# US 8,785,467 B2 · Alkoxy pyrimidine PDE10 inhibitors

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- Number: US 8,785,467 B2
- Document ID: US8785467B2
- Status: Granted
- Kind: B2
- Application number: 13/820,648
- Filed: 2011-09-26
- Published: 2013-06-20
- Granted: 2014-07-22
- Earliest claimed: 2010-09-30
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Christopher D. Cox; Izzat T. Raheem; William D. Shipe; Cory R. Theberge
- Inventors: Christopher D. Cox; Izzat T. Raheem; William D. Shipe; Cory R. Theberge
- Web page: https://patentgrep.com/patent/US8785467B2

## CPC

- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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
- A61P 25/30: for treating abuse or dependence
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- C07D 239/30: Halogen atoms or nitro radicals
- C07D 239/48: Two nitrogen atoms
- C07D 239/52: Two oxygen atoms
- C07D 239/56: One oxygen atom and one sulfur atom
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention is directed to 2-alkoxy pyrimidine compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

## Claims

### Claim 1

A compound of the formula I:
wherein:
R1 is C1-6alkyl or C1-6alkyl-C3-6cycloalkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:
(1) phenyl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8,
(2) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8,
(3) —O-phenyl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8, and
(4) —O-heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8;
R2 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) C1-6alkyl,
(4) —O—C1-6alkyl,
(5) hydrogen,
(6) —CN,
(7) —S—C1-6alkyl,
(8) —NR10R11, wherein R10 and R11 are independently selected from the group consisting of hydrogen and C1-6alkyl, and
(9) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8,
R3 is
C1-6alkyl, which is unsubstituted or substituted with halogen;
R4 is selected from the group consisting of:
(1) hydrogen, and
(2) C1-6alkyl;
R5 is C1-6alkyl, C1-6alkyl-C3-6cycloalkyl or C2-6alkenyl which is unsubstituted or substituted with a substituent selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) —O—C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(4) phenyl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8, and
(5) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R6, R7 and R8;
R6, R7 and R8 are independently selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) C1-6alkyl, which is unsubstituted or substituted with fluoro,
(4) —O—C1-6alkyl, which is unsubstituted or substituted with fluoro,
(5) —NR10R11,
(6) —(C═O)—NR10R11,
(7) —S(O)2—NR10R11,
(8) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the group consisting of hydrogen and C1-6alkyl, and
(9) —CN;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 of the formula Ic:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 of the formula Id:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1 of the formula Ig:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1 of the formula Ih:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —CH2CH2CH2— substituted with (2), (3), (4), (5), or (6), or —CH2-cyclopropyl, which is substituted with a substituent selected from the group consisting of:
(1) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(2) —O—C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(3) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —NH2, —NH—C1-6alkyl, or —N(C1-6alkyl)(C1-6alkyl), —O—C1-6alkyl or C1-6alkyl, which is unsubstituted or substituted with fluoro,
(4) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —NH2, —NH—C1-6alkyl, or —N(C1-6alkyl)(C1-6alkyl), —O—C1-6alkyl or C1-6alkyl, which is unsubstituted or substituted with fluoro,
(5) —O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —NH2, —NH—C1-6alkyl, or —N(C1-6alkyl)(C1-6alkyl), —O—C1-6alkyl or C1-6alkyl, which is unsubstituted or substituted with fluoro, and
(6) —O-heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —NH2, —NH—C1-6alkyl, or —N(C1-6alkyl)(C1-6alkyl), —O—C1-6alkyl or C1-6alkyl, which is unsubstituted or substituted with fluoro.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is chloro or methoxy.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of: hydrogen and methyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of:

### Claim 12

A compound which is selected from the group consisting of:
2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methylpyrimidin-4-amine;
{6-Chloro-5-methyl-2-[2-([1,8]naphthyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-(2,4-dimethylthiazol-5-ylmethyl)-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[3-(quinolin-2-yl)propoxy]pyrimidin-4-amine;
trans 6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-{[2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-5-methylpyrimidin-4-amine;
6-methoxy-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[(1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxy-5-methylpyrimidin-4-amine;
2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-ethyl-5-methylpyrimidin-4-amine;
2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-5-methyl-N-prop-2-en-1-ylpyrimidin-4-amine;
6-chloro-2-(3-imidazo[1,2-a]pyridin-2-ylpropoxy)-5-methyl-N-(1-methylethyl)pyrimidin-4-amine;
6-chloro-5-methyl-N-propyl-2-(3-[1,2,4]triazolo[1,5-a]pyridin-2-ylpropoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine;
6-chloro-5-methyl-N-propyl-2-(3-quinolin-2-ylpropoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(pyridin-4-ylmethoxy)pyrimidin-4-amine;
2-[3-(1,3-benzoxazol-2-yl)propoxy]-6-chloro-N-(2-fluoroprop-2-en-1-yl)-5-methylpyrimidin-4-amine;
6-chloro-N-(2-fluoroprop-2-en-1-yl)-5-methyl-2-[3-(1,8-naphthyridin-2-yl)propoxy]pyrimidin-4-amine;
1-[({2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-5-methylpyrimidin-4-yl}amino)methyl]cyclopropanol;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2-phenylethoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2-pyridin-3-ylethoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine;
1-{[6-chloro-5-methyl-2-(3-[1,2,4]triazolo[1,5-a]pyridin-2-ylpropoxy)pyrimidin-4-yl]amino}-2-methylpropan-2-ol;
1-{[6-chloro-5-methyl-2-(3-quinoxalin-2-ylpropoxy)pyrimidin-4-yl]amino}-2-methylpropan-2-ol;
6-chloro-2-[3-(6-methoxy-1,5-naphthyridin-2-yl)propoxy]-5-methyl-N-(1-methylethyl)pyrimidin-4-amine;
6-chloro-5-methyl-2-[3-(1,5-naphthyridin-2-yl)propoxy]-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine;
2-[3-(1,3-benzoxazol-2-yl)propoxy]-6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-{[2-pyridin-2-ylcyclopropyl]methoxy}pyrimidin-4-amine;
6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-[3-(1,5-naphthyridin-2-yl)propoxy]pyrimidin-4-amine;
6-chloro-5-methyl-N-[(3-methylisoxazol-5-yl)methyl]-2-[3-(1,8-naphthyridin-2-yl)propoxy]pyrimidin-4-amine;
6-chloro-5-methyl-N-[(3-methylisoxazol-5-yl)methyl]-2-(3-quinoxalin-2-ylpropoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-[2-(1H-indol-3-yl)ethoxy]-5-methylpyrimidin-4-amine;
2-[3-(2-bromoimidazo[2,1-b][1,3]thiazol-6-yl)propoxy]-6-chloro-N-ethyl-5-methylpyrimidin-4-amine;
6-chloro-2-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methylpyrimidin-4-amine;
2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methylpyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-(3-imidazo[2,1-b][1,3]thiazol-6-ylpropoxy)-5-methylpyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-quinolin-2-ylpropoxy)pyrimidin-4-amine;
6-chloro-2-[3-(6-methoxy-1,5-naphthyridin-2-yl)propoxy]-5-methyl-N-[(5-methylisoxazol-3-yl)methyl]pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[2-(3-pyridin-2-yl-1H-pyrazol-1-yl)ethoxy]pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[2-(1,8-naphthyridin-2-yloxy)ethoxy]pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-thieno[3,2-b]pyridin-5-ylpropoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-thieno[2,3-b]pyridin-6-ylpropoxy)pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-{2-[(6-methoxy-1,8-naphthyridin-2-yl)oxy]ethoxy}-5-methylpyrimidin-4-amine;
2-[3-(2-bromoimidazo[2,1-b][1,3]thiazol-6-yl)propoxy]-6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrimidin-4-amine;
6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-{[2-(quinolin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;
6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;
6-methoxy-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[(1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;
6-((1-methyl-1H-pyrazol-4-yl)methylamino)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidine-4-carbonitrile;
6-((2,4-dimethylthiazol-5-yl)methylamino)-5-methyl-2-(2-(pyridin-2-yl)ethoxy)pyrimidine-4-carbonitrile;
5-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(methylthio)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-amine;
N4,N4,5-trimethyl-N-6-((1-methyl-1H-pyrazol-4-yl)methyl)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidine-4,6-diamine;
2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-N-((2,4-dimethylthiazol-5-yl)methyl)-5-methylpyrimidin-4-amine;
N-((2,4-dimethylthiazol-5-yl)methyl)-5-methyl-6-(oxazol-2-yl)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-amine;
2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)methyl)-5-methylpyrimidin-4-amine;
2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((2,4-dimethyloxazol-5-yl)methyl)-5-methylpyrimidin-4-amine;
2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((1,3-dimethyl-1H-1,2,4-triazol-5-yl)methyl)-5-methylpyrimidin-4-amine;
6-chloro-2-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-5-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)pyrimidin-4-amine; and
2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-5-methylpyrimidin-4-amine;
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

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