IP Library › Granted Patent US 8,455,476

Granted Patent B2

US 8,455,476 · App. 12/765,103 · Granted Jun 4, 2013

Azetidinyl diamides as monoacylglycerol lipase inhibitors

Inventors: Haiyan Bian (Princeton, NJ); Kristen Chevalier (Collegeville, PA); Jose Clemente (Spring House, PA); Pete Connolly (Spring House, PA); Chris Flores (Springhouse, PA); Shu-Chen Lin (Doylestown, PA); Li Liu (Doylestown, PA); John Mabus (East Greenville, PA); Mark Macielag (Spring House, PA); Mark McDonnell (Lansdale, PA); Philip Pitis (No. Wales, PA); Yue-Mei Zhang (Springhouse, PA); Sui-Po Zhang (Radnor, PA); Bin Zhu (Spring House, PA)

Assignee: Janssen Pharmaceutica, NV

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Quick Facts

Patent No.: US 8,455,476
App. No.: 12/765,103
Granted: Jun 4, 2013
Kind: B2

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Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: wherein Y, Z, R 1 , and s are defined herein.

Claims (757)

1. A compound of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

Group a) is

i) substituted C 6-10 aryl,

ii) C 3-8 cycloalkyl optionally substituted with one to two fluoro substituents,

iii) trifluoromethyl, or

iv) heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrimidinyl, isoxazolyl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl, and [1,2,3]thiadiazolyl;

wherein C 6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C 1-4 alkyl, C 1-4 alkoxy, cyano, C 1-4 alkylcarbonylamino, and trifluoromethyl;

Group b) is

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of thiazolyl, pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinolinyl, quinazolinyl, furanyl, [1,2,3]triazolyl, thienyl, oxazolyl, [1,3,4] oxadiazol-2-yl, pyrrolyl, pyrazolyl, and benzimidazolyl;

iii) 2,3-dihydro-1H-indolyl;

iv) 2,3 diphenyl-indolyl;

v) diphenyl-imidazolyl;

vi) 1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;

vii) 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-indazol-2-yl;

viii) 1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl; or

ix) diphenyl-1H-pyrazol-3-yl; wherein each phenyl is optionally substituted with one to two chloro substituents; and wherein said pyrazolyl is optionally substituted with one methyl substituent;

wherein C 6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, isoxazolyl, thiazolyl, benzimidazolyl, pyrrolyl, furanyl, pyrimidinyl, and pyrazolyl; or

iii) 5,6-dihydro-4H-cyclopentapyrazol-2-yl;

wherein said heteroaryl and 5,6-dihydro-4H-cyclopentapyrazol-2-yl are optionally substituted with one phenyl substituent, and said phenyl substituent is optionally substituted with one to two chloro substituents or trifluoromethyl;

and wherein phenyl of the C 6-10 aryl and heteroaryl are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkoxycarbonylamino; C 1-4 alkyl; cyanomethyl; C 1-4 alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C 1-4 alkylcarbonyl; C 1-4 alkoxycarbonyl; C 1-4 alkoxycarbonyl(C 2-4 )alkenyl; cyano(C 2-4 )alkenyl; (2-cyano)ethylaminocarbonyl; cyano; carboxy; aminocarbonyl; C 1-4 alkylaminocarbonyl; di(C 1-4 alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy; di(C 1-4 alkyl)aminosulfonyl; C 1-4 alkylsulfonyl; di(C 1-4 alkyl)aminosulfonyl; morpholin-4-ylsulfonyl; —OCH 2 O— attached at adjacent carbon atoms; and NR c R d ; wherein R c is hydrogen or C 1-6 alkyl and wherein R d is hydrogen, C 1-6 alkyl, cyano(C 1-4 )alkyl, C 3-8 cycloalkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 3-8 cycloalkylcarbonyl, C 3-8 cycloalkyl(C 1-4 alkyl, aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 6-10 arylcarbonyl; di(C 1-4 alkyl)aminosulfonyl, and C 1-4 alkylsulfonyl;

s is 0, 1 or 2; provided that when s is 2, R 1 is independently selected from the group consisting of phenyl, C 1-3 alkyl, and C 6-10 aryl(C 1-3 )alkyl;

when s is 1, R 1 is C 6-10 aryl, C 1-3 alkyl, benzyloxymethyl, hydroxy(C 1-3 )alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo, or aryl(C 1-3 )alkyl; or, when s is 2 and R 1 is C 1-3 alkyl, the C 1-3 alkyl substituents are taken with the piperizinyl ring to form a 3,8-diaza-bicyclo[3.2.1]octanyl or 2,5-diaza-bicyclo[2.2.2]octanyl ring system;

and with the proviso that a compound of formula (I) is other than

a compound wherein Y is 3-chlorobenzothien-2-yl, Z is 4-biphenyl, and s is 0;

a compound wherein Y is 3-chlorothien-2-yl, Z is 4-biphenyl, and s is 0;

a compound wherein Y is 2-cyanophenyl, Z is 4-biphenyl, and s is 0;

a compound wherein Y is 5-methyl-isoxazol-3-yl, Z is 4-biphenyl, and s is 0;

a compound wherein Y is thiazol-2-yl, Z is 5-(4-chlorophenyl)oxazol-4-yl, and s is 0;

a compound wherein Y is thiazol-2-yl, Z is 3-phenyl-1H-pyrazol-4-yl, and s is 0;

a compound wherein Y is thiazol-2-yl, Z is 5-(2-fluoropyridin-3-yl)-1H-benzimidazol-2-yl, and s is 0;

a compound wherein Y is thiazol-4-yl, Z is 1-phenyl-5-trifluoromethyl-pyrazol-4-yl, and s is 0;

a compound wherein Y is pyrimidin-2-yl, Z is 4-biphenyl, and s is 0;

a compound wherein Y is thiazol-4-yl, Z is 4-biphenyl, s is 1, and R 1 is 3-phenyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein

Group a) is

i) substituted C 6-10 aryl,

ii) C 3-8 cycloalkyl optionally substituted with one to two fluoro substituents,

iii) trifluoromethyl, or

iv) heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, benzothienyl, thieno[3,2-b]thiophen-2-yl, triazolyl, and [1,2,3]thiadiazolyl;

3. The compound of claim 2 wherein

Group a) is

i) substituted C 6-10 aryl,

ii) C 3-8 cycloalkyl optionally substituted with one to two fluoro substituents,

iii) trifluoromethyl, or

iv) heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, thieno[3,2-b]thiophen-2-yl, and [1,2,3]thiadiazolyl;

4. The compound of claim 3 wherein

Group a) is

i) cyclopropyl optionally substituted with one to two fluoro substituents,

ii) trifluoromethyl, or

iii) heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, and isoxazolyl;

wherein C 6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, and trifluoromethyl.

5. The compound of claim 1 wherein

Group b) is

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of thiazolyl, pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, furanyl, [1,2,3]triazolyl, thienyl, oxazolyl, [1,3,4]oxadiazol-2-yl, pyrrolyl, pyrazolyl, and benzimidazolyl;

iii) 2,3-dihydro-1H-indolyl;

iv) 2,3 diphenyl-indolyl;

v) diphenyl-imidazolyl;

vi) 1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;

vii) 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-indazol-2-yl;

viii) 1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl; or

ix) diphenyl-1H-pyrazol-3-yl; wherein each phenyl is optionally substituted with one to two chloro substituents; and wherein said pyrazolyl is optionally substituted with one methyl substituent;

wherein C 6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, isoxazolyl, thiazolyl, benzimidazolyl, pyrrolyl, furanyl, pyrimidinyl, and pyrazolyl; or

iii) 5,6-dihydro-4H-cyclopentapyrazol-2-yl;

wherein said heteroaryl and 5,6-dihydro-4H-cyclopentapyrazol-2-yl are optionally substituted with one phenyl substituent, and said phenyl is optionally substituted with one to two chloro substituents or trifluoromethyl;

6. The compound of claim 5 wherein

Group b) is

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of thiazolyl, pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, furanyl, [1,2,3]triazolyl, thienyl, oxazolyl, [1,3,4]oxadiazol-2-yl, pyrazolyl, and benzimidazolyl;

iii) 2,3-dihydro-1H-indolyl;

iv) 2,3 diphenyl-indolyl;

v) diphenyl-imidazolyl;

vi) 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-indazol-2-yl; or

vii) diphenyl-1H-pyrazol-3-yl; wherein each phenyl is optionally substituted with one to two chloro substituents; and wherein said pyrazolyl is optionally substituted with one methyl substituent;

wherein C 6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of thienyl, quinolinyl, pyridinyl, isoxazolyl, benzimidazolyl, furanyl, pyrimidinyl, and pyrazolyl; or

iii) 5,6-dihydro-4H-cyclopentapyrazol-2-yl;

and wherein phenyl of the C 6-10 aryl and heteroaryl are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl; cyanomethyl; C 1-4 alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; C 1-4 alkylcarbonyl; C 1-4 alkoxycarbonyl(C 2-4 )alkenyl; cyano(C 2-4 )alkenyl; (2-cyano)ethylaminocarbonyl; cyano; aminocarbonyl; formyl; nitro; bromo; hydroxy; di(C 1-4 alkyl)aminosulfonyl; C 1-4 alkylsulfonyl; —OCH 2 O— attached at adjacent carbon atoms; and NR c R d ; wherein R c is hydrogen or C 1-6 alkyl and wherein R d is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, and C 1-4 alkylsulfonyl.

7. The compound of claim 6 wherein

Group b) is

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of thiazolyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, quinazolinyl, furanyl, thienyl, [1,3,4] oxadiazol-2-yl, and benzimidazolyl;

iii) 2,3-dihydro-1H-indolyl;

iv) 2,3 diphenyl-indolyl;

v) diphenyl-imidazolyl;

vi) 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-indazol-2-yl; or

vii) diphenyl-1H-pyrazol-3-yl; wherein each phenyl is optionally substituted with one to two chloro substituents;

wherein C 6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, pyrimidinyl, and pyrazolyl; or

iii) 5,6-dihydro-4H-cyclopentapyrazol-2-yl;

and wherein phenyl of the C 6-10 aryl and heteroaryl are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl; cyanomethyl; C 1-4 alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; C 1-4 alkylcarbonyl; C 1-4 alkoxycarbonyl(C 2-4 )alkenyl; cyano(C 2-4 )alkenyl; cyano; formyl; nitro; bromo; hydroxy; di(C 1-4 alkyl)aminosulfonyl; C 1-4 alkylsulfonyl; —OCH 2 O— attached at adjacent carbon atoms; and NR c R d ; wherein R c is hydrogen or C 1-6 alkyl and wherein R d is hydrogen, C 1-6 alkoxycarbonyl, and C 1-4 alkylsulfonyl.

8. The compound of claim 1 wherein s is 0 or 1.

9. The compound of claim 8 wherein s is 0.

10. The compound of claim 1 wherein R 1 is C 6-10 aryl, C 1-3 alkyl, or aryl(C 1-3 )alkyl.

11. The compound of claim 10 wherein R 1 is phenyl or C 1-3 alkyl.

12. The compound of claim 11 wherein R 1 is phenyl.

13. A compound of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

Group a) is

i) substituted C 6-10 aryl,

ii) C 3-8 cycloalkyl optionally substituted with one to two fluoro substituents,

iii) trifluoromethyl, or

Group b) is

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of thiazolyl, pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, furanyl, [1,2,3]triazolyl, thienyl, oxazolyl, [1,3,4]oxadiazol-2-yl, pyrrolyl, pyrazolyl, and benzimidazolyl;

iii) 2,3-dihydro-1H-indolyl;

iv) 2,3 diphenyl-indolyl;

v) diphenyl-imidazolyl;

vi) 1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;

vii) 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-indazol-2-yl;

viii) 1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl; or

ix) diphenyl-1H-pyrazol-3-yl; wherein each phenyl is optionally substituted with one to two chloro substituents; and wherein said pyrazolyl is optionally substituted with one methyl substituent;

wherein C 6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C 6-10 aryl;

ii) heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, isoxazolyl, thiazolyl, benzimidazolyl, pyrrolyl, furanyl, pyrimidinyl, and pyrazolyl; or

iii) 5,6-dihydro-4H-cyclopentapyrazol-2-yl;

s is 0 or 1;

R 1 is C 6-10 aryl, C 1-3 alkyl, or aryl(C 1-3 )alkyl;

and with the proviso that a compound of formula (I) is other than a compound wherein Y is 3-chlorobenzothien-2-yl, Z is 4-biphenyl, and s is 0; a compound wherein Y is 3-chlorothien-2-yl, Z is 4-biphenyl, and s is 0;