US 9,428,492 B2Granted

Secondary alcohol substituted triazoles as PDE10 inhibitors

AssigneeMerck Sharp & Dohme Corp.

InventorsScott D. Kuduk, Christopher D. Cox, Vadim Y. Dudkin, Carol A. McVean, Thomas S. Reger, Justin T. Steen

Life of this patent

Estimating the term…

Abstract

The present invention is directed to secondary alcohol substituted triazole 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.

Claims16

Dependent claims

A compound of the formula I:

wherein:
A represents
R represents H or C1-6alkyl;
R1 is selected from the groups consisting of (CH2)nC1-4haloalkyl, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, said alkyl cycloalkyl, and aryl is unsubstituted or substituted with 1 to 3 groups of Ra;
R2 is selected from the group consisting of H, O—R, CN, O(CH2)nOR, OCHR(CH2)nOR, SR, SO2R, S(O)R, N(R)2, C(O)N(R)2, C1-3 haloalkyl, O(CH2)nC1-3haloalkyl, O(CH2)nC3-6cycloalkyl, (CH2)nC5-10 heterocycle, C1-6 alkyl, and C3-10cycloalkyl, said alkyl, cycloalkyl, and heterocycle is unsubstituted or substituted with 1 to 3 groups of Ra;
Ra is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) C1-6alkyl,
(4) —(CH2)nO—R,
(5) (CH2)n C6-10aryl,
(6) (CH2)nC5-10 heterocycle,
(7) OC1-5 haloalkyl;
(8) CO2R;
(9) C(O)N(R)2;
(10) (CH2)nC(O)R;
(11) CN,
(12) (CH2)nN(R)2;
(13) (CH2)nC3-6cycloalkyl,
(14) (CH2)nC1-3 haloalkyl;
n represents 0-4,
or a pharmaceutically acceptable salt thereof.

19 more elements

A compound which is:

1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(S)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(R)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl) ethanol;
1-(3-methyl-1-(6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
1-(1-(2-methoxy-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;
1-(1-(2-cyclopropyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;
2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(S)-2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(R)-2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
2,2-difluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
2-fluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(S)-cyclohexyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;
(R)-cyclohexyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;
(S)-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;
(R)-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;
1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;
2-methyl-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;
cyclopropyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;
3,3,3-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;
1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(R)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(S)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(R)-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;
(S)-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;
2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;
2-methyl-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;
1-(3-methyl-1-(6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
(S)-1-(3-methyl-1-(6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;
1-(1-(2-cyclopropyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol
(S)-1-(1-(2-cyclopropyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;
or a pharmaceutically acceptable salt thereof.

29 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/442,838Filed 11 Nov 2013 · us provisional application
Priority: 15 Nov 2012
Published: US 2015/0284368 A18 Oct 2015
Granted: 30 Aug 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings

Family

Application61/726,655Us provisional application · filed 15 Nov 2012
US 2015/0284368 A1Pre-grant publication · published 8 Oct 2015
US 9,428,492 B2This patent

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

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Abstract

Facts

Application

14/442,838Filed 11 Nov 2013 · us provisional application

Priority

15 Nov 2012

Published

US 2015/0284368 A18 Oct 2015

Granted

30 Aug 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings