Granted Patent B2

US 9,676,721 · App. 13/820,489 · Granted Jun 13, 2017

Inventors: Kenneth W. Bair (Watertown, MA); Alexandre J. Buckmelter (Watertown, MA); Bingsong Han (Watertown, MA); Jian Lin (Watertown, MA); Dominic J. Reynolds (Watertown, MA); Chase C. Smith (Watertown, MA); Zhongguo Wang (Watertown, MA); Xiaozhang Zheng (Watertown, MA)

Assignee: FORMA TM, LLC

C07D213/75A61K31/437A61K31/4406A61K31/4409A61K45/06C07D213/74C07D401/04C07D471/04

Abstract

Claims (136)

1. Compounds of the Formula II:

wherein

Ar 1 is unsubstituted pyridine or imidazopyridine;

Ar 2 is phenyl;

R 1 is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein said cycloalkyl or aryl is 5 to 13 membered monocyclic or bicyclic cycloalkyl or aryl, and said heterocycloalkyl or heteroaryl is 5 to 13 membered monocyclic or bicyclic heterocycloalkyl or heteroaryl comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O with the proviso that no two adjacent ring heteroatoms on a ring are both S or both O; and

(i) wherein each of said cycloalkyl, aryl, heterocycloalkyl and heteroaryl is either unsubstituted or optionally independently substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of:

deuterium, halo, cyano, alkyl, hydroxyalkyl, cyanoalkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylalkoxy, haloalkoxy, aryloxy, —NR a R b , —CONR a R b , —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 N(alkyl) 2 , —S(O) 2 —CF 3 , —C(O)alkyl, —NH—C(O)alkyl, —NH—C(O)aryl, methylenedioxy, —(CH 2 ) q cycloalkyl, —(CH 2 ) q aryl, —(CH 2 ) q heteroaryl, and —(CH 2 ) q heterocycloalkyl,

R a and R b are independently H, alkyl, alkoxy, aryl, alkoxyalkyl, —S(O) 2 alkyl or cycloalkyl, or R a and R b can form a 5 or 6 membered heterocycloalkyl group together with the nitrogen atom to which they are attached, wherein said heterocycloalkyl group may contain one or more additional heteroatom(s) selected from the group consisting of N, S and O;

R 2 and R 3 are H or deuterium; and

m, n, p and q are independently 0, 1 or 2;

and stereoisomers thereof;

and pharmaceutically acceptable salts thereof.

2. The compounds of claim 1 , wherein Ar 1 is unsubstituted pyridine.

3. The compounds of claim 1 , wherein Ar 1 is imidazopyridine.

4. The compounds of claim 1 , wherein R 1 is heteroaryl that is unsubstituted or substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy, heterocycloalkyl, —N(R a R b ), wherein R a and R b are as defined in claim 1 .

5. The compounds of claim 4 , wherein the heteroaryl is 5 to 13 membered monocyclic or bicyclic heteroaryl comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O with the proviso that no two adjacent ring heteroatoms are both S or both O.

6. The compounds of claim 5 , wherein the heteroaryl is selected from the group consisting of pyridine, quinolone, benzodioxole, and indazole.

7. A compound selected from the group consisting of:

2-cyano-1-[(4-{[3-(dimethylsulfamoyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

(E)-3-({4-[(3-chlorobenzene)sulfonyl]phenyl}methyl)-2-cyano-1-(pyridin-4-yl)guanidine;

1-[(4-{[4-chloro-3-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(ethanesulfonyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-[4-(benzenesulfonyl)phenyl]-2-cyano-3-(pyridin-3-ylmethyl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[3-(trifluoromethoxy)benzene]sulfonyl}phenyl)methyl]guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(quinoline-8-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-({4-[(3,5-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(quinoline-6-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-[(4-{[2-(morpholin-4-ylmethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(2-methylpyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(6-methylpyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

4-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-ethylbenzamide;

2-cyano-1-[(4-{[4-(propan-2-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

3-({4-[(3-chlorobenzene)sulfonyl]phenyl}methyl)-2-cyano-1-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,4-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(1-methyl-1H-pyrazole-4-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-fluoro-5-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-methanesulfonylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[6-(morpholin-4-yl)pyridine-3-sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-4-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(propan-2-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-fluoro-4-(2,2,2-trifluoroethoxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[4-(propan-2-yloxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,4-dichlorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[2-methoxy-4-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-cyclopentylbenzamide;

(E)-3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-(pyridin-3-ylmethyl)guanidine;

1-{[4-(2H-1,3-benzodioxole-5-sulfonyl)phenyl]methyl}-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,5-difluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[3-chloro-2-(morpholin-4-yl)pyridine-4-sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-ethylbenzamide;

2-cyano-1-({4-[(2-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine

2-cyano-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(phenylsulfonyl)benzyl)guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-{imidazo[1,2-a]pyridin-7-yl}guanidine;

2-cyano-1-({4-[(3,4-dimethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-ethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N,N-diethyl-4-fluorobenzamide;

2-cyano-1-{[4-(4-methylpyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N,N-dimethylbenzamide;

2-cyano-1-({4-[2-(dimethylamino)pyrimidine-5-sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,5-dichlorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(propan-2-yloxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-fluoro-2-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(2,3-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(2, 6-dimethoxypyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

1-({4-[(4-acetylbenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-ethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-3-{[4-(phenylmethane)sulfonylphenyl]methyl}-1-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-cyanobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(2-ethoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-({4-[(4-chloro-3-fluorobenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-({4-[(4-fluorobenzene)sulfonyl]phenyl}methyl)-1-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-5-methylbenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-{imidazo[1,2-a]pyridin-7-ylmethyl}guanidine;

2-cyano-1-({4-[(3-fluoro-5-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-({3-[(morpholin-4-yl)carbonyl]benzene}sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-fluoro-3-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[(4-chloro-2-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-4-methylbenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(5-fluoro-2-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-{[4-(2H-1,3-benzodioxole-4-sulfonyl)phenyl]methyl}-2-cyano-3-(pyridin-4-yl)guanidine;

1-({4-[(5-chloro-2-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-({4-[(pyrrolidin-1-yl)carbonyl]benzene}sulfonyl)phenyl]methyl}guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[4-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-5-fluoro-N,N-dimethylbenzamide;

2-cyano-1-{[4-(1-propyl-1H-pyrazole-4-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[4-(trifluoromethoxy)benzene]sulfonyl}phenyl)methyl]guanidine;

2-cyano-1-({4-[(4-ethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-methoxy-3-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-({4-[(3-chloro-4-propoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(naphthalene-1-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-cyanobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(propane-1-sulfonamido)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

5-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-methylpyridine-2-carboxamide;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-cyclopropylbenzamide;

1-({4-[(3-chloro-5-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

1-({4-[(4-chlorobenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-[(4-{[3-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-(pyridin-3-yl)guanidine;

1-({4-[(3-chloro-5-fluorobenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3,4-difluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(5-methoxypyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-fluoro-4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-{2-[4-(benzenesulfonyl)phenyl]ethyl}-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluoro-4-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine

2-cyano-3-[(4-{8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl}phenyl)methyl]-1-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluoro-4-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-phenylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-fluoro-5-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine

2-cyano-1-{[4-(1-methyl-1H-indazole-6-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(5-fluoropyridine-3-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[3-(methoxymethyl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

1-({4-[(5-acetyl-2-methoxybenzene)sulfonyl]phenyl}methyl)-2-cyano-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(quinoline-3-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-({4-[(4-methoxybenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

3-{[4-(benzenesulfonyl)phenyl]methyl}-2-cyano-1-(pyridin-4-yl)guanidine;

2-cyano-1-{[4-(1-methyl-1H-indole-2-sulfonyl)phenyl]methyl}-3-(pyridin-4-yl)guanidine;

2-cyano-3-(pyridin-4-yl)-1-{[4-(pyridine-3-sulfonyl)phenyl]methyl}guanidine;

2-cyano-1-[(4-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

3-chloro-5-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N,N-diethylbenzamide;

2-cyano-1-[(4-{[2-methoxy-5-(propan-2-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-[(4-{[4-(morpholin-4-yl)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(3-methoxy-4-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

2-cyano-1-(pyridin-4-yl)-3-[(4-{[2-(trifluoromethoxy)benzene]sulfonyl}phenyl)methyl]guanidine;

2-cyano-1-[(4-{[3-fluoro-5-(2,2,2-trifluoroethoxy)benzene]sulfonyl}phenyl)methyl]-3-(pyridin-4-yl)guanidine;

2-cyano-1-({4-[(4-ethoxy-3-fluorobenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

3-[(4-{[2-cyano-3-(pyridin-4-yl)carbamimidamido]methyl}benzene)sulfonyl]-N-(propan-2-yl)benzamide;

2-cyano-1-({4-[(2,4-dimethylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

1-[(4-{[3-chloro-5-(trifluoromethyl)benzene]sulfonyl}phenyl)methyl]-2-cyano-3-(pyridin-4-yl)guanidine; and

2-cyano-1-({4-[(2-methylbenzene)sulfonyl]phenyl}methyl)-3-(pyridin-4-yl)guanidine;

and pharmaceutically acceptable salts thereof.

Assignments (8)

Continuity (4)