5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS

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 (K_m=0.05 uM) and cGMP (K_m=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 V_maxfor 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 vivo (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 13, 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 stereotypes 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):

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Wherein:

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

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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-C₈alkyl, 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;

R_1ais selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl with the proviso that when R_1ais not hydrogen, R_1bis hydrogen or that when R_1bis absent, R_1amust be hydrogen;

R_1bis selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl with the proviso that when R_1bis not hydrogen, R_1ais hydrogen;

Each R₂is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl with the proviso that when two R₂are present, at least one R₂is hydrogen;

R₃and R₄are independently selected from hydrogen, C₁-C₄alkyl, CF₃and optionally substituted cycloalkyl with the proviso that at least one R₃or R₄group must be hydrogen;

R₅is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;

R₇is 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 A10.

In another embodiment, HET is Formula A11.

In another embodiment, HET is Formula A12.

In another embodiment, HET is Formula A13.

In another embodiment, HET is Formula A14.

In another embodiment, HET is Formula A15.

In another embodiment, HET is Formula A16.

In another embodiment, HET is Formula A17.

In another embodiment, HET is Formula A18.

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-C₈alkyl, 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-C₈alkyl. 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:

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wherein R₆is selected from hydrogen and C₁-C₆alkyl, C₃-C₆cycloalkyl and C₃-C₆cycloalkylalkyl, 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-C₄alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄alkoxy, CF₃, carboxyl, alkoxyalkyl, C₁-C₄cycloalkylalkoxy, 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-C₄alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄alkoxy, CF₃, carboxyl, alkoxyalkyl, C₁-C₄cycloalkylalkoxy, 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-C₄alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄alkoxy, CF₃, carboxyl, alkoxyalkyl, C₁-C₄cycloalkylalkoxy, 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-C₄alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C₁-C₄alkoxy, CF₃, amino, alkylamino, dialkylamino, thioalkyl, halogen or cyano.

In a further embodiment, X is 3-pyridinyl optionally substituted with one group selected from C₁-C₄alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C₁-C₄alkoxy, CF₃, amino, alkylamino, dialkylamino, thioalkyl, halogen or cyano.

In a further embodiment, X is 4-pyridinyl optionally substituted with one group selected from C₁-C₄alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C₁-C₄alkoxy, 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]oxadiazoyl, 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]oxadiazoyl 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, CH₂CF₃and 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 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 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, R_1ais selected from cycloalkyl and alkyl with the proviso that R_1bis hydrogen.

In another embodiment, R_1ais selected from hydrogen and alkyl with the proviso that R_1bis hydrogen when R_1ais alkyl.

In an additional embodiment, R_1ais cycloalkyl with the proviso that R_1bis hydrogen.

In another embodiment, R_1ais alkyl with the proviso that R_1bis hydrogen

In another embodiment, R_1ais fully saturated C₁-C₄alkyl with the proviso that R_1bis hydrogen

In another embodiment, R_1ais hydrogen.

In one embodiment, R_1bis selected from cycloalkyl and alkyl with the proviso that R_1ais hydrogen.

In one embodiment, R_1bis selected from hydrogen and alkyl with the proviso that R_1ais hydrogen when R_1bis alkyl.

In one embodiment, R_1bis selected from hydrogen and fully saturated C₁-C₄alkyl with the proviso that R_1ais hydrogen when R_1bis alkyl.

In another embodiment, R_1bis cycloalkyl with the proviso that R_1ais hydrogen.

In a further embodiment, R_1bis alkyl with the proviso that R_1ais hydrogen.

In another embodiment, R_1bis hydrogen.

In one embodiment, each R₂is independently selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl with the proviso that at least one R₂is hydrogen;

In another embodiment, each R₂is independently selected from hydrogen, alkyl and cycloalkyl with the proviso that at least one R₂is hydrogen;

In another embodiment, each R₂is independently selected from hydrogen and alkyl with the proviso that at least one R₂is hydrogen.

In another embodiment, each R₂is independently selected from hydrogen and fully saturated C₁-C₄alkyl with the proviso that at least one R₂is hydrogen.

In an additional embodiment, each R₂is hydrogen.

In one embodiment, R₃and R₄are independently selected from hydrogen and cycloalkyl with the proviso that at least one R₃or R₄group must be hydrogen;

in a further embodiment, R₃and R₄are independently selected from hydrogen and C₁-C₄alkyl with the proviso that at least one R₃or R₄group must be hydrogen;

In a further embodiment, R₃and R₄are hydrogen.

In one embodiment, R₅is selected from cycloalkylalkyl and alkoxyalkyl.

In an additional embodiment, R₅is selected from cycloalkyl and alkyl.

In another embodiment, R₅is cycloalkyl.

In another embodiment, R₅is alkyl.

In one embodiment n is 1.

In another embodiment n is 2.

In one embodiment, R₇is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.

In another embodiment, R₇is selected from alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.

In another embodiment, R₇is selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl.

In another embodiment, R₇is selected from alkyl, cycloalkyl and cycloalkylalkyl.

In another embodiment, R₇is selected from cycloalkyl and cycloalkylalkyl.

In another embodiment, R₇is selected from alkyl and cycloalkyl.

In another embodiment, R₇is alkyl.

In another embodiment, R₇is cycloalkyl.

In another embodiment, R₇is cycloalkylalkyl.

In a further embodiment, R₇is 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 C_1-6alkyl 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-toluene 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 conjunction 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-C₈hydrocarbon 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-C₄alkyl 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, C_x-C_yincludes all subsets, e.g., C₁-C₄includes C₁-C₂, C₂-C₄, C₁-C₃etc.

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

Alkoxy is an alkyl-O— group wherein alkyl is as defined above. C₁-C₄alkoxy 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-C₄alkyl)- 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)R_a, —OC(O)OR_a, —OC(O)NHR_a, —OC(O)N(R_a), —SR_a, —S(O)R_a, —NH₂, —NHR_a, —N(R_a)(R_b), —NHC(O)R_a, —N(R_a)C(O)R_b, —NHC(O)OR_a, —N(R_a)C(O)OR_b, —N(R_a)C(O)NH(R_b), —N(R_a)C(O)NH(R_b)₂, —C(O)NH₂, —C(O)NHR_a, —C(O)N(R_a)(R_b), —CO₂H, —CO₂R_a, —COR_awherein R_aand R_b, 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, ^tPr, ^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 R_aand R_btaken 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-C₄alkyl)-O— group wherein aryl is as defined above.

Carboxy is a CO₂H or CO₂R_cgroup wherein R_cis independently chosen from, alkyl, C₁-C₄alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, CF₃, and alkoxyalkyl, wherein alkyl is as defined above.

Cycloalkyl is a C₃-C₇cyclic 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-C₆cycloalkyloxy is the subset of cycloalkyl-O— where cycloalkyl contains 3-6 carbon atoms.

Cycloalkylalkyl is a cycloalkyl-(C₁-C₄alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.

Cycloalkylalkoxy is a cycloalkyl-(C₁-C₄alkyl)-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, pyrazolyl, 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)R_a, —OC(O)OR_a, —OC(O)NHR_a, —OC(O)N(R_a), —SR_a, —S(O)R_a, —NH₂, —NHR_a, —N(R_a)(R_b), —NHC(O)R_a, —N(R_a)C(O)R_b, —NHC(O)OR_a, —N(R_a)C(O)OR_b, —N(R_a)C(O)NH(R_b), —N(R_a)C(O)NH(R_b)₂, —C(O)NH₂, —C(O)NHR_a, —C(O)N(R_a)(R_b), —CO₂H, —CO₂R_a, —COR_awherein R_aand R_bare 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, ^tPr, ^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 R_aand R_btaken together with the atom(s) to which they are attached form a 5-6 membered ring.

Heteroarylalkyl is a heteroaryl-(C₁-C₄alkyl)- 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-C₄alkyl)-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-C₆cycloalkyloxy, 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]oxadiazoyl, 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]isothiazoyl, benzo[c]isoxazoyl, furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 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]pyridinyl, 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)₂group. 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]octanoyl, 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-C₄alkyl)- group wherein heterocycloalkyl is as defined above.

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

Heterocycloalkylalkoxy is a heterocycloalkyl-(C₁-C₄alkyl)-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)R_a, —OC(O)OR_a, —OC(O)NHR_a, —OC(O)N(R_a), —SR_a, —S(O)R_a, —NH₂, —NHR_a, —N(R_a)(R_b), —NHC(O)R_a, —N(R_a)C(O)R_b, —NHC(O)OR_a, —N(R_a)C(O)OR_b, —N(R_a)C(O)NH(R_b), —N(R_a)C(O)NH(R_b)₂, —C(O)NH₂, —C(O)NHR_a, —C(O)N(R_a)(R_b), —CO₂H, —CO₂R_a, —COR_awherein R_aand R_bare 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, ^tPr, ^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 R_aand R_btaken 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)R_a, —OC(O)OR_a, —OC(O)N(R_a), —N(R_a)(R_b), —NHC(O)R_a, —N(R_a)C(O)R_b, —NHC(O)OR_a, —N(R_a)C(O)OR_b, —C(O)N(R_a)(R_b), —COR_awherein R_aand R_bare 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, ^tPr, ^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 R_aand R_btaken 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 Hexamethyldisilazide
- LDA Lithium Di-isopropylamide
- m Multiplet
- m- eta
- 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
- PhNTf₂1,1,1-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.

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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

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Compounds of the disclosure of Formulas (I), (II) or (III) 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.

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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:

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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.

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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.

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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, 5 um
Mobile Phase: AcN (A): 0.1% TFA in Water (B).