Compositions and method for inhibiting TGF-β
This invention provides compounds that are inhibitors of the TGF-β signaling pathway. The compounds are represented by formula I: where A′ is N or CH; Ring B is preferably an triazolyl, imidazolyl, or thiazolyl ring; —X-D- is a linker group; and G is an optionally substituted aryl or heteroaryl ring. The compounds are useful for treating cardiovascular disease.
1. A compound of formula V:
or a pharmaceutically acceptable salt thereof, wherein:
A′ is N or CH;
Ring A is optionally substituted by 1-3 R 1 ;
Ring B is a heteroaryl ring that is optionally substituted at a substitutable nitrogen by R 3 and optionally substituted at a substitutable carbon by R 2a , wherein (i) W is NH, Z is CH, and Y is N, (ii) W is CH, Z is NH, and Y is N, (iii) W is S, Z is N, and Y is CH, (iv) W is S, Z is N, and Y is N, (v) W is N, Z is S, and Y is CH, or (vi) W is S, Z is CH, and Y is N;
X is —NH—, —O—, —CH 2 — or —S—;
D is C 1-3 alkylidene;
G is an aryl or heteroaryl ring that is optionally substituted by 1-4 R 5 ;
Each R 1 is independently selected from -R 2 , -T-R 2 , or —V-T-R 2 ;
Each R 2 is independently selected from C 1-3 aliphatic, hydroxy, —N(R 3 ) 2 , halo, cyano, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —S(O)R 4 , —SO 2 R 4 , —N(R 3 )C(O)R 4 , —N(R 3 )CO 2 R 4 , —N(R 3 )SO 2 R 4 , —C(O)N(R 3 ) 2 , —SO2N(R 3 ) 2 , —N(R 3 )C(O)N(R 3 ) 2 , —OC(O)R 4 , phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;
R 2a is C 1-6 alkyl;
Each T is independently a C 1-5 alkylidene that is optionally interrupted by —O—, —C(O)—, —S—, —S(O)—, —SO 2 —, or —N(R 3 )—;
Each V is independently selected from —O—, —S—, —S(O)—, —SO 2 —, —C(O)—, —N(R 3 )—, —N(R 3 )C(O)—, or —N(R 3 )CO 2 —, —N(R 3 )SO 2 —, —C(O)N(R 3 )—, —SO 2 N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, or —OC(O)—;
Each R 3 is independently selected from hydrogen, C 1-6 aliphatic, —C(O)R 4 , —CO 2 R 4 , —SO 2 R 4 , or two R 3 on the same nitrogen together with their intervening nitrogen form a 5-6 membered heterocyclyl or heteroaryl ring having 1-3 ring heteroatoms selected from N, O, or S;
R 4 is a C 1-6 aliphatic group;
Each R 5 is independently selected from —R 6 , -Q-R 6 , or —V-Q-R 6 ;
Each Q is independently a C 1-5 alkylidene that is optionally interrupted by —O—, —C(O)—, —S—, —S(O)—, —SO 2 —, or —N(R 3 )—; and
Each R 6 is independently selected from C 1-3 aliphatic, hydroxy, —N(R 3 ) 2 , halo, cyano, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —S(O)R 4 , —SO 2 R 4 , —N(R 3 )C(O)R 4 , or —N(R 3 )CO 2 R 4 , —N(R 3 )SO 2 R 4 , —C(O)N(R 3 ) 2 , —SO 2 N(R 3 ) 2 , —N(R 3 )C(O)N(R 3 ) 2 , —OC(O)R 4 , phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.
2. The compound of claim 1 wherein G is an optionally substituted phenyl ring.
3. The compound of claim 1 wherein A′ is CH.
4. The compound of claim 3 wherein Ring B is selected from the group consisting of:
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A compound selected from the group consisting of:
N-(3-Chloro-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(3-Chloro-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfinyl)-acetamide;
N-(3-chloro-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfonyl)-acetamide;
N-(3-chlorophenyl)-2-(2-isopropyl-5-pyridin-4-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(3-Chloro-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylamino)-acetamide;
N-(3-chlorophenyl)-3-(5-pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-propionamide;
N-(3-chloro-phenyl)-2-(4-pyridin-4-1H-imidazol-2-ylsulfanyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-pyridin-4-yl-oxazol-2-ylsulfanyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-pyridin-4-yl-oxazol-2-ylsulfanyl)-acetamide;
N-(3-Chloro-phenyl)-2-(5-pyridin-4-yl-[1,3,4]triadiazol-2-ylsulfanyl)-acetamide; and
N-(3-Chloro-phenyl)-2-(4-pyridin-4-yl-thiazol-2-ylsulfanyl)-acetamide.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 , and a pharmaceutically acceptable carrier.