mL) was added triethylamine (10 mL, 0.07 mol) under an inert atmosphere. The reaction mixture was then refluxed for 2 h, concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude product. The crude material was purified via silica gel column chromatography to afford 3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (140 mg, 8%).

3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one

A mixture of 3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (1.0 g, 0.002 mol) in 33% HBr/AcOH (50 mL) was refluxed for 3 h. The reaction mixture was quenched with a saturated NaHCO3 solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one (0.7 g, 95%).

4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 37)

To a stirred solution of 3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one (700 mg, 2.76 mmol) in DMF (10 mL) was added K2CO3 (763.6 mg, 5.5 mmol) followed by 2-(chloromethyl)quinoline (711 mg, 3.32 mmol). The reaction mixture was then heated at 80° C. for 2 h, quenched with cold water, and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (190 mg, 19%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.61 (d, J=7.7 Hz, 2H), 8.42 (d, J=7.1 Hz, 1H), 8.04-7.96 (m, 2H), 7.81-7.76 (m, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.44-7.36 (m, 4H), 7.11 (d, J=7.2 Hz, 2H), 5.40 (s, 2H), 5.34 (s, 2H). MS: M+H: m/z=395.1 and HPLC: 95%, (Condition-H).

Synthesis of 4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 37), Route B Ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a stirred solution of compound ethyl 2-(4-hydroxyphenyl)acetate (30 g, 0.16 mol) in acetonitrile (300 mL) was added K2CO3 (114.9 g, 0.83 mol) and 2-(chloromethyl) quinoline (42.7 g, 0.19 mol) at RT. The reaction mixture was refluxed for 16 h, filtered and the resulting solid residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (50 g, 93%) as a solid.

2-(4-(Quinolin-2-ylmethoxy)phenyl)acetic acid

To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (8 g, 0.02 mol) in MeOH: THF (300 mL; 1:1) was added LiOH.H2O (5.21 g, 0.124 mol). The reaction mixture was stirred at RT for 1 h and then concentrated in vacuo to obtain the crude compound. The crude material was acidified with HCl (1N), filtered and dried in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (7.0 g, 95%) as a solid.

4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 37)

To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (3.0 g, 0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (2.86 g, 0.01 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 1 h and then cooled to 0° C. DBU (46.6 g, 0.03 mol) was then added and the reaction mixture was stirred for 2 h at 0° C. and quenched with HCl (1 N). The aqueous layer was basified with a NaHCO3 solution and extracted with DCM (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 25% EtOAc in hexanes to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (600 mg, 15%) as a solid.

Synthesis of 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 94) (Z)-4-Hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide

A solution of 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 0.002 mol) and MeNH2 in MeOH (25 mL) was refluxed for 1 h. The reaction mixture was concentrated in vacuo to afford (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-cnamide (920 mg, 86%) as a solid.

1-Methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 94)

To a 0° C. solution of (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide (430 mg, 1.01 mmol) in 1:1 ether:DCM (20 mL), PBr3 (0.114 mL, 1.21 mol) was added. The reaction mixture was stirred at RT for 2 h, diluted with DCM and basified with a NaHCO3 solution. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (350 mg, 85%) as a solid. 1H NMR (500 MHz, CD3OD): δ 8.81 (d, J=7.8 Hz, 2H), 8.24-8.19 (m, 2H), 8.11-7.94 (m, 3H), 7.85-7.80 (m, 1H), 7.59 (d, J=7.2 Hz, 2H), 7.44 (s, 2H), 7.21 (d, J=7.2 Hz, 2H), 5.61 (s, 2H), 3.38 (s, 2H), 3.09 (s, 3H). MS: M+H: m/z=408.2. HPLC: 89%, (Condition-B).

Synthesis of 4-morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 1085) 2-((4-Bromophenoxy)methyl)quinoline

To a stirred solution of 4-bromophenol (10 g, 0.057 mol) and 2-(chloro methyl)quinoline (15.4 g, 0.063 mol) in AcN (25 mL) was added K2CO3 (24 g, 0.17 mol). The reaction mixture was refluxed for 3 h, filtered and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain 2-((4-bromophenoxy)methyl)quinoline (9 g, 50%) as a solid.

2-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline

To a stirred solution of 2-((4-bromophenoxy)methyl)quinoline (3 g, 0.008 mol) in dioxane (20 mL) was added bispinacolato diborane (2.7 g, 0.010 mol) followed by potassium acetate (2.59 g, 0.026 mol) at room temperature under a N2 atmosphere. The reaction mixture was stirred for 10 minutes and then P(Cy)3 (0.18 g, 0.65 mmol) followed by Pd(dba)2 (0.32 g, 0.35 mmol) were added to reaction mixture. The reaction mixture was then refluxed for 1 h, diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-((4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl) quinoline (2.5 g, 74%) as a solid.

3,4-Dibromofuran-2(5H)-one

To a stirred solution of 3,4-dibromo-5-hydroxyfuran-2(5H)-one (3.0 g, 0.011 mol) in MeOH (27 mL) was added NaBH4 (660 mg, 0.017 mol) at 0° C. under a N2 atmosphere. The reaction mixture was stirred for 30 minutes and then a solution of H2SO4 (1.8 g) in MeOH (9 mL) was added. The reaction mixture was stirred for an additional 1 h, concentrated in vacuo and the residue was dissolved in DCM (100 mL). The organic layer was then washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 3,4-dibromofuran-2(5H)-one (2.6 g, 93%) as a solid.

3-Bromo-4-morpholinofuran-2(5H)-one

To a stirred solution of 3,4-dibromofuran-2(5H)-one (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3 (1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) at room temperature under a N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 3-bromo-4-morpholinofuran-2(5H)-one (0.87 g, 85%) as a solid.

4-Morpholino-3-4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 1085)

To a stirred solution of 3-bromo-4-morpholinofuran-2(5H)-one (300 mg, 1.20 mmol) in 2:1 toluene/H2O (8 mL) were added 2-((4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (480 mg, 1.33 mmol), Cs2CO3 (1.54 g, 4.23 mmol) and Pd(dppf)Cl2 (197.5 mg, 0.24 mmol). The reaction mixture was then refluxed for 4 h, filtered and the filtrate was partitioned between water and EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 4-morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (50 mg, 10%) as a solid. 1H NMR (500 MHz, ds-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.04-7.96 (m, 2H), 7.82-7.76 (m, 1H), 7.70-7.67 (m, 1H), 7.65-7.59 (m, 1H), 7.17 (d, J=7.2 Hz, 2H), 7.05 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 4.91 (s, 2H), 3.60 (bs, 4H), 3.19 (bs, 4H). MS: M+H: m/z=403.1; M+Na: m/z=425.2 HPLC: 90%, (Condition-J).

Synthesis of 3-(4-methoxyphenyl)-4-(4-(2-(quinolin-2-yl)ethyl)phenyl)furan-2(5H)-one (Example 14) Ethyl 2-(4-methoxyphenyl)acetate

To a solution of ethyl 2-(4-hydroxyphenyl)acetate (15 g, 0.09 mmol) in acetonitrile (100 mL) were added anhydrous K2CO3 (27.23 g, 0.19 mol) followed by Me2SO4 (14.94 g, 0.11 mol) at RT. The reaction mixture was then refluxed for 5 h, filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (300 mL). The organic layer was then washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-methoxyphenyl)acetate (16 g, 84%) as a solid.

2-(4-Methoxyphenyl)acetic acid

To a solution of ethyl 2-(4-methoxyphenyl)acetate (5.0 g, 0.025 mol) in 2:2:1 MeOH:

THF: H2O (50 mL) was added LiOH.H2O (5.14 g, 0.128 mol). The reaction mixture was stirred at RT for 16 h and concentrated in vacuo to obtain the crude product. The crude material was acidified with HCl (IN) to pH 2 and then the product was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (4.05 g, 94%) as a solid.

1-(4-(Benzyloxy)phenyl)ethanone

To a solution of 1-(4-hydroxyphenyl)ethanone (10 g, 0.07 mol) in DMF (15 mL), were added anhydrous K2CO3 (20.3 g, 0.14 mol) and benzyl chloride (11.16 g, 0.08 mmol). The reaction mixture was then stirred at RT for 16 h, quenched with ice, and a solid was precipitated. The obtained solid residue was filtered and dried in vacuo to afford 1-(4-(benzyloxy)phenyl)ethanone (14.7 g, 89%) as a solid.

1-(4-(Benzyloxy)phenyl)-3-phenylpropan-1-one

To a solution of 1-(4-(benzyloxy)phenyl)ethanone (5.0 g, 0.02 mol) in MeOH (120 mL) was added a solution of Br2 (4.22 g, 0.026 mol) in MeOH (13 mL). The reaction mixture was stirred at RT for 3 h and then concentrated in vacuo. The residue was then treated with HCl (1N, 20 mL), quenched with ice, and the resulting solid precipitate was filtered and dried in vacuo to afford 1-(4-(benzyloxy)phenyl)-3-phenylpropan-1-one (6 g, 89%) as a white solid.

2-(4-(Benzyloxy)phenyl)-2-oxoethyl 2-(4-methoxyphenyl)acetate

To a stirred solution of 2-(4-methoxyphenyl)acetic acid (3 g, 0.01 mol) in acetonitrile (60 mL) were added TEA (16.5 mL, 0.129 mol) and 1-(4-(benzyloxy)phenyl)-3-phenylpropan-1-one (6.6 g, 0.02 mol). The reaction mixture was stirred at RT for 16 h, concentrated in vacuo and the resulting residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-(benzyloxy)phenyl)-2-oxoethyl 2-(4-methoxyphenyl)acetate (5 g, 71%) as a brown solid.

4-(4-(Benzyloxy)phenyl)-3-(4-methoxyphenyl)furan-2(5H)-one

To a 0° C. solution of 2-(4-(benzyloxy)phenyl)-2-oxo-ethyl 2-(4-methoxyphenyl)acetate (3.0 g, 0.007 mol) in DMF (20 mL) was added NaH (0.96 g, 0.01 mol). The reaction mixture was stirred at RT for 30 minutes and quenched with ice to obtain a solid precipitate. The solid precipitate was filtered and dried in vacuo to afford 4-(4-(benzyloxy)phenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (2.4 g, 84%) as a solid.

4-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one

To a 0° C. solution of 4-(4-(benzyloxy)phenyl)-3-(4-methoxyphenyl) furan-2(5H)-one (1.5 g, 0.004 mol) in MeOH (50 mL) was added Pd(OH)2 (150 mg, 1.068 mol) under an inert atmosphere. The reaction mixture was then stirred under a hydrogen atmosphere for 2 h at RT, filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (900 mg, 81%) as a solid.

3-(4-Methoxyphenyl)-4-(4-(2-(quinolin-2-yl)ethyl)phenyl)furan-2(5H)-one (Example 14)

To a stirred solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (280 mg, 0.99 mol) in DMF (5 mL) were added K2CO3 (274 mg, 1.98 mol) and 2-(chloromethyl)quinoline (255 mg, 1.19 mol) at RT. The reaction mixture was then heated at 80° C. for 3 h, quenched with ice and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 20% ethyl acetate in hexanes to afford 3-(4-methoxyphenyl)-4-(4-(2-(quinolin-2-yl)ethyl)phenyl)furan-2(5H)-one (50 mg, 12%) as a yellow solid.

1H NMR (500 MHz, d6-DMSO): δ 8.41 (d, J=7.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.78 (t, J=7.6 Hz, 1H), 7.68-7.52 (m, 1H), 7.23 (d, J=7.2 Hz, 2H), 7.25 (d, J=7.6 Hz, 2H), 7.10 (d, J=7.6 Hz, 2H), 6.98 (d, J=7.2 Hz, 2H), 5.40 (s, 2H), 5.25 (s, 2H), 3.79 (s, 3H). MS: M+H: m/z=424.2. HPLC: 97%, (Condition-H).

Synthesis of 3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one (Example 1095) 2,6-Dimethylpyridine 1-oxide

To a 0° C. solution of 2,6-dimethylpyridine (1.0 g, 0.009 mol) in CHCl3 (25 mL) was added mCPBA (3.17 g, 0.01 mol). The reaction mixture was then stirred for 12 h at RT, quenched with a saturated Na2CO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford 2,6-dimethylpyridine 1-oxide (980 mg, 85%) as a solid.

(6-Methylpyridin-2-yl)methyl acetate

A solution of 2,6-dimethylpyridine 1-oxide (980 mg, 0.79 mmol) in acetic anhydride (5 mL) was refluxed for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 20% ethyl acetate in hexanes to afford (6-methylpyridin-2-yl)methyl acetate (1.0 g) as a solid.

(6-Methylpyridin-2-yl)methanol hydrochloride

A solution of (6-methylpyridin-2-yl)methyl acetate (1.0 g) in concentrated HCl (3 mL) was refluxed for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude product. The crude material was azeotroped with toluene, and the residue obtained was filtered and dried in vacuo to afford (6-methylpyridin-2-yl)methanol hydrochloride (811 mg) as a solid.

2-(Chloromethyl)-6-methylpyridine

A solution of (6-methylpyridin-2-yl)methanol hydrochloride (1.0 g, 0.008 mol) in SOCl2 (3 mL) was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude product. The crude material was azeotroped with toluene and the resulting residue was filtered and dried in vacuo to afford 2-(chloromethyl)-6-methylpyridine (800 mg, 63%) as a light brown solid.

3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one (Example 1095)

To a solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (300 mg, 1.06 mmol) in DMF (10 mL) were added K2CO3 (294 mg, 2.12 mmol), 2-(chloromethyl)-6-methylpyridine (225 mg, 1.59 mol) at RT. The reaction mixture was then heated at 80° C. for 16 h, quenched with ice and then extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one (10 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=7.2 Hz, 1H), 7.79 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.38-7.27 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.99-6.92 (m, 2H), 5.41 (s, 2H), 5.33 (s, 2H), 2.79 (s, 3H). MS: M+H: m/z=388.2.

Synthesis of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (Example 54) 2-Bromo-1-(3-chloro-4-methoxyphenyl)ethanone

To a solution of 1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 5.42 mmol) in MeOH (29.5 mL) was added a solution of bromine (0.33 mL, 6.50 mmol) in MeOH (10 mL) at RT. The reaction mixture was then stirred for 2 h, quenched with ice and extracted with DCM (2×20 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 70%) as solid.

2-(3-chloro-4-methoxyphenyl)-2-oxoethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (1.0 g, 5.42 mmol) in acetonitrile (20 mL) were added Et3N (5.54 mL, 43.4 mmol) and 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.07 g, 3.65 mmol) under an inert atmosphere. The reaction mixture was then stirred at RT for 1 h and concentrated in vacuo to obtain the crude product. The crude material was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(3-chloro-4-methoxyphenyl)-2-oxoethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 29%) as a solid.

4-(3-Chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 54)

To a 0° C. solution of 2-(3-chloro-4-methoxyphenyl)-2-oxo-ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 1.58 mmol) in DMF (10 mL) was added NaH (190 mg, 3.95 mmol). The reaction mixture was then stirred at RT for 1 h, quenched with ice and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (40 mg, 6%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42-8.38 (m, 1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.66 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m, 1H), 7.29-7.20 (m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.85 (s, 3H). MS: M+H: m/z=458.1. HPLC: 93%, (Condition-H).

Synthesis of 4-3-fluoro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (Example 53) 4-(3-fluoro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 53)

Following the procedures for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone provided the title compound. 1H NMR (500 MHz, d6-DMSO): δ 8.42-8.38 (m, 1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.66 (d, J=8.2 Hz, 1H); 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m, 1H), 7.29-7.20 (m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.85 (s, 3H). MS: M+H: m/z=442.2 and HPLC: 92%, (Condition-J).

Synthesis of 4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 59) 4-(4-Methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 59)

Following the procedure for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(4-methoxyphenyl)ethanone provided the title compound. 1H NMR (500 MHz, CDCl3): δ 8.86-8.78 (m, 2H), 8.21 (d, J=7.8 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.58-7.50 (m, 1H), 7.39 (d, J=7.2 Hz, 2H), 7.29-7.21 (m, 1H), 7.02 (d, J=7.4 Hz, 2H), 6.92 (d, J=7.4 Hz, 2H), 5.41 (s, 2H), 5.05 (s, 2H), 3.92 (s, 3H). MS: M+H: m/z=424.2; M+Na: m/z=446.1. HPLC: 90%, (Condition-C).

Synthesis of 4-(4-methoxyphenyl)-1-methy-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 125) 4-(4-Methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 125)

A stirred solution of 4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (500 mg, 1.18 mmol) in 2N methanolic MeNH2 (50 mL) was refluxed for 3 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 4N HCl in dioxane The reaction mixture was refluxed for 16 h, then basified with aqueous NaHCO3 solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (150 mg, 29%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.39 (m, 1H), 8.04-7.98 (m, 2H), 7.82-7.56 (m, 3H), 7.18-7.09 (m, 4H), 7.04 (d, J=: 7.2 Hz, 2H), 6.82 (d, J=7.2 Hz, 2H), 5.39 (s, 2H), 4.38 (s, 2H), 3.78 (s, 3H), 2.99 (s, 3H). MS: M+H: m/z=437.1; M+Na: m/z=459.2; M+K: m/z=475.2 and HPLC: 87%, (Condition-B).

Synthesis of 2-methoxy-5-(5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl)benzonitrile (Example 55)

5-(2-bromoacetyl)-2-methoxybenzonitrile may be prepared by the following scheme.

2-Methoxy-5-(5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl)benzonitrile (Example 55)

Following the procedure for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one- using 5-(2-bromoacetyl)-2-methoxybenzonitrile provided the title compound. 1H NMR (500 MHz, d6-DMSO): δ 8.32-8.28 (m, 1H), 8.06-7.95 (m, 2H), 7.81-7.76 (m, 2H), 7.62-7.56 (m, 1H), 7.49-7.39 (m, 2H), 7.26-7.18 (m, 3H), 7.12-7.05 (m, 2H), 5.41 (s, 2H), 5.33 (s, 2H), 3.89 (s, 3H). MS: M+H: m/z=449.0. HPLC: 91%. (Condition-H).

Synthesis of 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (Example 1099) Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a 0° C. solution of ethyl 2-(4-hydroxyphenyl)acetate (5.0 g, 0.02 mol) in THF (100 mL) was added NCS (4.45 g, 0.03 mol). The reaction mixture was then stirred at RT for 16 h and then extracted with EtOAc (2×200 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (5 g, 84%) as a solid.

Ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate

To a solution of compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (2.0 g, 0.009 mol) in DMF (10 mL) was added K2CO3 (3.8 g, 0.02 mol) at RT. The reaction mixture was stirred for 10 minutes and then 2-(chloromethyl)quinoline (1.2 g, 0.19 mol) was added. The reaction mixture was refluxed for 16 h, quenched with ice water and filtered. The residue that was obtained was extracted with DCM (2×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 45%) as a solid.

2-(3-Chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid

To a solution of ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.0 g, 0.02 mol) in 1:1 MeOH:THF (20 mL) was added LiOH.H2O (1.76 g, 0.008 mol). The reaction mixture was then stirred at RT for 16 h and then concentrated in vacuo to obtain the crude product. The crude material was diluted with water and adjusted to pH 4 using 1N HCl. The mixture was then filtered and the residue was dried in vacuo to afford 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (800 mg, 86%) as a solid.

3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (Example 1099)

To a stirred solution of 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (6.0 g, 0.01 mol) in acetonitrile (50 mL) were added TEA (2.58 mL, 0.02 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (6.16 g, 0.02 mol) at RT wider an inert atmosphere. The reaction mixture was stirred for 30 minutes, cooled to 0° C., and then DBU (5.5 mL, 0.03 mol) was added. The reaction was stirred for an additional 15 minutes and then quenched with HCl (1 N) and extracted with DCM (2×300 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (500 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64 (d, J=7.8 Hz, 2H), 8.50-8.44 (m, 1H), 8.04-7.98 (m, 2H), 7.8 (t, J=7.2 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.38-7.32 (m, 3H), 7.26-7.22 (m, 1H), 5.55 (s, 2H), 5.38 (s, 2H). MS: M+H: m/z=429.1. HPLC: 90%, (Condition-I).

Tables

In the following tables of examples, if a specific example contains a single value in the column “R1a and R1b”, then both R1a and R1b (if present) are taken to be this value. If this column contains multiple values separated by a comma, the first value is taken to be R1a and the second to be R1b. In the following tables, if a specific example contains multiple instances of R2, they will be separated by commas in the table (e.g. Me, Me or Et, Me). If the R2 column contains a value “-group-” e.g. “-cyclopropyl-”, then both R2 values are taken together to be a spiro ring.

In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (I):

Ex. # HET X Y Z R1a, R1b R2 R3 R4 R7   1 A1  4-pyridinyl OCH2 2-quinoline — — H H —   2 A1  4-pyridinyl OCH2 2-benzimidazole — — H H —   3 A1  4-pyridinyl OCH2 2-tetrahydroisoquinoline — — H H —   4 A1  4-pyridinyl OCH2 2-pyridinyl — — H H —   5 A1  4-pyridinyl OCH2 2-benzoxazole — — H H —   6 A1  4-pyridinyl OCH2 2-benzthiazole — — H H —   7 A1  4-pyridinyl OCH2 2-quinoxaline — — H H —   8 A1  4-pyridinyl OCH2 2-naphthyridine — — H H —   9 A1  4-pyridinyl OCH2 2-quinazoline — — H H —  10 A1  3-pyridinyl OCH2 2-quinoline — — H H —  11 A1  3,4-diOMe—Ph OCH2 2-quinoline — — H H —  12 A1  3-Me-4-pyridinyl OCH2 2-quinoline — — H H —  13 A1  3-OMe-4-pyridinyl OCH2 2-quinoline — — H H —  14 A1  4-OMe-phenyl OCH2 2-quinoline — — H H —  15 A1  4-pyridinyl CH2O 2-quinoline — — H H —  16 A2  4-pyridinyl OCH2 2-quinoline — — H H H  17 A2  4-pyridinyl OCH2 2-benzimidazole — — H H Me  18 A2  4-pyridinyl OCH2 2-tetrahydroisoquinoline — — H H Me  19 A2  4-pyridinyl OCH2 2-pyridinyl — — H H Me  20 A2  4-pyridinyl OCH2 2-benzoxazole — — H H Me  21 A2  4-pyridinyl OCH2 2-benzthiozole — — H H Me  22 A2  4-pyridinyl OCH2 2-quinoxaline — — H H Me  23 A2  4-pyridinyl OCH2 2-naphthyridine — — H H Me  24 A2  4-pyridinyl OCH2 2-quinazoline — — H H Me  25 A2  3-pyridinyl OCH2 2-quinoline — — H H H  26 A2  3,4-diOMe—Ph OCH2 2-quinoline — — H H H  27 A2  3-Me-4-pyridinyl OCH2 2-quinoline — — H H H  28 A2  3-OMe-4-pyridinyl OCH2 2-quinoline — — H H H  29 A2  4-OMe-phenyl OCH2 2-quinoline — — H H H  30 A2  4-pyridinyl OCH2 2-quinoline — — H H Me  31 A2  4-pyridinyl CH2O 2-quinoline — — H H H  32 A2  4-pyridinyl CH2O 2-quinoline — — H H Me  33 A3  4-pyridinyl OCH2 2-quinoline — — — — H  34 A3  4-pyridinyl CH2O 2-quinoline — — — — H  35 A6  4-pyridinyl OCH2 2-quinoline H, — — — — H  36 A6  4-pyridinyl CH2O 2-quinoline H, — — — — H  37 A7  4-pyridinyl OCH2 2-quinoline — — H H —  38 A7  4-pyridinyl OCH2 2-tetrahydroisoquinoline — — H H —  39 A7  4-pyridinyl OCH2 2-pyridinyl — — H H —  40 A7  4-pyridinyl OCH2 2-benzoxazole — — H H —  41 A7  4-pyridinyl OCH2 2-benzthiazole — — H H —  42 A7  4-pyridinyl OCH2 2-quinoxaline — — H H —  43 A7  4-pyridinyl OCH2 2-naphthyridine — — H H —  44 A7  4-pyridinyl OCH2 2-quinazoline — — H H —  45 A7  4-pyridinyl CH2O 2-quinoline — — H H —  46 A7  4-pyramidinyl OCH2 2-quinoline — — H H —  47 A7  4-pyrazolyl OCH2 2-quinoline — — H H —  48 A7  5-pyridin-2(1H)-onyl OCH2 2-quinoline — — H H —  49 A7  4-pyridin-2(1H)-onyl OCH2 2-quinoline — — H H —  50 A7  4-pyridazinyl OCH2 2-quinoline — — H H —  51 A7  3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H —  52 A7  4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H —  53 A7  3-F,4-OMe phenyl OCH2 2-quinoline — — H H —  54 A7  3-Cl,4-OMe phenyl OCH2 2-quinoline — — H H —  55 A7  3-CN,4-OMe phenyl OCH2 2-quinoline — — H H —  56 A7  3-OMe,4-F phenyl OCH2 2-quinoline — — H H —  57 A7  3-OMe,4-Cl phenyl OCH2 2-quinoline — — H H —  58 A7  3-OMe,4-CN phenyl OCH2 2-quinoline — — H H —  59 A7  OCH2 2-quinoline — — H H —  60 A7  OCH2 2-quinoline — — H H —  61 A7  OCH2 2-quinoline — — H H —  62 A7  OCH2 2-quinoline — — H H —  63 A7  OCH2 2-quinoline — — H H —  64 A7  OCH2 2-quinoline — — H H —  65 A7  OCH2 2-quinoline — — H H —  66 A7  OCH2 2-quinoline — — H H —  67 A7  OCH2 2-quinoline — — H H —  68 A7  OCH2 2-quinoline — — H H —  69 A7  OCH2 2-quinoline — — H H —  70 A7  OCH2 2-quinoline — — H H —  71 A7  OCH2 2-quinoline — — H H —  72 A7  OCH2 2-quinoline — — H H —  73 A7  OCH2 2-quinoline — — H H —  74 A7  OCH2 2-quinoline — — H H —  75 A7  OCH2 2-quinoline — — H H —  76 A7  OCH2 2-quinoline — — H H —  77 A7  OCH2 2-quinoline — — H H —  78 A7  OCH2 2-quinoline — — H H —  79 A7  OCH2 2-quinoline — — H H —  80 A7  OCH2 2-quinoline — — H H —  81 A7  OCH2 2-quinoline — — H H —  82 A7  OCH2 2-quinoline — — H H —  83 A7  OCH2 2-quinoline — — H H —  84 A7  OCH2 2-quinoline — — H H —  85 A8  4-pyridinyl OCH2 2-quinoline — — H H H  86 A8  4-pyridinyl OCH2 2-benzimidazole — — H H Me  87 A8  4-pyridinyl OCH2 2-tetrahydroisoquinoline — — H H Me  88 A8  4-pyridinyl OCH2 2-pyridinyl — — H H Me  89 A8  4-pyridinyl OCH2 2-benzoxazole — — H H Me  90 A8  4-pyridinyl OCH2 2-benzthiazole — — H H Me  91 A8  4-pyridinyl OCH2 2-quinoxaline — — H H Me  92 A8  4-pyridinyl OCH2 2-naphthyridine — — H H Me  93 A8  4-pyridinyl OCH2 2-quinazoline — — H H Me  94 A8  4-pyridinyl OCH2 2-quinoline — — H H Me  95 A8  4-pyridinyl CH2O 2-quinoline — — H H H  96 A8  4-pyridinyl CH2O 2-quinoline — — H H Me  97 A8  4-pyridinyl OCH2 2-quinoline — — H H cyclopropyl  98 A8  4-pyridinyl OCH2 2-quinoline — — H H —CH2CF3  99 A8  OCH2 2-quinoline — — H H H  100 A8  OCH2 2-quinoline — — H H H  101 A8  OCH2 2-quinoline — — H H H  102 A8  OCH2 2-quinoline — — H H H  103 A8  OCH2 2-quinoline — — H H H  104 A8  OCH2 2-quinoline — — H H H  105 A8  OCH2 2-quinoline — — H H H  106 A8  OCH2 2-quinoline — — H H H  107 A8  OCH2 2-quinoline — — H H H  108 A8  OCH2 2-quinoline — — H H H  109 A8  OCH2 2-quinoline — — H H H  110 A8  OCH2 2-quinoline — — H H H  111 A8  OCH2 2-quinoline — — H H H  112 A8  OCH2 2-quinoline — — H H H  113 A8  OCH2 2-quinoline — — H H H  114 A8  OCH2 2-quinoline — — H H H  115 A8  OCH2 2-quinoline — — H H H  116 A8  OCH2 2-quinoline — — H H H  117 A8  OCH2 2-quinoline — — H H H  118 A8  OCH2 2-quinoline — — H H H  119 A8  OCH2 2-quinoline — — H H H  120 A8  OCH2 2-quinoline — — H H H  121 A8  OCH2 2-quinoline — — H H H  122 A8  OCH2 2-quinoline — — H H H  123 A8  OCH2 2-quinoline — — H H H  124 A8  OCH2 2-quinoline — — H H H  125 A8  OCH2 2-quinoline — — H H Me  126 A8  OCH2 2-quinoline — — H H Me  127 A8  OCH2 2-quinoline — — H H Me  128 A8  OCH2 2-quinoline — — H H Me  129 A8  OCH2 2-quinoline — — H H Me  130 A8  OCH2 2-quinoline — — H H Me  131 A8  OCH2 2-quinoline — — H H Me  132 A8  OCH2 2-quinoline — — H H Me  133 A8  OCH2 2-quinoline — — H H Me  134 A8  OCH2 2-quinoline — — H H Me  135 A8  OCH2 2-quinoline — — H H Me  136 A8  OCH2 2-quinoline — — H H Me  137 A8  OCH2 2-quinoline — — H H Me  138 A8  OCH2 2-quinoline — — H H Me  139 A8  OCH2 2-quinoline — — H H Me  140 A8  OCH2 2-quinoline — — H H Me  141 A8  OCH2 2-quinoline — — H H Me  142 A8  OCH2 2-quinoline — — H H Me  143 A8  OCH2 2-quinoline — — H H Me  144 A8  OCH2 2-quinoline — — H H Me  145 A8  OCH2 2-quinoline — — H H Me  146 A8  OCH2 2-quinoline — — H H Me  147 A8  OCH2 2-quinoline — — H H Me  148 A8  OCH2 2-quinoline — — H H Me  149 A8  OCH2 2-quinoline — — H H Me  150 A8  OCH2 2-quinoline — — H H Me  151 A10 4-pyridinyl OCH2 2-quinoline H, — — — — —  153 A11 4-pyridinyl OCH2 2-quinoline H, — — — — —  154 A11 4-pyridinyl CH2O 2-quinoline H, — — — — —  155 A12 4-pyridinyl OCH2 2-quinoline H, — — — — —  156 A12 4-pyridinyl CH2O 2-quinoline H, — — — — —  157 A13 4-pyridinyl OCH2 2-quinoline H, H — — — —  158 A13 4-pyridinyl CH2O 2-quinoline H, H — — — —  159 A14 4-pyridinyl OCH2 2-quinoline H, H — — — —  160 A14 4-pyridinyl CH2O 2-quinoline H, H — — — —  161 A14 4-pyridinyl CH2O 2-quinoline H, Me — — — —  162 A15 4-pyridinyl OCH2 2-quinoline H, — — — — —  163 A15 4-pyridinyl CH2O 2-quinoline H, — — — — —  164 A25 4-pyridinyl OCH2 2-quinoline — H — — —  165 A29 OCH2 2-quinoline — H, H — — —  166 A29 OCH2 2-quinoline — H, H — — —  167 A29 OCH2 2-quinoline — H, H — — —  168 A29 OCH2 2-quinoline — H, H — — —  169 A29 OCH2 2-quinoline — H, H — — —  170 A29 OCH2 2-quinoline — H, H — — —  171 A29 OCH2 2-quinoline — H, H — — —  172 A29 OCH2 2-quinoline — H, H — — —  173 A29 OCH2 2-quinoline — H, H — — —  174 A29 OCH2 2-quinoline — H, H — — —  175 A29 OCH2 2-quinoline — H, H — — —  176 A29 OCH2 2-quinoline — H, H — — —  177 A29 OCH2 2-quinoline — H, H — — —  178 A29 OCH2 2-quinoline — H, H — — —  179 A29 OCH2 2-quinoline — H, H — — —  180 A29 OCH2 2-quinoline — H, H — — —  181 A29 OCH2 2-quinoline — H, H — — —  182 A29 OCH2 2-quinoline — H, H — — —  183 A29 OCH2 2-quinoline — H, H — — —  184 A29 OCH2 2-quinoline — H, H — — —  185 A29 OCH2 2-quinoline — H, H — — —  186 A29 OCH2 2-quinoline — H, H — — —  187 A29 OCH2 2-quinoline — H, H — — —  188 A29 OCH2 2-quinoline — H, H — — —  189 A29 OCH2 2-quinoline — H, H — — —  190 A29 OCH2 2-quinoline — H, H — — —  191 A29 OCH2 2-quinoline — H, H — — —  192 A29 OCH2 2-quinoline — H, H — — —  193 A29 OCH2 2-quinoline — H, H — — —  194 A29 OCH2 2-quinoline — H, H — — —  195 A29 OCH2 2-quinoline — H, H — — —  196 A29 OCH2 2-quinoline — H, H — — —  197 A29 OCH2 2-quinoline — H, H — — —  198 A29 OCH2 2-quinoline — H, H — — —  199 A29 OCH2 2-quinoline — H, H — — —  200 A29 OCH2 2-quinoline — H, H — — —  201 A29 OCH2 2-quinoline — H, H — — —  202 A29 OCH2 2-quinoline — H, H — — —  203 A29 OCH2 2-quinoline — H, H — — —  204 A29 OCH2 2-quinoline — H, H — — —  205 A29 OCH2 2-quinoline — H, H — — —  206 A29 OCH2 2-quinoline — H, H — — —  207 A29 OCH2 2-quinoline — H, H — — —  208 A29 OCH2 2-quinoline — H, H — — —  209 A29 OCH2 2-quinoline — H, H — — —  210 A29 OCH2 2-quinoline — H, H — — —  211 A29 OCH2 2-quinoline — H, H — — —  212 A29 OCH2 — H, H — — —  213 A29 OCH2 — H, H — — —  214 A29 OCH2 — H, H — — —  215 A29 OCH2 — H, H — — —  216 A29 OCH2 — H, H — — —  217 A29 OCH2 — H, H — — —  218 A29 OCH2 — H, H — — —  219 A29 OCH2 — H, H — — —  220 A29 OCH2 — H, H — — —  221 A29 OCH2 — H, H — — —  222 A29 OCH2 — H, H — — —  223 A29 OCH2 — H, H — — —  224 A29 OCH2 — H, H — — —  225 A29 OCH2 — H, H — — —  226 A29 OCH2 — H, H — — —  227 A29 OCH2 — H, H — — —  228 A29 OCH2 — H, H — — —  229 A29 OCH2 — H, H — — —  230 A29 OCH2 — H, H — — —  231 A29 OCH2 — H, H — — —  232 A29 OCH2 — H, H — — —  233 A29 OCH2 — H, H — — —  234 A29 OCH2 — H, H — — —  235 A29 OCH2 — H, H — — —  236 A29 OCH2 — H, H — — —  237 A29 OCH2 — H, H — — —  238 A29 OCH2 — H, H — — —  239 A29 OCH2 — H, H — — —  240 A29 OCH2 — H, H — — —  241 A29 OCH2 — H, H — — —  242 A29 OCH2 — H, H — — —  243 A29 OCH2 — H, H — — —  244 A29 OCH2 — H, H — — —  245 A29 OCH2 — H, H — — —  246 A29 OCH2 — H, H — — —  247 A29 OCH2 — H, H — — —  248 A29 OCH2 — H, H — — —  249 A29 OCH2 — H, H — — —  250 A29 OCH2 — H, H — — —  251 A29 OCH2 — H, H — — —  252 A29 OCH2 — H, H — — —  253 A29 OCH2 — H, H — — —  254 A29 OCH2 — H, H — — —  255 A29 OCH2 — H, H — — —  256 A29 OCH2 — H, H — — —  257 A29 OCH2 — H, H — — —  258 A30 OCH2 2-quinoline — H, H — — H  259 A30 OCH2 2-quinoline — H, H — — H  260 A30 OCH2 2-quinoline — H, H — — H  261 A30 OCH2 2-quinoline — H, H — — H  262 A30 OCH2 2-quinoline — H, H — — H  263 A30 OCH2 2-quinoline — H, H — — H  264 A30 OCH2 2-quinoline — H, H — — H  265 A30 OCH2 2-quinoline — H, H — — H  266 A30 OCH2 2-quinoline — H, H — — H  267 A30 OCH2 2-quinoline — H, H — — H  268 A30 OCH2 2-quinoline — H, H — — H  269 A30 OCH2 2-quinoline — H, H — — H  270 A30 OCH2 2-quinoline — H, H — — H  271 A30 OCH2 2-quinoline — H, H — — H  272 A30 OCH2 2-quinoline — H, H — — H  273 A30 OCH2 2-quinoline — H, H — — H  274 A30 OCH2 2-quinoline — H, H — — H  275 A30 OCH2 2-quinoline — H, H — — H  276 A30 OCH2 2-quinoline — H, H — — H  277 A30 OCH2 2-quinoline — H, H — — H  278 A30 OCH2 2-quinoline — H, H — — H  279 A30 OCH2 2-quinoline — H, H — — H  280 A30 OCH2 2-quinoline — H, H — — H  281 A30 OCH2 2-quinoline — H, H — — H  282 A30 OCH2 2-quinoline — H, H — — Me  283 A30 OCH2 2-quinoline — H, H — — Me  284 A30 OCH2 2-quinoline — H, H — — Me  285 A30 OCH2 2-quinoline — H, H — — Me  286 A30 OCH2 2-quinoline — H, H — — Me  287 A30 OCH2 2-quinoline — H, H — — Me  288 A30 OCH2 2-quinoline — H, H — — Me  289 A30 OCH2 2-quinoline — H, H — — Me  290 A30 OCH2 2-quinoline — H, H — — Me  291 A30 OCH2 2-quinoline — H, H — — Me  292 A30 OCH2 2-quinoline — H, H — — Me  293 A30 OCH2 2-quinoline — H, H — — Me  294 A30 OCH2 2-quinoline — H, H — — Me  295 A30 OCH2 2-quinoline — H, H — — Me  296 A30 OCH2 2-quinoline — H, H — — Me  297 A30 OCH2 2-quinoline — H, H — — Me  298 A30 OCH2 2-quinoline — H, H — — Me  299 A30 OCH2 2-quinoline — H, H — — Me  300 A30 OCH2 2-quinoline — H, H — — Me  301 A30 OCH2 2-quinoline — H, H — — Me  302 A30 OCH2 2-quinoline — H, H — — Me  303 A30 OCH2 2-quinoline — H, H — — Me  304 A30 OCH2 2-quinoline — H, H — — Me  305 A30 OCH2 2-quinoline — H, H — — Me  306 A31 4-pyridinyl OCH2 2-quinoline — H, H — — —  307 A31 OCH2 2-quinoline — H, H — — —  308 A31 OCH2 2-quinoline — H, H — — —  309 A31 OCH2 2-quinoline — H, H — — —  310 A31 OCH2 2-quinoline — H, H — — —  311 A31 OCH2 2-quinoline — H, H — — —  312 A31 OCH2 2-quinoline — H, H — — —  313 A31 OCH2 2-quinoline — H, H — — —  314 A31 OCH2 2-quinoline — H, H — — —  315 A31 OCH2 2-quinoline — H, H — — —  316 A31 OCH2 2-quinoline — H, H — — —  317 A31 OCH2 2-quinoline — H, H — — —  318 A31 OCH2 2-quinoline — H, H — — —  319 A31 OCH2 2-quinoline — H, H — — —  320 A31 OCH2 2-quinoline — H, H — — —  321 A31 OCH2 2-quinoline — H, H — — —  322 A31 OCH2 2-quinoline — H, H — — —  323 A31 OCH2 2-quinoline — H, H — — —  324 A31 OCH2 2-quinoline — H, H — — —  325 A31 OCH2 2-quinoline — H, H — — —  326 A31 OCH2 2-quinoline — H, H — — —  327 A31 OCH2 2-quinoline — H, H — — —  328 A31 OCH2 2-quinoline — H, H — — —  329 A31 OCH2 2-quinoline — H, H — — —  330 A31 OCH2 2-quinoline — H, H — — —  331 A31 OCH2 2-quinoline — H, H — — —  332 A31 OCH2 2-quinoline — H, H — — —  333 A31 OCH2 2-quinoline — H, H — — —  334 A31 OCH2 2-quinoline — H, H — — —  335 A31 OCH2 2-quinoline — H, H — — —  336 A31 OCH2 2-quinoline — H, H — — —  337 A31 OCH2 2-quinoline — H, H — — —  338 A31 OCH2 2-quinoline — H, H — — —  339 A31 OCH2 2-quinoline — H, H — — —  340 A31 OCH2 2-quinoline — H, H — — —  341 A31 OCH2 2-quinoline — H, H — — —  342 A31 OCH2 2-quinoline — H, H — — —  343 A31 OCH2 2-quinoline — H, H — — —  344 A31 OCH2 2-quinoline — H, H — — —  345 A31 OCH2 2-quinoline — H, H — — —  346 A31 OCH2 2-quinoline — H, H — — —  347 A31 OCH2 2-quinoline — H, H — — —  348 A31 OCH2 2-quinoline — H, H — — —  349 A31 OCH2 2-quinoline — H, H — — —  350 A31 OCH2 2-quinoline — H, H — — —  351 A31 OCH2 2-quinoline — H, H — — —  352 A31 OCH2 2-quinoline — H, H — — —  353 A31 OCH2 2-quinoline — H, H — — —  354 A31 OCH2 — H, H — — —  355 A31 OCH2 — H, H — — —  356 A31 OCH2 — H, H — — —  357 A31 OCH2 — H, H — — —  358 A31 OCH2 — H, H — — —  359 A31 OCH2 — H, H — — —  360 A31 OCH2 — H, H — — —  361 A31 OCH2 — H, H — — —  362 A31 OCH2 — H, H — — —  363 A31 OCH2 — H, H — — —  364 A31 OCH2 — H, H — — —  365 A31 OCH2 — H, H — — —  366 A31 OCH2 — H, H — — —  367 A31 OCH2 — H, H — — —  368 A31 OCH2 — H, H — — —  369 A31 OCH2 — H, H — — —  370 A31 OCH2 — H, H — — —  371 A31 OCH2 — H, H — — —  372 A31 OCH2 — H, H — — —  373 A31 OCH2 — H, H — — —  374 A31 OCH2 — H, H — — —  375 A31 OCH2 — H, H — — —  376 A31 OCH2 — H, H — — —  377 A31 OCH2 — H, H — — —  378 A31 OCH2 — H, H — — —  379 A31 OCH2 — H, H — — —  380 A31 OCH2 — H, H — — —  381 A31 OCH2 — H, H — — —  382 A31 OCH2 — H, H — — —  383 A31 OCH2 — H, H — — —  384 A31 OCH2 — H, H — — —  385 A31 OCH2 — H, H — — —  386 A31 OCH2 — H, H — — —  387 A31 OCH2 — H, H — — —  388 A31 OCH2 — H, H — — —  389 A31 OCH2 — H, H — — —  390 A31 OCH2 — H, H — — —  391 A31 OCH2 — H, H — — —  392 A31 OCH2 — H, H — — —  393 A31 OCH2 — H, H — — —  394 A31 OCH2 — H, H — — —  395 A31 OCH2 — H, H — — —  396 A31 OCH2 — H, H — — —  397 A31 OCH2 — H, H — — —  398 A31 OCH2 — H, H — — —  399 A31 OCH2 — H, H — — —  400 A31 OCH2 — H, H — — —  401 A31 OCH2 — H, H — — —  402 A31 OCH2 — H, H — — —  403 A31 OCH2 — H, H — — —  404 A31 OCH2 — H, H — — —  405 A31 OCH2 — H, H — — —  406 A31 OCH2 — H, H — — —  407 A31 OCH2 — H, H — — —  408 A31 OCH2 — H, H — — —  409 A31 OCH2 — H, H — — —  410 A31 OCH2 — H, H — — —  411 A31 OCH2 — H, H — — —  412 A31 OCH2 — H, H — — —  413 A31 OCH2 — H, H — — —  414 A31 OCH2 — H, H — — —  415 A31 OCH2 — H, H — — —  416 A31 OCH2 — H, H — — —  417 A31 OCH2 — H, H — — —  418 A31 OCH2 — H, H — — —  419 A31 OCH2 — H, H — — —  420 A31 OCH2 — H, H — — —  421 A31 OCH2 — H, H — — —  422 A31 OCH2 — H, H — — — 1085 A7  OCH2 2-quinoline — — H H — 1086 A7  OCH2 2-quinoline — — H H — 1087 A7  OCH2 2-quinoline — — H H — 1088 A8  OCH2 2-quinoline — — H H H 1089 A8  OCH2 2-quinoline — — H H H 1090 A8  OCH2 2-quinoline — — H H H 1091 A8  OCH2 2-quinoline — — H H Me 1092 A8  OCH2 2-quinoline — — H H Me 1093 A8  OCH2 2-quinoline — — H H Me 1094 A16 OCH2 2-quinoline H — — — — 1095 A1  OCH2 — — H H — 1096 A18 OCH2 2-quinoline H, H — — — — 1097 A18 OCH2 2-quinoline Me, H — — — — 1098 A7  OCH2 2-quinoline — — H H — 1100 A13 4-pyridinyl OCH2 2-quinoline Me, H — — — — 1101 A14 4-pyridinyl OCH2 2-quinoline Me, H — — — —

In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (II):

Ex. # HET W X Y Z R1a, R1b R2 R3 R4 R7 423 A1  Cl 4-pyridinyl OCH2 2-quinoline — — H H — 424 A1  Cl 4-OMe-phenyl OCH2 2-quinoline — — H H — 425 A1  Cl 4-pyrazolyl OCH2 2-quinoline — — H H — 426 A1  C1 3-(1-methyl- OCH2 2-quinoline — — H H — 1H-pyrazolyl) 427 A1  Cl 4-(1-methyl- OCH2 2-quinoline — — H H — 1H-pyrazolyl) 428 A1  Cl OCH2 2-quinoline — — H H — 429 A1  Cl OCH2 2-quinoline — — H H — 430 A1  Cl OCH2 2-quinoline — — H H — 431 A1  Cl OCH2 2-quinoline — — H H — 432 A1  Cl OCH2 2-quinoline — — H H — 433 A1  Cl OCH2 2-quinoline — — H H — 434 A1  Cl OCH2 2-quinoline — — H H — 435 A1  Cl OCH2 2-quinoline — — H H — 436 A2  Cl 4-pyridinyl OCH2 2-quinoline — — H H H 437 A2  Cl 4-pyridinyl OCH2 2-quinoline — — H H Me 439 A2  Cl 4-OMe-phenyl OCH2 2-quinoline — — H H H 440 A2  Cl 4-OMe-phenyl OCH2 2-quinoline — — H H Me 442 A2  Cl 4-pyrazolyl OCH2 2-quinoline — — H H H 443 A2  Cl 4-pyrazolyl OCH2 2-quinoline — — H H Me 445 A2  Cl 3-(1-methyl- OCH2 2-quinoline — — H H H 1H-pyrazolyl) 446 A2  Cl 3-(1-methyl- OCH2 2-quinoline — — H H Me 1H-pyrazolyl) 448 A2  Cl 4-(1-methyl- OCH2 2-quinoline — — H H H 1H-pyrazolyl) 449 A2  Cl 4-(1-methyl- OCH2 2-quinoline — — H H Me 1H-pyrazolyl) 450 A2  Cl 4-(1-methyl- OCH2 2-quinoline — — Me Me H 1H-pyrazolyl) 451 A2  Cl OCH2 2-quinoline — — H H H 452 A2  Cl OCH2 2-quinoline — — H H Me 454 A2  Cl OCH2 2-quinoline — — H H H 455 A2  Cl OCH2 2-quinoline — — H H Me 457 A2  Cl OCH2 2-quinoline — — H H H 458 A2  Cl OCH2 2-quinoline — — H H Me 460 A2  Cl OCH2 2-quinoline — — H H H 461 A2  Cl OCH2 2-quinoline — — H H Me 463 A2  Cl OCH2 2-quinoline — — H H H 464 A2  Cl OCH2 2-quinoline — — H H Me 466 A2  Cl OCH2 2-quinoline — — H H H 467 A2  Cl OCH2 2-quinoline — — H H Me 469 A2  Cl OCH2 2-quinoline — — H H H 470 A2  Cl OCH2 2-quinoline — — H H Me 472 A2  Cl OCH2 2-quinoline — — H H H 473 A2  Cl OCH2 2-quinoline — — H H Me 475 A6  Cl 4-pyridinyl OCH2 2-quinoline H, — — — — H 476 A6  Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — H 477 A6  Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — H 478 A6  Cl 3-(1-methyl- OCH2 2-quinoline H, — — — — H 1H-pyrazolyl) 479 A6  Cl 4-(1-methyl- OCH2 2-quinoline H, — — — — H 1H-pyrazolyl) 480 A6  Cl OCH2 2-quinoline H, — — — — H 481 A6  Cl OCH2 2-quinoline H, — — — — H 482 A6  Cl OCH2 2-quinoline H, — — — — H 483 A6  Cl OCH2 2-quinoline H, — — — — H 484 A6  Cl OCH2 2-quinoline H, — — — — H 485 A6  Cl OCH2 2-quinoline H, — — — — H 486 A6  Cl OCH2 2-quinoline H, — — — — H 487 A6  Cl OCH2 2-quinoline H, — — — — H 488 A11 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — — 489 A11 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 490 A11 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — — 491 A11 Cl 3-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 492 A11 Cl 4-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 493 A11 Cl OCH2 2-quinoline H, — — — — — 494 A11 Cl OCH2 2-quinoline H, — — — — — 495 A11 Cl OCH2 2-quinoline H, — — — — — 496 A11 Cl OCH2 2-quinoline H, — — — — — 497 A11 Cl OCH2 2-quinoline H, — — — — — 498 A11 Cl OCH2 2-quinoline H, — — — — — 499 A11 Cl OCH2 2-quinoline H, — — — — — 500 A11 Cl OCH2 2-quinoline H, — — — — — 501 A12 C1 4-pyridinyl OCH2 2-quinoline H, — — — — — 502 A12 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 503 A12 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — — 504 A12 Cl 3-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 505 A12 Cl 4-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 506 A12 Cl OCH2 2-quinoline H, — — — — — 507 A12 Cl OCH2 2-quinoline H, — — — — — 508 A12 Cl OCH2 2-quinoline H, — — — — — 509 A12 Cl OCH2 2-quinoline H, — — — — — 510 A12 Cl OCH2 2-quinoline H, — — — — — 511 A12 Cl OCH2 2-quinoline H, — — — — — 512 A12 Cl OCH2 2-quinoline H, — — — — — 513 A12 Cl OCH2 2-quinoline H, — — — — — 514 A13 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — — 515 A13 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 516 A13 Cl 4-pyrazolyl OCH2 2-quinoline H, H — — — — 517 A13 Cl 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 518 A13 Cl 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 519 A13 Cl OCH2 2-quinoline H, H — — — — 520 A13 Cl OCH2 2-quinoline H, H — — — — 521 A13 Cl OCH2 2-quinoline H, H — — — — 522 A13 Cl OCH2 2-quinoline H, H — — — — 523 A13 Cl OCH2 2-quinoline H, H — — — — 524 A13 Cl OCH2 2-quinoline H, H — — — — 525 A13 Cl OCH2 2-quinoline H, H — — — — 526 A13 Cl OCH2 2-quinoline H, H — — — — 527 A14 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — — 528 A14 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 529 A14 Cl 4-pyrazolyl OCH2 2-quinoline H, H — — — — 530 A14 Cl 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 531 A14 Cl 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 532 A14 Cl OCH2 2-quinoline H, H — — — — 533 A14 Cl OCH2 2-quinoline H, H — — — — 534 A14 Cl OCH2 2-quinoline H, H — — — — 535 A14 Cl OCH2 2-quinoline H, H — — — — 536 A14 Cl OCH2 2-quinoline H, H — — — — 537 A14 Cl OCH2 2-quinoline H, H — — — — 538 A14 Cl OCH2 2-quinoline H, H — — — — 539 A14 Cl OCH2 2-quinoline H, H — — — — 540 A15 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — — 541 A15 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 542 A15 Cl 4-pyrazolyl OCH2 2-quinoline H, H — — — — 543 A15 Cl 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 544 A15 Cl 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 545 A15 Cl OCH2 2-quinoline H, H — — — — 546 A15 Cl OCH2 2-quinoline H, H — — — — 547 A15 Cl OCH2 2-quinoline H, H — — — — 548 A15 Cl OCH2 2-quinoline H, H — — — — 549 A15 Cl OCH2 2-quinoline H, H — — — — 550 A15 Cl OCH2 2-quinoline H, H — — — — 551 A15 Cl OCH2 2-quinoline H, H — — — — 552 A15 Cl OCH2 2-quinoline H, H — — — — 553 A19 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — — 554 A19 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 555 A19 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — — 556 A19 Cl 3-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 557 A19 Cl 4-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 558 A19 Cl OCH2 2-quinoline H, — — — — — 559 A19 Cl OCH2 2-quinoline H, — — — — — 560 A19 Cl OCH2 2-quinoline H, — — — — — 561 A19 Cl OCH2 2-quinoline H, — — — — — 562 A19 Cl OCH2 2-quinoline H, — — — — — 563 A19 Cl OCH2 2-quinoline H, — — — — — 564 A19 Cl OCH2 2-quinoline H, — — — — — 565 A19 Cl OCH2 2-quinoline H, — — — — — 566 A20 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — — 567 A20 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 568 A20 Cl 4-pyrazolyl OCH2 2-quinoline H, H — — — — 569 A20 Cl 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 570 A20 Cl 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 571 A20 Cl OCH2 2-quinoline H, H — — — — 572 A20 Cl OCH2 2-quinoline H, H — — — — 573 A20 Cl OCH2 2-quinoline H, H — — — — 574 A20 Cl OCH2 2-quinoline H, H — — — — 575 A20 Cl OCH2 2-quinoline H, H — — — — 576 A20 Cl OCH2 2-quinoline H, H — — — — 577 A20 Cl OCH2 2-quinoline H, H — — — — 578 A20 Cl OCH2 2-quinoline H, H — — — — 579 A32 Cl 4-pyridinyl OCH2 2-quinoline — H, H — — H 580 A32 Cl 4-OMe-phenyl OCH2 2-quinoline — H, H — — H 581 A32 Cl 4-pyrazolyl OCH2 2-quinoline — H, H — — H 582 A32 Cl 3-(1-methyl- OCH2 2-quinoline — H, H — — H 1H-pyrazolyl) 583 A32 Cl 4-(1-methyl- OCH2 2-quinoline — H, H — — H 1H-pyrazolyl) 584 A32 Cl OCH2 2-quinoline — H, H — — H 585 A1 CN 4-pyridinyl OCH2 2-quinoline — — H H — 586 A1 CN 4-OMe-phenyl OCH2 2-quinoline — — H H — 587 A1 CN 4-pyrazolyl OCH2 2-quinoline — — H H — 588 A1 CN 3-(1-methyl- OCH2 2-quinoline — — H H — 1H-pyrazolyl) 589 A1 CN 4-(1-methyl- OCH2 2-quinoline — — H H — 1H-pyrazolyl) 590 A1 CN OCH2 2-quinoline — — H H — 591 A1 CN OCH2 2-quinoline — — H H — 592 A1 CN OCH2 2-quinoline — — H H — 593 A1 CN OCH2 2-quinoline — — H H — 594 A1 CN OCH2 2-quinoline — — H H — 595 A1 CN OCH2 2-quinoline — — H H — 596 A1 CN OCH2 2-quinoline — — H H — 597 A1 CN OCH2 2-quinoline — — H H — 598 A2 CN 4-pyridinyl OCH2 2-quinoline — — H H H 599 A2 CN 4-pyridinyl OCH2 2-quinoline — — H H Me 601 A2 CN 4-OMe-phenyl OCH2 2-quinoline — — H H H 602 A2 CN 4-OMe-phenyl OCH2 2-quinoline — — H H Me 604 A2 CN 4-pyrazolyl OCH2 2-quinoline — — H H H 605 A2 CN 4-pyrazolyl OCH2 2-quinoline — — H H Me 607 A2 CN 3-(1-methyl- OCH2 2-quinoline — — H H H 1H-pyrazolyl) 608 A2 CN 3-(1-methyl- OCH2 2-quinoline — — H H Me 1H-pyrazolyl) 610 A2 CN 4-(1-methyl- OCH2 2-quinoline — — H H H 1H-pyrazolyl) 611 A2 CN 4-(1-methyl- OCH2 2-quinoline — — H H Me 1H-pyrazolyl) 613 A2 CN OCH2 2-quinoline — — H H H 614 A2 CN OCH2 2-quinoline — — H H Me 616 A2 CN OCH2 2-quinoline — — H H H 617 A2 CN OCH2 2-quinoline — — H H Me 619 A2 CN OCH2 2-quinoline — — H H H 620 A2 CN OCH2 2-quinoline — — H H Me 622 A2 CN OCH2 2-quinoline — — H H H 623 A2 CN OCH2 2-quinoline — — H H Me 625 A2 CN OCH2 2-quinoline — — H H H 626 A2 CN OCH2 2-quinoline — — H H Me 628 A2 CN OCH2 2-quinoline — — H H H 629 A2 CN OCH2 2-quinoline — — H H Me 631 A2 CN OCH2 2-quinoline — — H H H 632 A2 CN OCH2 2-quinoline — — H H Me 634 A2 CN OCH2 2-quinoline — — H H H 635 A2 CN OCH2 2-quinoline — — H H Me 637 A6 CN 4-pyridinyl OCH2 2-quinoline H, — — — — H 638 A6 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — H 639 A6 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — H 640 A6 CN 3-(1-methyl- OCH2 2-quinoline H, — — — — H 1H-pyrazolyl) 641 A6 CN 4-(1-methyl- OCH2 2-quinoline H, — — — — H 1H-pyrazolyl) 642 A6 CN OCH2 2-quinoline H, — — — — H 643 A6 CN OCH2 2-quinoline H, — — — — H 644 A6 CN OCH2 2-quinoline H, — — — — H 645 A6 CN OCH2 2-quinoline H, — — — — H 646 A6 CN OCH2 2-quinoline H, — — — — H 647 A6 CN OCH2 2-quinoline H, — — — — H 648 A6 CN OCH2 2-quinoline H, — — — — H 649 A6 CN OCH2 2-quinoline H, — — — — H 650 A11 CN 4-pyridinyl OCH2 2-quinoline H, — — — — — 651 A11 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 652 A11 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — — 653 A11 CN 3-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 654 A11 CN 4-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 655 A11 CN OCH2 2-quinoline H, — — — — — 656 A11 CN OCH2 2-quinoline H, — — — — — 657 A11 CN OCH2 2-quinoline H, — — — — — 658 A11 CN OCH2 2-quinoline H, — — — — — 659 A11 CN OCH2 2-quinoline H, — — — — — 660 A11 CN OCH2 2-quinoline H, — — — — — 661 A11 CN OCH2 2-quinoline H, — — — — — 662 A11 CN OCH2 2-quinoline H, — — — — — 663 A12 CN 4-pyridinyl OCH2 2-quinoline H, — — — — — 664 A12 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 665 A12 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — — 666 A12 CN 3-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 667 A12 CN 4-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 668 A12 CN OCH2 2-quinoline H, — — — — — 669 A12 CN OCH2 2-quinoline H, — — — — — 670 A12 CN OCH2 2-quinoline H, — — — — — 671 A12 CN OCH2 2-quinoline H, — — — — — 672 A12 CN OCH2 2-quinoline H, — — — — — 673 A12 CN OCH2 2-quinoline H, — — — — — 674 A12 CN OCH2 2-quinoline H, — — — — — 675 A12 CN OCH2 2-quinoline H, — — — — — 676 A13 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 677 A13 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 678 A13 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 679 A13 CN 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 680 A13 CN 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 681 A13 CN OCH2 2-quinoline H, H — — — — 682 A13 CN OCH2 2-quinoline H, H — — — — 683 A13 CN OCH2 2-quinoline H, H — — — — 684 A13 CN OCH2 2-quinoline H, H — — — — 685 A13 CN OCH2 2-quinoline H, H — — — — 686 A13 CN OCH2 2-quinoline H, H — — — — 687 A13 CN OCH2 2-quinoline H, H — — — — 688 A13 CN OCH2 2-quinoline H, H — — — — 689 A14 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 690 A14 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 691 A14 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 692 A14 CN 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 693 A14 CN 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 694 A14 CN OCH2 2-quinoline H, H — — — — 695 A14 CN OCH2 2-quinoline H, H — — — — 696 A14 CN OCH2 2-quinoline H, H — — — — 697 A14 CN OCH2 2-quinoline H, H — — — — 698 A14 CN OCH2 2-quinoline H, H — — — — 699 A14 CN OCH2 2-quinoline H, H — — — — 700 A14 CN OCH2 2-quinoline H, H — — — — 701 A14 CN OCH2 2-quinoline H, H — — — — 702 A15 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 703 A15 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 704 A15 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 705 A15 CN 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 706 A15 CN 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 707 A15 CN OCH2 2-quinoline H, — — — — — 708 A15 CN OCH2 2-quinoline H, — — — — — 709 A15 CN OCH2 2-quinoline H, — — — — — 710 A15 CN OCH2 2-quinoline H, — — — — — 711 A15 CN OCH2 2-quinoline H, — — — — — 712 A15 CN OCH2 2-quinoline H, — — — — — 713 A15 CN OCH2 2-quinoline H, — — — — — 714 A15 CN OCH2 2-quinoline H, — — — — — 715 A19 CN 4-pyridinyl OCH2 2-quinoline H, — — — — — 716 A19 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 717 A19 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — — 718 A19 CN 3-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 719 A19 CN 4-(1-methyl- OCH2 2-quinoline H, — — — — — 1H-pyrazolyl) 720 A19 CN OCH2 2-quinoline H, — — — — — 721 A19 CN OCH2 2-quinoline H, — — — — — 722 A19 CN OCH2 2-quinoline H, — — — — — 723 A19 CN OCH2 2-quinoline H, — — — — — 724 A19 CN OCH2 2-quinoline H, — — — — — 725 A19 CN OCH2 2-quinoline H, — — — — — 726 A19 CN OCH2 2-quinoline H, — — — — — 727 A19 CN OCH2 2-quinoline H, — — — — — 728 A20 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 729 A20 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 730 A20 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 731 A20 CN 3-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 732 A20 CN 4-(1-methyl- OCH2 2-quinoline H, H — — — — 1H-pyrazolyl) 733 A20 CN OCH2 2-quinoline H, H — — — — 734 A20 CN OCH2 2-quinoline H, H — — — — 735 A20 CN OCH2 2-quinoline H, H — — — — 736 A20 CN OCH2 2-quinoline H, H — — — — 737 A20 CN OCH2 2-quinoline H, H — — — — 738 A20 CN OCH2 2-quinoline H, H — — — — 739 A20 CN OCH2 2-quinoline H, H — — — — 740 A20 CN OCH2 2-quinoline H, H — — — — 741 A32 CN 4-pyridinyl OCH2 2-quinoline — H, H — — H 742 A32 CN 4-OMe-phenyl OCH2 2-quinoline — H, H — — H 743 A32 CN 4-pyrazolyl OCH2 2-quinoline — H, H — — H 744 A32 CN 3-(1-methyl- OCH2 2-quinoline — H, H — — H 1H-pyrazolyl) 745 A32 CN 4-(1-methyl- OCH2 2-quinoline — H, H — — H 1H-pyrazolyl) 746 A32 CN OCH2 2-quinoline — H, H — — H 747 A32 CN OCH2 2-quinoline — H, H — — H 748 A32 CN OCH2 2-quinoline — H, H — — H 749 A32 CN OCH2 2-quinoline — H, H — — H 750 A32 CN OCH2 2-quinoline — H, H — — H 751 A32 CN OCH2 2-quinoline — H, H — — H 752 A32 CN OCH2 2-quinoline — H, H — — H 753 A32 CN OCH2 2-quinoline — H, H — — H 1102 A13 Cl 4-pyrazolyl OCH2 2-quinoline Me, H — — — — 1103 A13 Cl 3-(1-methyl- OCH2 2-quinoline Me, H — — — — 1H-pyrazolyl) 1104 A13 Cl 4-(1-methyl- OCH2 2-quinoline Me, H — — — — 1H-pyrazolyl) 1105 A13 Cl OCH2 2-quinoline Me, H — — — — 1106 A13 Cl OCH2 2-quinoline Me, H — — — — 1107 A13 Cl OCH2 2-quinoline Me, H — — — — 1108 A13 Cl OCH2 2-quinoline Me, H — — — — 1109 A13 Cl OCH2 2-quinoline Me, H — — — — 1110 A13 Cl OCH2 2-quinoline Me, H — — — — 1111 A13 Cl OCH2 2-quinoline Me, H — — — — 1112 A13 Cl OCH2 2-quinoline Me, H — — — —

In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (III):

Ex. # HET W X Y Z R1a, R1b R2 R3 R4 R7  754 A1 Cl 4-pyridinyl OCH2 2-quinoline — — H H —  755 A1 Cl 4-OMe-phenyl OCH2 2-quinoline — — H H —  756 A1 Cl 4-pyrazolyl OCH2 2-quinoline — — H H —  757 A1 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H —  758 A1 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H —  759 A1 Cl OCH2 2-quinoline — — H H —  760 A1 Cl OCH2 2-quinoline — — H H —  761 A1 Cl OCH2 2-quinoline — — H H —  762 A1 Cl OCH2 2-quinoline — — H H —  763 A1 Cl OCH2 2-quinoline — — H H —  764 A1 Cl OCH2 2-quinoline — — H H —  765 A1 Cl OCH2 2-quinoline — — H H —  766 A1 Cl OCH2 2-quinoline — — H H —  767 A2 Cl 4-pyridinyl OCH2 2-quinoline — — H H H  768 A2 Cl 4-pyridinyl OCH2 2-quinoline — — H H Me  770 A2 Cl 4-OMe-phenyl OCH2 2-quinoline — — H H H  771 A2 Cl 4-OMe-phenyl OCH2 2-quinoline — — H H Me  773 A2 Cl 4-pyrazolyl OCH2 2-quinoline — — H H H  774 A2 Cl 4-pyrazolyl OCH2 2-quinoline — — H H Me  776 A2 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H H  777 A2 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H Me  779 A2 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H H  780 A2 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H Me  782 A2 Cl OCH2 2-quinoline — — H H H  783 A2 Cl OCH2 2-quinoline — — H H Me  785 A2 Cl OCH2 2-quinoline — — H H H  786 A2 Cl OCH2 2-quinoline — — H H Me  788 A2 Cl OCH2 2-quinoline — — H H H  789 A2 Cl OCH2 2-quinoline — — H H Me  791 A2 Cl OCH2 2-quinoline — — H H H  792 A2 Cl OCH2 2-quinoline — — H H Me  794 A2 Cl OCH2 2-quinoline — — H H H  795 A2 Cl OCH2 2-quinoline — — H H Me  797 A2 Cl OCH2 2-quinoline — — H H H  798 A2 Cl OCH2 2-quinoline — — H H Me  800 A2 Cl OCH2 2-quinoline — — H H H  801 A2 Cl OCH2 2-quinoline — — H H Me  803 A2 Cl OCH2 2-quinoline — — H H H  804 A2 Cl OCH2 2-quinoline — — H H Me  806 A6 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — H  807 A6 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — H  808 A6 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — H  809 A6 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — H  810 A6 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — H  811 A6 Cl OCH2 2-quinoline H, — — — — H  812 A6 Cl OCH2 2-quinoline H, — — — — H  813 A6 Cl OCH2 2-quinoline H, — — — — H  814 A6 Cl OCH2 2-quinoline H, — — — — H  815 A6 Cl OCH2 2-quinoline H, — — — — H  816 A6 Cl OCH2 2-quinoline H, — — — — H  817 A6 Cl OCH2 2-quinoline H, — — — — H  818 A6 Cl OCH2 2-quinoline H, — — — — H  819 A11 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — —  820 A11 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — —  821 A11 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — —  822 A11 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  823 A11 Cl 4-(1-methyl-1H -pyrazolyl) OCH2 2-quinoline H, — — — — —  824 A11 Cl OCH2 2-quinoline H, — — — — —  825 A11 Cl OCH2 2-quinoline H, — — — — —  826 A11 Cl OCH2 2-quinoline H, — — — — —  827 A11 Cl OCH2 2-quinoline H, — — — — —  828 A11 Cl OCH2 2-quinoline H, — — — — —  829 A11 Cl OCH2 2-quinoline H, — — — — —  830 A11 Cl OCH2 2-quinoline H, — — — — —  831 A11 Cl OCH2 2-quinoline H, — — — — —  832 A12 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — —  833 A12 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — —  834 A12 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — —  835 A12 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  836 A12 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  837 A12 Cl OCH2 2-quinoline H, — — — — —  838 A12 Cl OCH2 2-quinoline H, — — — — —  839 A12 Cl OCH2 2-quinoline H, — — — — —  840 A12 Cl OCH2 2-quinoline H, — — — — —  841 A12 Cl OCH2 2-quinoline H, — — — — —  842 A12 Cl OCH2 2-quinoline H, — — — — —  843 A12 Cl OCH2 2-quinoline H, — — — — —  844 A12 Cl OCH2 2-quinoline H, — — — — —  845 A13 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — —  846 A13 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — —  847 A13 Cl 4-pyrazolyl OCH2 2-quinoline H — — — —  848 A13 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — —  849 A13 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — —  850 A13 Cl OCH2 2-quinoline H, H — — — —  851 A13 Cl OCH2 2-quinoline H, H — — — —  852 A13 Cl OCH2 2-quinoline H, H — — — —  853 A13 Cl OCH2 2-quinoline H, H — — — —  854 A13 Cl OCH2 2-quinoline H, H — — — —  855 A13 Cl OCH2 2-quinoline H, H — — — —  856 A13 Cl OCH2 2-quinoline H, H — — — —  857 A13 Cl OCH2 2-quinoline H, H — — — —  858 A14 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — —  859 A14 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — —  860 A14 Cl 4-pyrazolyl OCH2 2-quinoline H, H — — — —  861 A14 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — —  862 A14 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — —  863 A14 Cl OCH2 2-quinoline H, H — — — —  864 A14 Cl OCH2 2-quinoline H, H — — — —  865 A14 Cl OCH2 2-quinoline H, H — — — —  866 A14 Cl OCH2 2-quinoline H, H — — — —  867 A14 Cl OCH2 2-quinoline H, H — — — —  868 A14 Cl OCH2 2-quinoline H, H — — — —  869 A14 Cl OCH2 2-quinoline H, H — — — —  870 A14 Cl OCH2 2-quinoline H, H — — — —  871 A15 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — —  872 A15 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — —  873 A15 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — —  874 A15 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  875 A15 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  876 A15 Cl OCH2 2-quinoline H, — — — — —  877 A15 Cl OCH2 2-quinoline H, — — — — —  878 A15 Cl OCH2 2-quinoline H, — — — — —  879 A15 Cl OCH2 2-quinoline H, — — — — —  880 A15 Cl OCH2 2-quinoline H, — — — — —  881 A15 Cl OCH2 2-quinoline H, — — — — —  882 A15 Cl OCH2 2-quinoline H, — — — — —  883 A15 Cl OCH2 2-quinoline H, — — — — —  884 A19 Cl 4-pyridinyl OCH2 2-quinoline H, — — — — —  885 A19 Cl 4-OMe-phenyl OCH2 2-quinoline H, — — — — —  886 A19 Cl 4-pyrazolyl OCH2 2-quinoline H, — — — — —  887 A19 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  888 A19 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  889 A19 Cl OCH2 2-quinoline H, — — — — —  890 A19 Cl OCH2 2-quinoline H, — — — — —  891 A19 Cl OCH2 2-quinoline H, — — — — —  892 A19 Cl OCH2 2-quinoline H, — — — — —  893 A19 Cl OCH2 2-quinoline H — — — — —  894 A19 Cl OCH2 2-quinoline H, — — — — —  895 A19 Cl OCH2 2-quinoline H, — — — — —  896 A19 Cl OCH2 2-quinoline H, — — — — —  897 A20 Cl 4-pyridinyl OCH2 2-quinoline H, H — — — —  898 A20 Cl 4-OMe-phenyl OCH2 2-quinoline H, H — — — —  899 A20 Cl 4-pyrazolyl OCH2 2-quinoline H, H — — — —  900 A20 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — —  901 A20 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — —  902 A20 Cl OCH2 2-quinoline H, H — — — —  903 A20 Cl OCH2 2-quinoline H, H — — — —  904 A20 Cl OCH2 2-quinoline H, H — — — —  905 A20 Cl OCH2 2-quinoline H, H — — — —  906 A20 Cl OCH2 2-quinoline H, H — — — —  907 A20 Cl OCH2 2-quinoline H, H — — — —  908 A20 Cl OCH2 2-quinoline H, H — — — —  909 A20 Cl OCH2 2-quinoline H, H — — — —  910 A32 Cl 4-pyridinyl OCH2 2-quinoline — H, H — — H  911 A32 Cl 4-OMe-phenyl OCH2 2-quinoline — H, H — — H  912 A32 Cl 4-pyrazolyl OCH2 2-quinoline — H, H — — H  913 A32 Cl 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — H, H — — H  914 A32 Cl 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — H, H — — H  915 A32 Cl OCH2 2-quinoline — H, H — — H  916 A1 CN 4-pyridinyl OCH2 2-quinoline — — H H —  917 A1 CN 4-OMe-phenyl OCH2 2-quinoline — — H H —  918 A1 CN 4-pyrazolyl OCH2 2-quinoline — — H H —  919 A1 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H —  920 A1 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H —  921 A1 CN OCH2 2-quinoline — — H H —  922 A1 CN OCH2 2-quinoline — — H H —  923 A1 CN OCH2 2 -quinoline — — H H —  924 A1 CN OCH2 2-quinoline — — H H —  925 A1 CN OCH2 2-quinoline — — H H —  926 A1 CN OCH2 2-quinoline — — H H —  927 A1 CN OCH2 2-quinoline — — H H —  928 A1 CN OCH2 2-quinoline — — H H —  929 A2 CN 4-pyridinyl OCH2 2-quinoline — — H H H  930 A2 CN 4-pyridinyl OCH2 2-quinoline — — H H Me  932 A2 CN 4-OMe-phenyl OCH2 2-quinoline — — H H H  933 A2 CN 4-OMe-phenyl OCH2 2-quinoline — — H H Me  935 A2 CN 4-pyrazolyl OCH2 2-quinoline — — H H H  936 A2 CN 4-pyrazolyl OCH2 2-quinoline — — H H Me  938 A2 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H H  939 A2 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H Me  941 A2 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H H  942 A2 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — — H H Me  944 A2 CN OCH2 2-quinoline — — H H H  945 A2 CN OCH2 2-quinoline — — H H Me  947 A2 CN OCH2 2-quinoline — — H H H  948 A2 CN OCH2 2-quinoline — — H H Me  950 A2 CN OCH2 2-quinoline — — H H H  951 A2 CN OCH2 2-quinoline — — H H Me  953 A2 CN OCH2 2-quinoline — — H H H  954 A2 CN OCH2 2-quinoline — — H H Me  956 A2 CN OCH2 2-quinoline — — H H H  957 A2 CN OCH2 2-quinoline — — H H Me  959 A2 CN OCH2 2-quinoline — — H H H  960 A2 CN OCH2 2-quinoline — — H H Me  962 A2 CN OCH2 2-quinoline — — H H H  963 A2 CN OCH2 2-quinoline — — H H Me  965 A2 CN OCH2 2-quinoline — — H H H  966 A2 CN OCH2 2-quinoline — — H H Me  968 A6 CN 4-pyridinyl OCH2 2-quinoline H, — — — — H  969 A6 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — H  970 A6 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — H  971 AS CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — H  972 A6 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — H  973 A6 CN OCH2 2-quinoline H, — — — — H  974 A6 CN OCH2 2-quinoline H, — — — — H  975 A6 CN OCH2 2-quinoline H, — — — — H  976 A6 CN OCH2 2-quinoline H, — — — — H  977 A6 CN OCH2 2-quinoline H, — — — — H  978 A6 CN OCH2 2-quinoline H, — — — — H  979 A6 CN OCH2 2-quinoline H, — — — — H  980 A6 CN OCH2 2-quinoline H, — — — — H  981 A11 CN 4-pyridinyl OCH2 2-quinoline H, — — — — —  982 A11 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — —  983 A11 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — —  984 A11 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  985 A11 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  986 A11 CN OCH2 2-quinoline H, — — — — —  987 A11 CN OCH2 2-quinoline H, — — — —  988 A11 CN OCH2 2-quinoline H, — — — — —  989 A11 CN OCH2 2-quinoline H, — — — — —  990 A11 CN OCH2 2-quinoline H, — — — — —  991 A11 CN OCH2 2-quinoline H, — — — — —  992 A11 CN OCH2 2-quinoline H, — — — — —  993 A11 CN OCH2 2-quinoline H, — — — — —  994 A12 CN 4-pyridinyl OCH2 2-quinoline H, — — — — —  995 A12 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — —  996 A12 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — —  997 A12 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  998 A12 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — —  999 A12 CN OCH2 2-quinoline H, — — — — — 1000 A12 CN OCH2 2-quinoline H, — — — — — 1001 A12 CN OCH2 2-quinoline H, — — — — — 1002 A12 CN OCH2 2-quinoline H, — — — — — 1003 A12 CN OCH2 2-quinoline H, — — — — — 1004 A12 CN OCH2 2-quinoline H, — — — — — 1005 A12 CN OCH2 2-quinoline H, — — — — — 1006 A12 CN OCH2 2-quinoline H, — — — — — 1007 A13 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 1008 A13 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 1009 A13 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 1010 A13 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — — 1011 A13 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — — 1012 A13 CN OCH2 2-quinoline H, H — — — — 1013 A13 CN OCH2 2-quinoline H, H — — — — 1014 A13 CN OCH2 2-quinoline H, H — — — — 1015 A13 CN OCH2 2-quinoline H, H — — — — 1016 A13 CN OCH2 2-quinoline H, H — — — — 1017 A13 CN OCH2 2-quinoline H, H — — — — 1018 A13 CN OCH2 2-quinoline H, H — — — — 1019 A13 CN OCH2 2-quinoline H, H — — — — 1020 A14 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 1021 A14 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 1022 A14 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 1023 A14 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — — 1024 A14 CN 4-(1-methyl-1H-pyrozolyl) OCH2 2-quinoline H, H — — — — 1025 A14 CN OCH2 2-quinoline H, H — — — — 1026 A14 CN OCH2 2-quinoline H, H — — — — 1027 A14 CN OCH2 2-quinoline H, H — — — — 1028 A14 CN OCH2 2-quinoline H, H — — — — 1029 A14 CN OCH2 2-quinoline H, H — — — — 1030 A14 CN OCH2 2-quinoline H, H — — — — 1031 A14 CN OCH2 2-quinoline H, H — — — — 1032 A14 CN OCH2 2-quinoline H, H — — — — 1033 A15 CN 4-pyridinyl OCH2 2-quinoline H, — — — — — 1034 A15 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 1035 A15 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — — 1036 A15 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — — 1037 A15 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — — 1038 A15 CN OCH2 2-quinoline H, — — — — — 1039 A15 CN OCH2 2-quinoline H, — — — — — 1040 A15 CN OCH2 2-quinoline H, — — — — — 1041 A15 CN OCH2 2-quinoline H, — — — — — 1042 A15 CN OCH2 2-quinoline H, — — — — — 1043 A15 CN OCH2 2-quinoline H, — — — — — 1044 A15 CN OCH2 2-quinoline H, — — — — — 1045 A15 CN OCH2 2-quinoline H, — — — — — 1046 A19 CN 4-pyridinyl OCH2 2-quinoline H, — — — — — 1047 A19 CN 4-OMe-phenyl OCH2 2-quinoline H, — — — — — 1048 A19 CN 4-pyrazolyl OCH2 2-quinoline H, — — — — — 1049 A19 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — — 1050 A19 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, — — — — — 1051 A19 CN OCH2 2-quinoline H, — — — — — 1052 A19 CN OCH2 2-quinoline H, — — — — — 1053 A19 CN OCH2 2-quinoline H, — — — — — 1054 A19 CN OCH2 2-quinoline H, — — — — — 1055 A19 CN OCH2 2-quinoline H, — — — — — 1056 A19 CN OCH2 2-quinoline H, — — — — — 1057 A19 CN OCH2 2-quinoline H, — — — — — 1058 A19 CN OCH2 2-quinoline H, — — — — — 1059 A20 CN 4-pyridinyl OCH2 2-quinoline H, H — — — — 1060 A20 CN 4-OMe-phenyl OCH2 2-quinoline H, H — — — — 1061 A20 CN 4-pyrazolyl OCH2 2-quinoline H, H — — — — 1062 A20 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — — 1063 A20 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline H, H — — — — 1064 A20 CN OCH2 2-quinoline H, H — — — — 1065 A20 CN OCH2 2-quinoline H, H — — — — 1066 A20 CN OCH2 2-quinoline H, H — — — — 1067 A20 CN OCH2 2-quinoline H, H — — — — 1068 A20 CN OCH2 2-quinoline H, H — — — — 1069 A20 CN OCH2 2-quinoline H, H — — — — 1070 A20 CN OCH2 2-quinoline H, H — — — — 1071 A20 CN OCH2 2-quinoline H, H — — — — 1072 A32 CN 4-pyridinyl OCH2 2-quinoline — H, H — — H 1073 A32 CN 4-OMe-phenyl OCH2 2-quinoline — H, H — — H 1074 A32 CN 4-pyrazolyl OCH2 2-quinoline — H, H — — H 1075 A32 CN 3-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — H, H — — H 1076 A32 CN 4-(1-methyl-1H-pyrazolyl) OCH2 2-quinoline — H, H — — H 1077 A32 CN OCH2 2-quinoline — H, H — — H 1078 A32 CN OCH2 2-quinoline — H, H — — H 1079 A32 CN OCH2 2-quinoline — H, H — — H 1080 A32 CN OCH2 2-quinoline — H, H — — H 1081 A32 CN OCH2 2-quinoline — H, H — — H 1082 A32 CN OCH2 2-quinoline — H, H — — H 1083 A32 CN OCH2 2-quinoline — H, H — — H 1084 A32 CN OCH2 2-quinoline — H, H — — H 1099 A7 Cl OCH2 2-quinoline — — H H —

Dosage and Administration

The present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formulas (I), (II) and (III), a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The dosage can be an oral dosage form that is a controlled release dosage form. The oral dosage form can be a tablet or a caplet. The compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. In one embodiment, the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt.

In another embodiment, the compound can be administered parenterally, such as intravenous (IV) administration. The formulations for administration will commonly comprise a solution of the compound of the Formulas (I), (II) and (III) dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of compound of Formulas (I), (II) and (III) in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

In one embodiment, a compound of Formulas (I), (II) and (II) can be administered by introduction into the central nervous system of the subject, e.g., into the cerebrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the compound of Formulas (I), (II) and (III) dissolved in a pharmaceutically acceptable carrier. In certain aspects, the compound of Formulas (I), (II) and (III) is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, the compound of Formulas (I), (II) and (III) is introduced intraocularly, to thereby contact retinal ganglion cells.

The pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.

In one embodiment, the pharmaceutical composition comprising a compound of Formulas (I), (II) and (III) is administered into a subject intrathecally. As used herein, the term “intrathecal administration” is intended to include delivering a pharmaceutical composition comprising a compound of Formulas (I), (II) and (III) directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, the contents of which are incorporated herein by reference). The term “lumbar region” is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term “cisterna magna” is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term “cerebral ventricle” is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a compound of Formulas (I), (II) and (III) to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the compound of Formulas (I), (II) and (III) or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.

In one embodiment, the pharmaceutical composition comprising a compound of Formulas (I), (II) and (III) is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.

In yet another embodiment, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.

For oral administration, the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Pharmaceutical preparations for oral use can be obtained through combination of a compound of Formulas (I), (II) and (III) with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

The suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.

The compounds may also be presented as aqueous or liposome formulations. Aqueous suspensions can contain a compound of Formulas (I), (II) and (III) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

Oil suspensions can be formulated by suspending a compound of Formulas (I), (II) and (III) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.

The compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formulas (I), (II) and (III), such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.

Biological Examples In Vivo Methods Subjects:

Male C57BL/6J mice (Charles River; 20-25 g) were used for all assays except prepulse inhibition (PPI) which used male DBA/2N mice (Charles River, 20-25 g). For all studies, animals were housed five/cage on a 12-h light/dark cycle with food and water available ad libitum.

Conditioned Avoidance Responding:

Testing was performed in commercially available avoidance boxes (Kinder Scientific, Poway Calif.). The boxes were divided into two compartments separated by an archway. Each side of the chamber has electronic grid flooring that is equipped to administer footshocks and an overhead light. Training consisted of repeated pairings of the light (conditioned stimulus) followed by a shock (unconditioned stimulus). For each trial the light was presented for 5 sec followed by a 0.5 mA shock that would terminate if the mouse crossed to the other chamber or after 10 seconds. The intertrial interval was set to 20 seconds. Each training and test session consisted a four min habituation period followed by 30 trials. The number of avoidances (mouse crossed to other side during presentation of the light,), escapes (mouse crossed to the other side during presentation of the shock) and failures (mouse did not cross during the entire trial period) were recorded by a computer. For study inclusion an animal had to reach a criterion of at least 80% avoidances for two consecutive test sessions.

PPI:

Mice were individually placed into the test chambers (StartleMonitor, Kinder Scientific, Poway Calif.). The animals were given a five min acclimation period to the test chambers with the background noise level set to 65 decibel (dB) which remained for the entire test session. Following acclimation, four successive trials 120 dB pulse for 40 msec were presented, however these trials were not included in data analysis. The mice were then subjected to five different types of trials in random order: pulse alone (120 dB for 40 msec), no stimulus and three different prepulse+pulse trials with the prepulse set at 67, 69 or 74 dB for 20 msec followed a 100 msec later by a120 dB pulse for 40 msec. Each animal received 12 trials for each condition for a total of 60 trials with an average intertrial interval of 15 sec. Percent PPI was calculated according to the following formula: (1−(startle response to prepulse+pulse)/startle response to pulse alone))×100.

MK-801-Induced Hyperactivity:

After a 30 min acclimation to the test room mice were individually placed into test cages for a 30 min habituation period. Following habituation to test cages, baseline activity was recorded for 60 min. Mice were then briefly removed and administered test compound and placed immediately back into the test cage. At 5 min prior to test time mice were again briefly removed from test cages and administered MK-801 (0.3 mg/kg, i.p. in 0.9% saline) and then immediately placed back into test cages and activity level recorded 1 hour. Activity level was measured as distance travelled in centimeters (Ethovision tracking software, Noldus Inc. Wageningen, Netherlands).

Catalepsy:

Mice were placed on a wire mesh screen set at a 60 degree angle with their heads facing upwards and the latency to move or break stance was recorded. Animals were given three trials per time point with a 30 sec cut-off per trial.

Data Analysis:

A one-way or two-way ANOVA was used to evaluate overall differences between treatments and a Tukey's post-hoc test or Student's t-test was used to evaluate differences between treatment groups for the one-way ANOVA and a Bonferroni test was used for the two-way ANOVA. The criterion for statistical significance was set to p≦0.05.

In Vitro Methods

hPDE10A1 Enzyme Activity:

50 μl samples of serially diluted Human PDE10A1 enzyme were incubated with 50 μl of [3H]-cAMP for 20 minutes (at 37° C.). Reactions were carried out in Greiner 96 deep well 1 ml master-block. The enzyme was diluted in 20 mM Tris HCl pH7.4 and [3H]-cAMP was diluted in 10 mM MgCl2, 40 mM Tris.HCl pH 7.4. The reaction was terminated by denaturing the PDE enzyme (at 70° C.) after which [3H]-5′-AMP was converted to [3H]-adenosine by adding 25 μl snake venom nucleotidase and incubating for 10 minutes (at 37° C.). Adenosine, being neutral, was separated from charged cAMP or AMP by the addition of 200 μl Dowex resin. Samples were shaken for 20 minutes then centrifuged for 3 minutes at 2,500 r.p.m. 50 μl of supernatant was removed and added to 200 μl of MicroScint-20 in white plates (Greiner 96-well Optiplate) and shaken for 30 minutes before reading on Perkin Elmer TopCount Scintillation Counter.

hPDE10A1 Enzyme Inhibition:

To check inhibition profile 11 μl of serially diluted inhibitor was added to 50 μl of [3H]-cAMP and 50 ul of diluted Human PDE10A1 and assay was carried out as in the enzyme activity assay. Data was analysed using Prism software (GraphPad Inc). Representative compounds of this disclosure are shown in the table below. A compound with the value “A” had an IC50 value less than or equal to 50 nM. A compound with the value “B” had an IC50 value greater than 50 nM:

hPDE1 Ex Name IC50 Ba 37 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxyl)phenyl)furan-2(5H)-one A 53 4-(3-fluoro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan- A 2(5H)-one 54 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan- A 2(5H)-one 55 2-methoxy-5-(5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5- A dihydrofuran-3-yl)benzonitrile 59 4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)- A one 94 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenl)-1H- A pyrrol-2(5H)-one 125 4-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H- A pyrrol-2(5H)-one 14 3-(4-methoxyphenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)- A one 424 4-(2-chloro-4-(quinolin-2-ylmethoxy)phenyl)-3-(4-methoxyphenyl)furan- B 2(5H)-one 1085 4-morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one B 1094 3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H)-one A 1095 3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2- B yl)methoxy)phenyl)furan-2(5H)-one 1096 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)- B one 1097 2-methyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H- B pyrazol-3(2H)-one 1098 4-(pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one B 1099 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan- B 2(5H)-one

Claims

1-118. (canceled)

119. A compound of Formula (I)

or pharmaceutically acceptable salt thereof,
wherein:
HET is a heterocyclic ring having formula A7 or A29
and the left most radical is connected to the X group;
X is optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
Y is —CH2O— or —OCH2— with the rightmost radical of the Y group connected to the Z substituent;
Z is optionally substituted heteroaryl;
each R2 is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl or optionally substituted alkoxyalkyl, with the proviso that at least one R2 is hydrogen;
R3 is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl or optionally substituted alkoxyalkyl; and
R4 is hydrogen.

120. The compound claim 119, wherein Y is —CH2O— with the right most radical connected to the Z substituent; or a pharmaceutically acceptable salt thereof.

121. The compound of claim 119, wherein Y is —OCH2— with the right most radical connected to the Z substituent; or a pharmaceutically acceptable salt thereof.

122. The compound of claim 119, wherein Z is an optionally substituted heteroaryl having only 6 ring atoms or an optionally substituted heterobicyclic ring system; or a pharmaceutically acceptable salt thereof.

123. The compound of claim 119, wherein Z is an optionally substituted heteroaryl having only 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two; said ring is optionally substituted with up to 2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro;

or a pharmaceutically acceptable salt thereof.

124. The compound of claim 119, wherein Z is benzimidazolyl, quinolinyl, tetrahydroquinolyl, imidazo[1,2-a]pyridin-2-yl, tetrahydroisoquinolyl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 6-fluoroquinolyl or isoquinolinyl substituted with up to 3 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro;

or a pharmaceutically acceptable salt thereof.

125. The compound of claim 119, wherein Z is unsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof.

126. The compound of claim 119, wherein X is a heterocycloalkyl having Formula B1-B16

and
R6 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl;
or a pharmaceutically acceptable salt thereof.

127. The compound of claim 119, wherein X is optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

128. The compound of claim 119, wherein X is phenyl, restricted phenyl or pyridinyl; or a pharmaceutically acceptable salt thereof.

129. The compound of claim 119, wherein X is benzo[d]oxazoyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, 1H-benzo[d]imidazoyl, benzo[d]thiazoyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, imidazo[1,2-a]pyridinyl or imidazo[1,5-a]pyridinyl; or a pharmaceutically acceptable salt thereof.

130. The compound of claim 119, wherein HET is A29;

X is optionally substituted heteroaryl;
Y is —OCH2—; and
each R2 is independently C1-C4 alkyl;
or a pharmaceutically acceptable salt thereof.

131. The compound of claim 130, wherein X is pyridinyl;

or a pharmaceutically acceptable salt thereof.

132. The compound of claim 119, wherein HET is A29;

X is pyridinyl;
Y is —OCH2—;
Z is unsubstituted heteroaryl; and
each R2 is independently C1-C4 alkyl;
or a pharmaceutically acceptable salt thereof.

133. The compound of claim 119, wherein HET is A29;

X is pyridinyl;
Y is —OCH2—;
Z is unsubstituted heteroaryl; and
each R2 is methyl;
or a pharmaceutically acceptable salt thereof.

134. The compound of claim 119, wherein HET is A29;

X is pyridinyl;
Y is —OCH2—;
Z is a heterobicyclic ring system containing exactly 9 ring atoms; and
each R2 is independently C1-C4 alkyl;
or a pharmaceutically acceptable salt thereof.

135. The compound of claim 119, wherein HET is A29;

X is pyridinyl;
Y is —OCH2—;
Z is a heterobicyclic ring system containing exactly 9 ring atoms; and
each R2 is methyl;
or a pharmaceutically acceptable salt thereof.

136. The compound of claim 119, wherein HET is A7;

X is optionally substituted heteroaryl;
Y is —OCH2—;
R3 is C1-C4 alkyl; and
R4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

137. The compound of claim 136, wherein X is pyridinyl;

or a pharmaceutically acceptable salt thereof.

138. The compound of claim 119, wherein HET is A7;

X is pyridinyl;
Y is —OCH2—;
Z is unsubstituted heteroaryl;
R3 is C1-C4 alkyl; and
R4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

139. The compound of claim 119, wherein HET is A7;

X is pyridinyl;
Y is —OCH2—;
Z is unsubstituted heteroaryl;
R3 is methyl; and
R4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

140. The compound of claim 119, wherein HET is A7;

X is pyridinyl;
Y is —OCH2—;
Z is a heterobicyclic ring system containing exactly 9 ring atoms;
R3 is C1-C4 alkyl; and
R4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

141. The compound of claim 119, wherein HET is A7;

X is pyridinyl;
Y is —OCH2—;
Z is a heterobicyclic ring system containing exactly 9 ring atoms;
R3 is methyl; and
R4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

142. A pharmaceutical composition comprising: (i) the compound of any of claims 119-141, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient.

Patent History
Publication number: 20140038965
Type: Application
Filed: Jun 17, 2013
Publication Date: Feb 6, 2014
Applicant: EnVivo Pharmaceuticals, Inc. (Watertown, MA)
Inventors: Amy RIPKA (Reading, MA), Gideon SHAPIRO (Gainesville, FL), Richard CHESWORTH (Boston, MA)
Application Number: 13/919,516