HETEROARYL PIPERIDINE ETHER ALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR

• US 20190315708A1
• Filed: 12/18/2017
• Published: 10/17/2019
• Est. Priority Date: 12/22/2016
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: BAO, Jianming, FERGUSON, Ronald, GAO, Xiaolei, HARRISON, Scott, KNOWLES, Sandra L., LO, Michael Man-Chu, Mazzola, Jr., Robert D., Shubert, Jeffrey W.
• Granted Patent: US 11,319,298 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 498/08 Bridged systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

The present invention is directed to heteroarylpiperidine ether compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.

Claims

1. A compound of the formula I:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein wherein the group:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:

benzodioxolyl, benzoimidazolyl, benzoxazoly, benzooxazinone, benzooxazolone, benzothiazolyl, chromanyl, cyclopentapyridinyl, dihydrobenzo[1,4]dioxinyl, dihydrobenzofuranyl, dihydrobenzo[1,4]oxazinyl, dihydrofuropyridinyl, dihydroisobenzofuranyl, dihydroisoquinolinone, dihydropyranopyridinyl, dihydroimidazopyridine, dihydropyrido[1,4]oxazinyl, dihydroquinolinone, indazolyl, indanyl, indolyl, isochromanone, isobenzofuranone, isochromanyl, isoindolinyl, isoxazolyl, oxoisoindolinyl, phenyl, pyrazolopyridinyl, pyrazolyl, pyridyl, pyrrolopyridinyl, pyrimidinyl, quinolinone, quinolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and tetrahydropyranyl, which is substituted with R^1a, R^1b and R^1c.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl or pyridyl, which is substituted with R^1a, R^1b and R^1c, wherein R^1a, R^1b and R^1c are independently selected from the group consisting of

(a) hydrogen,

(b) hydroxyl,

(c) halogen,

(d) C_1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:

hydroxy, fluoro, and —

OCH₃,

(e) —

O—

C_1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of;

hydroxy, fluoro, and —

OCH₃,

(g) —

CN.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl, which is unsubstituted or substituted with —

CN.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is pyridyl, which is unsubstituted or substituted with —

OCH₃.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen and R³ is hydrogen.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from the group consisting of:

(1) methyl,

(2) ethyl,

(3) —

CHF₂,

(4) -fluoro,

(5) -chloro,

(6) -bromo,

(7) —

CN,

(8) —

(C═

O)O-methyl, and

(9) —

CH₂(C═

O)O-methyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) -fluoro, and

(5) -chloro.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R¹⁰ and R¹¹ is independently selected from the group consisting of:

(1) hydrogen,

(2) fluoro,

(3) chloro,

(4) hydroxy,

(5) —

CH₃,

(6) —

CF₃,

(7) —

CH₂OH,

(8) —

CH₂CH₂OH,

(9) —

C(CH₃)₂OH,

(10) —

S—

CH₃,

(11) —

CH₂OCH₃,

(12) cyclopropyl,

(13) —

(C═

O)O—

CH₃,

(14) —

(C═

O)O—

CH₂CH₃,

(15) —

(C═

O)—

NH-tetrahydroquinolinyl,

(16) —

(C═

O)—

NH—

CH₂-pyridyl, and

(17) —

(C═

O)—

NH—

CH₂-tetrahydroquinolinyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R¹⁰ and R¹¹ is independently selected from the group consisting of:

(1) hydrogen, and

(2) —

C_1-6alkyl, which is unsubstituted or substituted with hydroxy, methoxy, 1-3 fluoro.

13. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal comprising the step of administering at least one compound of claim 1, or a pharmaceutically acceptable salt of said compound, to a patient in need thereof in an amount effective to treat said disorder.

17. The method of claim 16, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

18. The method of claim 16, wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M4 dysfunction.

19. The method of claim 16, wherein the disorder is a psychotic disorder.

20. The method of claim 19, wherein the psychotic disorder is selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder.

21. The method of claim 16, wherein the disorder is a cognitive disorder.

22. The method of claim 21 wherein the cognitive disorder is selected from amnesia, dementia, delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington'"'"'s disease, dementia due to Parkinson'"'"'s disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer'"'"'s type, age-related cognitive decline, and mild cognitive impairment.

12. A compound which is selected from the group consisting of:

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine;

7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2H-chromen-2-one;

(4-chloro-6-(4-(3-chloro-4-methylphenoxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

(4-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol;

(4-(4-(benzo[c][1,2,5]oxadiazol-5-yloxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3-methylquinazolin-4(3H)-one;

6-(4-methoxypiperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

(4-chloro-5-methyl-6-(4-(4-(methylsulfonyl)phenoxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methylisoquinolin-1(2H)-one;

methyl 6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate;

3-(4-(3-cyanophenoxy)piperidin-1-yl)-5,6-dimethylpyridazine-4-carbonitrile;

4-chloro-2,5-dimethyl-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine;

4-chloro-6-((cis)-3-fluoro-4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine;

4-chloro-5-methyl-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine;

4-chloro-5-methyl-2-(methylthio)-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine;

4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methyl-2-(methylthio)pyrimidine;

methyl 2-(4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)pyrimidin-5-yl)acetate;

2-methoxy-4-(4-(4-methoxyphenoxy)piperidin-1-yl)pyrimidine-5-carbonitrile;

2,5-dimethyl-4-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine;

5-methyl-2-(methylthio)-4-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)chroman-4-one;

5-methyl-6-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

3-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)-3,3-difluoropiperidin-4-yl)oxy)benzonitrile

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)isobenzofuran-1(3H)-one;

(4-chloro-6-((cis)-3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one;

(4-chloro-6-(4-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

5-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazin-3-yl)-3-methyl-1,2,4-oxadiazole;

(4-chloro-5-methyl-6-(4-((1-methyl-1H-indol-5-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3,4-dihydroquinolin-2(1H)-one;

(4-chloro-5-methyl-6-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-cyclopropylisoindolin-1-one;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methylisoindolin-1-one;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinonitrile;

(4-chloro-5-methyl-6-(4-(1,2,3,4-tetrahydroquinolin-7-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one;

methyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate;

7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one;

6-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

methyl 6-((3R,4S)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate;

7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one;

(4-chloro-5-methyl-6-(4-(3-(methylsulfonyl)phenoxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

6-(((3S,4R)-1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)-2-methylisoindolin-1-one;

(4-chloro-5-methyl-6-(4-((2-methylbenzo[d]thiazol-5-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

methyl 2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate;

dimethyl 2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridine-3,5-dicarboxylate;

(4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

5-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methoxybenzonitrile

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

3-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

3-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

(4-chloro-6-((3S,4R)-3-fluoro-4-((2-methylbenzo[d]oxazol-6-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

(4-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol;

(4-chloro-6-(4-(5-fluoro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

3-((1-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

5-((1-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-1-methyl-1H-indazole 4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine;

methyl 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate

5-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-1H-indazole;

5-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-1-methyl-1H-indazole;

4-chloro-2-(methoxymethyl)-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine;

4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-2,5-dimethylpyrimidine;

5-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-1-methyl-1H-indazole;

2-((5-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)pyridin-2-yl)oxy)ethan-1-ol;

(4-chloro-6-(4-((5-chloro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

5-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methyl-2H-indazole;

5-((1-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methyl-2H-indazole;

(4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

4-(4-(4-methoxyphenoxy)piperidin-1-yl)-2,5-dimethylpyrimidine;

methyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate;

3-(((3R,4R)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile;

1-((5-((1-(2, 5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)pyridin-2-yl)oxy)-2-methylpropan-2-amine;

4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methyl-2-(methylsulfonyl)pyrimidine;

4-(4-(5-fluoro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine;

3-(((3S,4R)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile;

3-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

2,4-dichloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine;

4-chloro-2-(methoxymethyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine;

6-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-1H-indazole;

3-(((3R,4S)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-2-(methylthio)pyrimidine;

3-(((3S,4S)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile;

4-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2-(methylthio)pyrimidine-5-carbonitrile;

3-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5,6-dimethylpyridazine-4-carbonitrile;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidin-4-amine;

4-(4-(3-cyanophenoxy)piperidin-1-yl)-2-methoxypyrimidine-5-carbonitrile;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-amine;

(4-((3S,4R)-4-((1H-indazol-5-yl)oxy)-3-fluoropiperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol;

5-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzofuran-3(2H)-one;

(4-chloro-6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

(4-chloro-5-methyl-6-(4-(1,2,3,4-tetrahydroquinolin-6-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol;

(4-chloro-6-(4-((1,3-dihydroisobenzofuran-5-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

4-(4-(4-methoxyphenoxy)piperidin-1-yl)-2-(methylthio)pyrimidine-5-carbonitrile;

2-(methylthio)-4-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine-5-carbonitrile;

4-chloro-2-cyclopropyl-5-methyl-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine;

4-chloro-2-cyclopropyl-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine;

5-bromo-4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyrimidine;

(4-chloro-6-(4-((3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol;

(4-(4-((1H-indol-5-yl)oxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol;

6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)isoindolin-1-one;

6-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)isobenzofuran-1(3H)-one;

6-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)isoindolin-1-one;

6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

methyl 2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate;

3-((1-(2,5,6-Trimethylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5,6-trimethylpyrimidine;

ethyl 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate

ethyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate;

6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

pyridin-4-ylmethyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate;

(R)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyridazine-3-carboxamide;

(R)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyridazine-3-carboxamide;

6-[4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-[4-(1H-indol-5-yloxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-[4-(1H-indazol-5-yloxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

2-cyano-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,3,4-thiadiazol-2-ylmethyl)pyridazine-3-carboxamide;

5-methyl-6-(4-phenoxypiperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-[(3S,4R)-4-(3-cyanophenoxy)-3-fluoropiperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

N-bicyclo[1.1.1]pent-2-yl-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1H-1,2,3-triazol-5-ylmethyl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1H-pyrazol-5-ylmethyl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-pyridin-4-ylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(3-methylpyridin-4-yl)methyl]pyridazine-3-carboxamide;

5-methyl-N-(pyridin-4-ylmethyl)-6-[4-(pyridin-3-yloxy)piperidin-1-yl]pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[2-(1H-pyrazol-4-yl)ethyl]pyridazine-3-carboxamide;

N-bicyclo[1.1.1]pent-2-yl-6-[4-(1H-indazol-5-yloxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide;

6-{(3S,4R)-3-fluoro-4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

(R)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

(S)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-methoxy-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-N,5-dimethylpyridazine-3-carboxamide;

(S)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

(R)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

N-bicyclo[1.1.1]pent-2-yl-6-[4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide;

6-[4-(3-cyanophenoxy)piperidin-1-yl]-N-methoxy-5-methylpyridazine-3-carboxamide;

6-[4-(cyclopropylmethoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]pyridazine-3-carboxamide;

5-methyl-6-{4-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]piperidin-1-yl}-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-pyridin-3-ylpyridazine-3-carboxamide;

6-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-((S)-5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

6-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-((R)-5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridazin-4-ylmethyl)pyridazine-3-carboxamide;

6-{4-[(5-fluoro-6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

(R)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

(S)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[2-(1H-1,2,3-triazol-1-yl)ethyl]pyridazine-3-carboxamide;

5-methyl-6-{4-[(2-methyl-1,3-benzoxazol-6-yl)oxy]piperidin-1-yl}-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

6-[4-(cyclopropylmethoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5-oxopyrrolidin-3-yl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridine-3-carboxamide;

N-bicyclo[1.1.1]pent-1-yl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-bicyclo[1.1.1]pent-2-yl-5-methyl-6-{4-[(2-methyl-1,3-benzoxazol-6-yl)oxy]piperidin-1-yl}pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyrimidin-4-ylmethyl)pyridazine-3-carboxamide;

N-[(3-chloropyridin-4-yl)methyl]-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide;

6-[4-(cyclopropylmethoxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

N-(3-cyanobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-[(3-chloropyridin-4-yl)methyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-[4-(3-chloro-4-methylphenoxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

N-bicyclo[1.1.1]pent-2-yl-5-methyl-6-{4-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]piperidin-1-yl}pyridazine-3-carboxamide;

N-(2-methoxybenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyridazine-3-carboxamide;

6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

N-cyclopropyl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-[2-(1H-imidazol-1-yl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide;

(S)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

(R)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide;

(R)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyridazine-3-carboxamide;

(S)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyridazine-3-carboxamide;

N-(1,3-benzodioxol-5-ylmethyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1H-1,2,4-triazol-5-ylmethyl)pyridazine-3-carboxamide;

N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-cyclopentyl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-(4-cyanobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-6-yl)pyridazine-3-carboxamide;

N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[4-(methylsulfonyl)benzyl]pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl]pyridazine-3-carboxamide;

N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-(2,3-dihydro-1H-inden-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-(2-cyanobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-[(1R)-2,3-dihydro-1H-inden-1-yl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(2-oxopyrrolidin-3-yl)pyridazine-3-carboxamide;

N-(3,5-difluoro-4-methoxybenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-[(1 S)-1-(4-methoxyphenyl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-(2-chloro-4-fluorobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

(S)—

N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

(R)—

N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1-methylcyclopentyl)pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-N-[4-methoxy-3-(trifluoromethyl)benzyl]-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyridazine-3-carboxamide;

N-[(1R)-1-(4-methoxyphenyl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-N,2,5-trimethylpyridine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[4-(2,2,2-trifluoroethyl)phenyl]-pyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-2,5-dimethylpyridine-3-carboxamide;

6-[4-(3-cyanophenoxy)piperidin-1-yl]-N-(isothiazol-4-ylmethyl)-5-methylpyridazine-3-carboxamide;

N-benzyl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-benzyl-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide;

N-(2-chlorobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(2-phenylethyl)pyridazine-3-carboxamide;

N-[2-(2-chlorophenyl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;

N-(2-chlorobenzyl)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide;

6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyridazine-3-carboxamide;

6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyridazine-3-carboxamide;

6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyridazine-3-carboxamide;

5-[(6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazin-3-yl)carbonyl]-3-pyridin-3-yl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine

3-[(1-{4-methyl-6-[(3-pyridin-3-yl-6,7-dihydroisothiazolo[4,5-c]pyridin-5(4H)-yl)carbonyl]pyridazin-3-yl}piperidin-4-yl)oxy]benzonitrile

6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

5-ethyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxamide;

4-chloro-N′

-isopropyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carbohydrazide

N-(bicyclo[1.1.1]pentan-1-yl)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-N-((3-chloropyridin-4-yl)methyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

N-(bicyclo[1.1.1]pentan-1-yl)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-N-isopropyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)pyrimidine-2-carboxamide;

N-(azetidin-3-yl)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyrimidine-2-carboxamide;

4-chloro-N-(2-chlorobenzyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(2-(pyridin-4-yl)propan-2-yl)pyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-2-carboxamide;

4-chloro-6-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

(R)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidine-2-carboxamide;

(S)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidine-2-carboxamide;

4-chloro-N-(isothiazol-4-ylmethyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-bromo-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-2-(methylsulfonyl)pyrimidine;

4-chloro-2-methoxy-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

2-((4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)amino)ethan-1-ol;

5-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine;

4-((3S,4 S)-3,4-difluoropyrrolidin-1-yl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

4-(3,3-difluoropyrrolidin-1-yl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

6-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine;

6-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-2-oxa-6-azaspiro[3 0.3 ]heptane;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N,5-dimethylpyrimidin-4-amine;

4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-ol;

4-(3,3-difluoroazetidin-1-yl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-(pyrrolidin-1-yl)pyrimidine;

5-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(3,3,3-trifluoropropyl)pyrimidin-4-amine;

6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N,5-dimethyl-N-(2-(pyridin-2-yl)ethyl)pyrimidin-4-amine;

(4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5,6-dimethylpyrimidin-2-yl)methanol;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5,6-dimethylpyrimidine;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-vinylpyrimidine;

3-((1-(5-methyl-6-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

3-((1-(5-methyl-6-vinylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

4-(6-fluoropyridin-3-yl)-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

3-((1-(5-methyl-6-(5-methylpyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-propylpyrimidine;

3-((1-(6-(furan-3-yl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

3-((1-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-(pyridin-3-yl)pyrimidine;

4-(furan-3-yl)-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

3-((1-(5-methyl-6-(4-oxo-1,4-dihydroquinazolin-7-yl)pyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

3-((1-(6-(4-fluorophenyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

4-isobutyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

4-butyl-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

4-(4-fluorophenyl)-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine;

6-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carbonitrile;

6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carbonitrile;

2-(hydroxymethyl)-5-methyl-6-(4-(3-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidin-1-yl)pyrimidine-4-carbonitrile;

3-((1-(6-ethyl-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile;

6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carbonitrile;

2-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazin-3-yl)-5-methyl-1,3,4-oxadiazole;

3-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazin-3-yl)-5-methyl-1,2,4-oxadiazole;

5-(difluoromethyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;

2-amino-6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)nicotinamide; and

methyl 2-chloro-6-(4-((1,3-dihydroisobenzofuran-5-yl)oxy)piperidin-1-yl)-5-methylnicotinate;

or a pharmaceutically acceptable salt thereof.

14. (canceled)

15. (canceled)