US 8,785,467 B2Granted

Alkoxy pyrimidine PDE10 inhibitors

AssigneeMerck Sharp & Dohme Corp.

InventorsChristopher D. Cox, Izzat T. Raheem, William D. Shipe, Cory R. Theberge

Life of this patent

Estimating the term…

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.

Claims13

Dependent claims

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.

35 more elements

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.

55 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/820,648Filed 26 Sep 2011 · us provisional application
Priority: 30 Sep 2010
Published: US 2013/0158056 A120 Jun 2013
Granted: 22 Jul 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…
A61K 31/513
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: 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
Drugs for disorders of the nervous system: for treating abnormal movements, e.g. chorea, dyskinesia

Family

Application61/388,280Us provisional application · filed 30 Sep 2010
US 2013/0158056 A1Pre-grant publication · published 20 Jun 2013
US 8,785,467 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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.

35 more elements

Facts

Application

13/820,648Filed 26 Sep 2011 · us provisional application

Priority

30 Sep 2010

Published

US 2013/0158056 A120 Jun 2013

Granted

22 Jul 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…
A61K 31/513
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: 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
Drugs for disorders of the nervous system: for treating abnormal movements, e.g. chorea, dyskinesia