Substituted pyrimidinyl-amines as protein kinase inhibitors

Abstract

The present invention provides novel substituted pyrimidinyl-amines that are useful as inhibitors of protein kinases, especially c-Jun N-terminal kinases (JNK) and pharmaceutical compositions thereof and methods of using the same for treating conditions responsive to the inhibition of the JNK pathway.

What is claimed is: 
     
         1 . A compound or pharmaceutically acceptable salt thereof of formula Ib: 
       
         
           
           
               
               
           
         
         wherein: 
         Z 1  and Z 2  are each independently CH or N, provided that at least one of Z 1  and Z 2  is N; 
         each R 1  is independently Cl, F, Br, I, CF 3 , OCF 3 , C 1-6 alkyl substituted with 0-2 R 5 , C 2-6 alkenyl substituted with 0-2 R 5 , C 2-6 alkynyl substituted with 0-2 R 5 , (CH 2 ) p NO 2 , (CH 2 ) p CN, (CH 2 ) p OR, (CH 2 ) p N(R) 2 , (CH 2 ) p COR, (CH 2 ) p OCOR, (CH 2 ) p CO 2 R, (CH 2 ) p CON(R) 2 , (CH 2 ) p OCON(R) 2 , (CH 2 ) p NRCOR, (CH 2 ) p NRCO 2 R, (CH 2 ) p NRCON(R) 2 , (CH 2 ) p C(═NH)NH 2 , (CH 2 ) p SOR, (CH 2 ) p SO 2 R, (CH 2 ) p SO 2 N(R) 2 , (CH 2 ) p NRSO 2 R, (CH 2 ) p NRSO 2 N(R) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R 5 ), or (CH 2 ) p -(4- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-2 R 5 , or two of R 1  that are attached to adjacent ring carbon atoms are taken together with the ring atoms through which they are connected to form a 5- to 6-membered heterocycloalkyl having 1 or 2 oxygen ring heteroatoms; 
         each R 2  is independently Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , or CON(R a ) 2 ; or R 1  and R 2  that are attached to adjacent ring carbon atoms are taken together with the ring atoms through which they are connected to form a 5- to 6-membered heterocycloalkyl having 1 or 2 oxygen ring members; 
         R 3  is H, CH 3 , CH 2 CH 3 , cyano, Cl, F, Br, or I; 
         R 4  is 3- to 10-membered carbocyclic ring substituted with 0-2 R 4a  or 5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 4a ; 
         each R 4a  is independently ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-6 alkyl substituted with 0-3 R 5 , C 2-6 alkenyl substituted with 0-3 R 5 , C 2-6 alkynyl substituted with 0-3 R 5 , (CH 2 ) p NO 2 , (CH 2 ) p CN, (CH 2 ) p OR, (CH 2 ) p N(R) 2 , (CH 2 ) p COR, (CH 2 ) p OCOR, (CH 2 ) p CO 2 R, (CH 2 ) p CON(R) 2 , (CH 2 ) p OCON(R) 2 , (CH 2 ) p NRCOR, (CH 2 ) p NRCO 2 R, (CH 2 ) p NRCON(R) 2 , (CH 2 ) p C(═NH)NH 2 , (CH 2 ) p SO 2 R, (CH 2 ) p SO 2 N(R) 2 , (CH 2 ) p NRSO 2 R, (CH 2 ) p NRSO 2 N(R) 2 , CH(CF 3 )NH 2 , or (CH 2 ) p -(5- to 6-membered heterocyclic ring) having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-3 R 5a ; 
         each R is independently H, C 1-6 alkyl substituted with 0-2 R 5 , C 2-6 alkenyl substituted with 0-2 R 5 , C 2-6 alkynyl substituted with 0-2 R 5 , 3- to 10-membered carbocyclic ring substituted with 0-2 R 5 , or 5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 5 ; or two R attached to the same N atom are taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered heterocycloalkyl substituted with 0-2 R 5    
         each R 5  is independently ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , CON(R a ) 2 , NR a COR a , NR a CO 2 R a , NR a CON(R a ) 2 , C(═NH)NH 2 , SO 2 R a , SO 2 N(R a ) 2 , NR a SO 2 R a , NR a SO 2 N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b ), or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with substituted with 0-2 R b ; or two R 5  taken together with a carbon atom to which they are both connected form a 1,3-dioxolane ring wherein the two oxygen ring atoms are attached to the connecting carbon atom; 
         R 5a  is selected from ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, (CH 2 ) p OR a , N(R a ) 2 , COR a , CO 2 R a , CON(R a ) 2 , NR a COR a , NR a CO 2 R a , NR a CON(R a ) 2 , C(═NH)NH 2 , SO 2 R a , SO 2 N(R a ) 2 , NR a SO 2 R a , NR a SO 2 N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b , or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-2 R b ; 
         each R a  is independently H, C 1-4 alkyl, C 3-6  cycloalkyl, CH 2 —C 3-6  cycloalkyl, phenyl, or benzyl; or two R a  attached to the same N atom are taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered heterocycloalkyl; 
         R b  is H, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl optionally substituted with OR a , C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , or CON(R a ) 2 ; 
         p is 0, 1, 2, 3, or 4; and 
         m and n are each independently the integer 0, 1, or 2, provided that the sum of m+n is 0, 1, or 2; 
       
       with the provisos that:
 (1) when R 4  is: 
 
       
         
           
           
               
               
           
         
          then R 4a  is other than ═O, halo, C 1-6 alkyl, OH, or O—C 1-6 alkyl; 
         (2) when R 4  is: 
       
       
         
           
           
               
               
           
         
          wherein R is a heterocyclic ring attached through a nitrogen ring atom; then R 4a  is other than halo, alkyl, OH, or O-alkyl. 
         (3) when R 4  is phenyl and at least one of R 4a  is (CH 2 ) p -(5- to 6-membered heterocyclic ring wherein p is 0, 1, or 2, then the heterocyclic ring has 3 or 4 heteroatom ring members; 
         (4) when R 4  is phenyl and at least one of R 4a  is (CH 2 ) p -(5- to 6-membered heterocyclic ring having one or two heteroatom ring members, then p is 3 or 4, 
         (5) when R 4  is phenyl and is substituted with only one R 4a , then R 4a  is ═O, Br, I, CF 3 , OCF 3 , C 1-6 alkyl substituted with 0-3 R 5 , C 2-6 alkenyl substituted with 0-3 R 5 , C 2-6 alkynyl substituted with 0-3 R 5 , (CH 2 ) p NO 2 , (CH 2 ) p OCOR, (CH 2 ) p OCON(R) 2 , (CH 2 ) p NRCON(R) 2 , (CH 2 ) p C(═NH)NH 2 , (CH 2 ) p NRSO 2 N(R) 2 , CH(CF 3 )NH 2 , or (CH 2 ) p -(5- to 6-membered heterocyclic ring; and 
         (6) the compound of formula I or pharmaceutically acceptable salt thereof is other than:
 N-[3-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)cyclohexyl]-2,6-dichlorobenzamide; 
 N-[4-(2-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrimidin-4-yl)phenyl]acetamide; 
 N-{4-[2-(1H-indazol-6-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; 
 N-{4-[2-(1H-indol-5-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; 
 N-{4-[2-(1H-indazol-5-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; 
 ′N-[6-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)pyridin-2-yl]-2,6-dichlorobenzamide 
 ′N-[6-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)pyrimidin-4-yl]-2,6-dichlorobenzamide; 
 N-(4-{2-[(6-aminopyridin-2-yl)amino]pyrimidin-4-yl}phenyl)acetamide; 
 N-(4-{2-[(6-aminopyrimidin-4-yl)amino]pyrimidin-4-yl}phenyl)acetamide; 
 (R)—N-(4-(2-(1,2,3,4-tetrahydroquinolin-6-ylamino)pyrimidin-4-yl)phenyl) pyrrolidine-2-carboxamide; 
 (R)—N-(4-(2-(6-morpholinopyridin-3-ylamino)pyrimidin-4-yl)phenyl) pyrrolidine-2-carboxamide; 
 N-{4-[2-(1H-benzimidazol-6-ylamino)-5-methylpyrimidin-4-yl]phenyl}acetamide; 
 ethyl 4-({4-[(acetylamino)phenyl]pyrimidin-2-yl}aminopiperidine-1-carboxylate; 
 1,1-dimethylethyl 4-({4-[4-(acetylamino)phenyl]pyrimidin-2-yl}amino)piperidine-1-carboxylate; or 
 N-{4-[2-(piperidin-4-ylamino)pyrimidin-4-yl]phenyl}acetamide; or N-{4-[2-({1-[(2,6-dichlorophenyl)carbonyl]piperidin-4-yl}amino)pyrimidin-4-yl]phenyl}acetamide. 
 
       
     
     
         2 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  is an aromatic carbocyclic ring. 
     
     
         3 . A compound or pharmaceutically acceptable salt thereof according to  claim 2 , wherein R 4  is phenyl substituted with 0-2 R 4a . 
     
     
         4 . A compound or pharmaceutically acceptable salt thereof according to  claim 3 , wherein at least one of R 4a  is —(CH 2 ) p -(5- to 6-membered heterocyclic ring). 
     
     
         5 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein p is 0 or 1. 
     
     
         6 . A compound or pharmaceutically acceptable salt thereof according to  claim 5 , wherein p is 0. 
     
     
         7 . A compound or pharmaceutically acceptable salt thereof according to  claim 6 , wherein R 4a  is -(5- to 6-membered heteroaromatic ring). 
     
     
         8 . A compound or pharmaceutically acceptable salt thereof according to  claim 7 , wherein R 4a  is -(5-membered heteroaromatic ring). 
     
     
         9 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 , wherein the heteroaromatic ring of R 4a  has 2, 3, or 4 heteroatom ring members are selected from N, O, and S. 
     
     
         10 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 , wherein the heteroaromatic ring of R 4a  heteroatom ring members are selected from N and O. 
     
     
         11 . A compound or pharmaceutically acceptable salt thereof according to  claim 10 , wherein the hetero aromatic ring of R 4a  has 3 or 4 heteroatom ring members. 
     
     
         12 . A compound or pharmaceutically acceptable salt thereof according to  claim 11 , wherein the hetero aromatic ring of R 4a  is substituted with Cl, F, Br, CF 3 , C 1-4 alkyl, C 2-4 alkenyl, (CH 2 ) p OR a , N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b , or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R b . 
     
     
         13 . A compound or pharmaceutically acceptable salt thereof according to  claim 12 , wherein the heteroaromatic ring of R 4a  is substituted with phenyl or benzyl. 
     
     
         14 . A compound or pharmaceutically acceptable salt thereof according to  claim 12 , wherein the heteroaromatic ring of R 4a  is substituted with (CH 2 ) p -(5- to 10-membered heterocyclic ring, and wherein the (CH 2 ) p -(5- to 10-membered heterocyclic ring is optionally substituted with Cl, F, CF 3 , C 1-4 alkyl optionally substituted with OR a , —CN, or OR a . 
     
     
         15 . A compound or pharmaceutically acceptable salt thereof according to  claim 14 , wherein the heteroaromatic ring of R 4a  is substituted with (CH 2 ) p -(5- to 10-membered heterocyclic ring, and wherein the 5- to 10-membered heterocyclic ring is pyridinyl, morpholinyl, piperidinyl, or piperazinyl, each optionally substituted. 
     
     
         16 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  is a 5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 4a . 
     
     
         17 . A compound or pharmaceutically acceptable salt thereof according to  claim 16 , wherein the heterocyclic ring is indazolyl, pyrazolyl, or piperidinyl, each optionally substituted. 
     
     
         18 . A compound or pharmaceutically acceptable salt thereof according to  claim 17 , wherein the indazolyl, pyrazolyl, or piperidinyl, is optionally substituted with Cl, F, C 1-6 alkyl substituted with 0-3 R 5 , (CH 2 ) p OR, (CH 2 ) p CON(R) 2 , (CH 2 ) p NRCO 2 R, or CH(CF 3 )NH 2 . 
     
     
         19 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein one of Z 1  and Z 2  is CH. 
     
     
         20 . A compound or pharmaceutically acceptable salt thereof according to  claim 19 , wherein Z 1  and Z 2  are each N. 
     
     
         21 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is H or F. 
     
     
         22 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is H. 
     
     
         23 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is Cl, F, Br, CF 3 , (CH 2 ) p CN, (CH 2 ) p OR, (CH 2 ) p N(R) 2 , (CH 2 ) p COR, (CH 2 ) p OCOR, (CH 2 ) p CO 2 R, (CH 2 ) p CON(R) 2 , (CH 2 ) p OCON(R) 2 , (CH 2 ) p SOR, (CH 2 ) p SO 2 R, (CH 2 ) p NRSO 2 R, (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R 5 ), or (CH 2 ) p -(4- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-2 R 5 , or two of R 1  that are attached to adjacent ring carbon atoms are taken together with the ring atoms through which they are connected to form a 5- to 6-membered heterocycloalkyl having 1 or 2 oxygen ring heteroatoms. 
     
     
         24 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is Cl, F, Br, CF 3 , NO 2 , —CN, OR a , N(R a ) 2 , or CON(R a ) 2 ; or R 1  and R 2  that are attached to adjacent ring carbon atoms are taken together with the ring atoms through which they are connected to form a 5- to 6-membered heterocycloalkyl having 1 or 2 oxygen ring members. 
     
     
         25 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and   an effective amount of a compound or a pharmaceutically acceptable salt thereof according to  claim 1 .   
     
     
         26 . A method of treating a disease or condition responsive to the inhibition of the JNK pathway, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  and Z 2  are each independently CH or N, provided that at least one of Z 1  and Z 2  is N; 
 each R 1  is independently Cl, F, Br, I, CF 3 , OCF 3 , C 1-6 alkyl substituted with 0-2 R 5 , C 2-6 alkenyl substituted with 0-2 R 5 , C 2-6 alkynyl substituted with 0-2 R 5 , (CH 2 ) p NO 2 , (CH 2 ) p CN, (CH 2 ) p OR, (CH 2 ) p N(R) 2 , (CH 2 ) p COR, (CH 2 ) p OCOR, (CH 2 ) p CO 2 R, (CH 2 ) p CON(R) 2 , (CH 2 ) p OCON(R) 2 , (CH 2 ) p NRCOR, (CH 2 ) p NRCO 2 R, (CH 2 ) p NRCON(R) 2 , (CH 2 ) p C(═NH)NH 2 , (CH 2 ) p SOR, (CH 2 ) p SO 2 R, (CH 2 ) p SO 2 N(R) 2 , (CH 2 ) p NRSO 2 R, (CH 2 ) p NRSO 2 N(R) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R 5 ), or (CH 2 ) p -(4- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-2 R 5 , or two of R 1  that are attached to adjacent ring carbon atoms are taken together with the ring atoms through which they are connected to form a 5- to 6-membered heterocycloalkyl having 1 or 2 oxygen ring heteroatoms; 
 each R 2  is independently Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , or CON(R a ) 2 ; or R 1  and R 2  that are attached to adjacent ring carbon atoms are taken together with the ring atoms through which they are connected to form a 5- to 6-membered heterocycloalkyl having 1 or 2 oxygen ring members; 
 R 3  is H, CH 3 , CH 2 CH 3 , cyano, Cl, F, Br, or I; 
 R 4  is 3- to 10-membered carbocyclic ring substituted with 0-2 R 4a  or 5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 4a ; 
 each R 4a  is independently ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-6 alkyl substituted with 0-3 R 5 , C 2-6 alkenyl substituted with 0-3 R 5 , C 2-6 alkynyl substituted with 0-3 R 5 , (CH 2 ) p NO 2 , (CH 2 ) p CN, (CH 2 ) p OR, (CH 2 ) p N(R) 2 , (CH 2 ) p COR, (CH 2 ) p OCOR, (CH 2 ) p CO 2 R, (CH 2 ) p CON(R) 2 , (CH 2 ) p OCON(R) 2 , (CH 2 ) p NRCOR, (CH 2 ) p NRCO 2 R, (CH 2 ) p NRCON(R) 2 , (CH 2 ) p C(═NH)NH 2 , (CH 2 ) p SO 2 R, (CH 2 ) p SO 2 N(R) 2 , (CH 2 ) p NRSO 2 R, (CH 2 ) p NRSO 2 N(R) 2 , CH(CF 3 )NH 2 , or (CH 2 ) p -(5- to 6-membered heterocyclic ring) having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-3 R a ; 
 each R is independently H, C 1-6 alkyl substituted with 0-2 R 5 , C 2-4 alkenyl substituted with 0-2 R 5 , C 2-6 alkynyl substituted with 0-2 R 5 , 3- to 10-membered carbocyclic ring substituted with 0-2 R 5 , or 5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 5 ; or two R attached to the same N atom are taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered heterocycloalkyl substituted with 0-2 R 5    
 each R 5  is independently ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , CON(R a ) 2 , NR a COR a , NR a CO 2 R a , NR a CON(R a ) 2 , C(═NH)NH 2 , SO 2 R a , SO 2 N(R a ) 2 , NR a SO 2 R a , NR a SO 2 N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b ), or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with substituted with 0-2 R b  or two R 5  taken together with a carbon atom to which they are both connected form a 1,3-dioxolane ring wherein the two oxygen ring atoms are attached to the connecting carbon atom; 
 R 5a  is selected from ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, (CH 2 ) p OR a , N(R a ) 2 , COR a , CO 2 R a , CON(R a ) 2 , NR a COR a , NR a CO 2 R a , NR a CON(R a ) 2 , C(═NH)NH 2 , SO 2 R a , SO 2 N(R a ) 2 , NR a SO 2 R a , NR a SO 2 N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b , or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-2 R b ; 
 each R a  is independently H, C 1-4 alkyl, C 3-6  cycloalkyl, CH 2 —C 3-4  cycloalkyl, phenyl, or benzyl; or two R a  attached to the same N atom are taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered heterocycloalkyl; 
 R b  is H, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 alkyl optionally substituted with OR a , C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , or CON(R a ) 2 ; 
 p is 0, 1, 2, 3, or 4; and 
 m and n are each independently the integer 0, 1, or 2, provided that the sum of m+n is 0, 1, or 2. 
 
     
     
         27 . A method of  claim 26 , wherein the disease or condition is selected from an inflammatory disease, an autoimmune disease, a cardiovascular disease, a metabolic disease, an ischemic disease, an infectious disease, and a proliferative disease. 
     
     
         28 . A method of  claim 27 , wherein the disease or condition is selected from Parkinson's disease, stroke, diabetes, cancer, myocardial infarction, multiple sclerosis, pulmonary fibrosis, and Alzheimers and pre-Alzheimers diseases. 
     
     
         29 . A method of treating a disease or condition responsive to the inhibition of the JNK pathway, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         30 . A method of  claim 29 , wherein the disease or condition is selected from an inflammatory disease, an autoimmune disease, a cardiovascular disease, a metabolic disease, an ischemic disease, an infectious disease, and a proliferative disease. 
     
     
         31 . A method of  claim 29 , wherein the disease or condition is selected from Parkinson's disease, stroke, diabetes, cancer, myocardial infarction, multiple sclerosis, pulmonary fibrosis, and Alzheimers and pre-Alzheimers diseases.