IP Library › Granted Patent US 7,517,878
Granted Patent B2
US 7,517,878 · App. 11/064,700 · Granted Apr 14, 2009

Heteroarylaminopyrazole derivatives useful for the treatment of diabetes

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Quick Facts
Patent No.
US 7,517,878
App. No.
11/064,700
Granted
Apr 14, 2009
Kind
B2
Abstract

The present invention relates to heteroarylaminopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.

Claims (240)

1. A heteroarylaminopyrazole compound of Formula (I)

wherein

is a substituted heterocyclic aromatic ring radical selected from

R is H, or (C 1 -C 6 )alkyl;

R 1 is H,

(C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 )alkyl]silyl,

(C 3 -C 6 )alkenyl,

(C 3 -C 6 )alkynyl,

(C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo,

(C 1 -C 3 )haloalkyl, or

phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and cyano;

R 2 is H,

halo,

(C 1 -C 6 )alkyl,

pyridyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, halo, and (C 1 -C 6 )alkyl,

phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

pyrimidyl,

thienyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

benzothienyl, optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

or furyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo;

R 3 is (C 1 -C 6 )alkyl,

(C 3 -C 6 )cycloalkyl,

(C 2 -C 3 )haloalkyl or

phenyl optionally substituted with up to four substituents selected from the group consisting of

(C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

halo,

(C 1 -C 3 )haloalkyl,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkoxy,

(C 1 -C 6 )alkylthio, and

cyano;

R 4 is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

(C 1 -C 6 )alkoxy,

(C 1 -C 6 )alkylthio,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, or

halo;

n =0, 1, 2, or 3;

X is CO 2 R 7 , CONR 5 R 6 , or SO 2 NH 2 ;

R 5 is H, (C 1 -C 6 )alkyl, phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo;

R 6 is H or (C 1 -C 6 )alkyl;

or

R 5 and R 6 , taken together with N atom to which they are attached, may form a piperidine, morpholine, thiomorpholine, or piperazine ring said piperazine optionally substituted on N with (C 1 -C 3 )alkyl;

R 7 is H,

(C 1 -C 6 )alkyl,

benzyl optionally substituted on the aryl ring with up to two substituents selected from the group consisting of

halo,

(C 1 -C 6 )alkyl,

(C 1 -C 3 )alkoxy,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, and

(C 1 -C 6 )alkylthio;

phenyl optionally substituted with up to two substituents selected from the group consisting of

(C 1 -C 6 )alkyl,

halo,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, and

(C 1 -C 6 )alkylthio;

or a pharmaceutically acceptable salt thereof;

provided that the compound of Formula (I) is not

2. The compound of claim 1 ,

wherein

is a substituted heterocyclic aromatic ring radical selected from

R is H, or (C 1 -C 6 )alkyl;

R 1 is H,

(C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 )alkyl]silyl,

(C 3 -C 6 )alkenyl,

(C 3 -C 6 )alkynyl,

(C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo,

(C 1 -C 3 )haloalkyl, or

phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 3 )haloalkoxy, and cyano;

R 2 is H,

halo

(C 1 -C 6 )alkyl,

pyridyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, halo, and (C 1 -C 6 )alkyl,

phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

pyrimidyl,

thienyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

benzothienyl, optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

or furyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo;

R 3 is (C 1 -C 6 )alkyl,

(C 3 -C 6 )cycloalkyl,

(C 2 -C 3 )haloalkyl or

phenyl optionally substituted with up to four substituents selected from the group consisting of

(C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

halo,

(C 1 -C 3 )haloalkyl,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkoxy,

(C 1 -C 6 )alkylthio, and cyano;

R 4 is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

(C 1 -C 6 )alkoxy,

(C 1 -C 6 )alkylthio,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, or

halo;

n =0, 1, 2, or 3;

X is CO 2 R 7 , CONR 5 R 6 , or SO 2 NH 2 ;

R 5 is H, (C 1 -C 6 )alkyl, phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo;

R 6 is H or (C 1 -C 6 )alkyl;

or

R 5 and R 6 , taken together with N atom to which they are attached, may form a piperidine, morpholine, thiomorpholine, or piperazine ring said piperazine optionally substituted on N with (C 1 -C 3 )alkyl;

R 7 is H,

(C 1 -C 6 )alkyl,

benzyl optionally substituted on the aryl ring with up to two substituents selected from the group consisting of

halo,

(C 1 -C 6 )alkyl,

(C 1 -C 3 )alkoxy,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, and

(C 1 -C 6 )alkylthio;

phenyl optionally substituted with up to two substituents selected from the group consisting of

(C 1 -C 6 )alkyl,

halo,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, and

(C 1 -C 6 )alkylthio;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 ,

wherein

is a substituted heterocyclic aromatic ring radical selected from

R is H, or (C 1 -C 6 )alkyl;

R 1 is H,

(C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 alkyl]silyl,

(C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo,

(C 1 -C 3 )haloalkyl, or

phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and cyano;

R 2 is H,

halo,

(C 1 -C 6 )alkyl,

pyridyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, halo, and (C 1 -C 6 )alkyl,

phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,

pyrimidyl;

R 3 is (C 1 -C 6 )alkyl,

(C 3 -C 6 )cycloalkyl,

(C 2 -C 3 )haloalkyl or

phenyl optionally substituted with up to four substituents selected from the group consisting of

(C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 ) alkoxy,

halo,

(C 1 -C 3 )haloalkyl,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkoxy,

(C 1 -C 6 )alkylthio, and

cyano;

R 4 is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

(C 1 -C 6 )alkoxy,

(C 1 -C 6 )alkylthio,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, or

halo;

n =0, 1, or 2;

X is CO 2 R 7 or CONR 5 R 6 ;

R 5 is H or (C 1 -C 6 )alkyl;

R 6 is H or (C 1 -C 6 )alkyl;

or

R 5 and R 6 , taken together with N atom to which they are attached, may form a piperidine, morpholine, thiomorpholine, or piperazine ring said piperazine optionally substituted on N with (C 1 -C 3 )alkyl;

R 7 is H,

(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 ,

wherein

is a substituted heterocyclic aromatic ring radical selected from

R is H, or (C 1 -C 6 )alkyl;

R 1 is H,

(C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 )alkyl]silyl,

(C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo,

(C 1 -C 3 )haloalkyl, or

phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and cyano;

R 2 is H,

halo,

(C 1 -C 6 )alkyl,

phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo;

R 3 is (C 1 -C 6 )alkyl,

(C 3 -C 6 )cycloalkyl,

(C 2 -C 3 )haloalkyl or

phenyl optionally substituted with up to four substituents selected from the group

consisting of

(C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

halo,

(C 1 -C 3 )haloalkyl,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkoxy,

(C 1 -C 6 )alkylthio, and cyano;

R 4 is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

(C 1 -C 6 )alkoxy,

(C 1 -C 6 )alkylthio,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, or

halo;

n =0, 1, or 2;

X is CO 2 R 7 or CONR 5 R 6 ;

R 5 is H or (C 1 -C 6 )alkyl;

R 6 is H or (C 1 -C 6 )alkyl;

R 7 is H,

(C 1 -C 6 )alkyl,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 ,

wherein

is a substituted heterocyclic aromatic ring radical selected from

R is H, or (C 1 -C 6 )alkyl;

R 1 is H,

(C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 )alkyl]silyl,

(C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo,

(C 1 -C 3 )haloalkyl, or

phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkythio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and cyano;

R 2 is H,

halo,

(C 1 -C 6 )alkyl,

phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo;

R 3 is (C 1 -C 6 )alkyl,

(C 3 -C 6 )cycloalkyl,

(C 2 -C 3 )haloalkyl or

phenyl optionally substituted with up to four substituents selected from the group

consisting of

(C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 ) alkoxy,

halo,

(C 1 -C 3 )haloalkyl,

(C 1 -C 6 )alkoxy,

(C 1 -C 3 )haloalkoxy,

(C 1 -C 6 )alkylthio, and

cyano;

R 4 is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,

(C 1 -C 6 )alkoxy,

(C 1 -C 6 )alkylthio,

(C 1 -C 3 )haloalkyl,

(C 1 -C 3 )haloalkoxy, or

halo;

n =0, 1, or 2;

X is C 2 R 7 or CONR 5 R 6 ;

R 5 is H or (C 1 -C 6 )alkyl;

R 6 is H or (C 1 -C 6 )alkyl;

R 7 is H,

(C 1 -C 6 )alkyl,

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 selected from the group consisting of 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-6-methylnicotinic acid; 2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino }nicotinic acid; 3-{[3-tert-butyl-1-(2-methyiphenyl)-1H-pyrazol-5-yl]amino }pyridine-2-carboxylic acid; 2-{[3-(2,2-dimethylpropyl)- 1-(2-methylphenyl)-1H-pyrazol-5-yl]amino }nicotinic acid; 2-{[1-(2-chlorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid; 2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[3-tert-butyl-1-(2,5 -dimethyiphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-6-methylnicotinic acid; 2-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}-6-methylnicotinic acid; 2-{[3-tert-butyl-1-(2,5-dimethyiphenyl)-1H-pyrazol-5-yl]amino }-6-methylnicotinic acid; 2-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}-5-fluoronicotinic acid; 2-{[3-tert-butyl-1-(2,6-dimethyiphenyl)-1H-pyrazol-5-yl]amino}-5-fluoronicotinic acid; 2-{[3-tert-butyl-1-(5 -fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-fluoronicotinic acid; 2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-fluoronicotinic acid; 2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-fluoronicotinic acid; 2-{[3-cyclohexyl-1-(2-methyiphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[1-(5-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino }nicotinic acid; 2-{[3-(4-fluorophenyl)-1-(2-methyiphenyl)-1H-pyrazol-5-yl]amino }nicotinic acid; 2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[3-(4-fluorophenyl)-1-(2-methoxy-5-methyiphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[3-(4-fluorophenyl)-1-(5-methoxy-2-methylphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-6-methylnicotinic acid; 2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5 -yl]amino}-6-methylnicotinic acid; 2-{[3-(4-fluorophenyl)-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}-6-methylnicotinic acid; 2-{[3-(1,1-dimethylpropyl)-1-(3-methoxy-2-methylphenyl)-1H-pyrazol-5-Yl]amino}nicotinic acid; 2-{[3-(1,1-dimethylpropyl)-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-Yl]amino}nicotinic acid; 2-{[3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[3-tert-butyl-1-(2,6-dimethyiphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; 2-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid; and 3-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}-5-(trifluoromethyl) pyridine-2-carboxylic acid.

7. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

8. A method of treating diabetes comprising administering to a subject in need thereof a therapeutically effective amount of i) a compound of claim 1 , or ii) a pharmaceutical composition of claim 7 .

9. The method of claim 8 , wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 12, 2005
From: RUDOLPH, JOACHIM; WICKENS, PHILIP; CHUANG, CHIH-YUAN; CHEN, LIBING; MAGNUSON, STEVEN; OLAGUE, ALAN; QI, NING
To: BAYER PHARMACEUTICALS CORPORATION
Reel/Frame 016006/0131 →