INDOLE-TYPE DERIVATIVES AS INHIBITORS OF p38 KINASE

Abstract

The invention is directed to methods to inhibit p38-α kinase using compounds of the formula and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein represents a single or double bond; one Z 2 is CA or CR 8 A and the other is CR 1 , CR 1 2 , NR 6 or N wherein each R 1 , R 6 and R 8 is independently hydrogen or noninterfering substituent; A is —W i —COX j Y wherein Y is COR 2 or an isostere thereof and R 2 is hydrogen or a noninterfering substituent, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1; Z 3 is NR 7 or O; each R 3 is independently a noninterfering substituent; n is 0-3; each of L 1 and L 2 is a linker; each R 4 is independently a noninterfering substituent; m is 0-4; Z 1 is CR 5 or N wherein R 5 is hydrogen or a noninterfering substituent; each of 1 and k is an integer from 0-2 wherein the sum of 1 and k is 0-3; Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring; and the distance between the atom of Ar linked to L 2 and the center of the α ring is 4.5-24 Å.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein  
         A is C(O)—Y, where Y is C(O)R;  
         Ar is a phenyl group substituted with 0-5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or forms thereof containing 1-2 O, S and/or N;  
         Z 1  is CR 5  or N;  
         L 1  is C(O);  
         L 2  is optionally substituted alkylene or NR, where R is H, alkyl (1-6C), or acyl (1-6C);  
         R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         R 2  is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , CN, COOR, CONR 2 , COR, or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N, or  
         wherein R 2  is OR, NR 2 , SR, NRCONR 2 , OCONR 2 , or NRSO 2 NR 2 , wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N, and wherein two R attached to the same atom may form a 3-8 member ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined;  
         each R 3  is independently halo, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR, or NR 2 , wherein R is H, alkyl, aryl, or forms thereof containing 1-2 O, S and/or N;  
         each R 4  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or forms thereof containing 1-2 O, S and/or N;  
         R 5  is H, alkyl, OR, halo, SR, or NR 2 , where R is H or alkyl;  
         R 7  is H or is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl or heteroalkyl, said heteroalkyl containing 1-2 O, S and/or N atoms or is SOR, SO 2 R, RCO, COOR, alkyl-COR, SO 3 R, CONR 2 , SO 2 NR 2 , CN, CF 3 , NR 2 , OR, alkyl-SR, alkyl-SOR, alkyl-SO 2 R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR 2 , or R 3 Si, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         n is 0 to 3; and  
         m is 0 to 4.  
       
     
     
         2 . The compound of  claim 1 , wherein L 1  is attached at position 5 of the indole ring.  
     
     
         3 . The compound of  claim 1 , wherein L 1  is attached at position 6 of the indole ring.  
     
     
         4 . The compound of  claim 2 , wherein Z 1  is N.  
     
     
         5 . The compound of  claim 2 , wherein Z 1  is CR 5 .  
     
     
         6 . The compound of  claim 3 , wherein Z 1  is N.  
     
     
         7 . The compound of  claim 3 , wherein Z 1  is CR 5 .  
     
     
         8 . The compound of  claim 5 , wherein L 2  is NR.  
     
     
         9 . The compound of  claim 7 , wherein L 2  is NR.  
     
     
         10 . The compound of  claim 4 , wherein L 2  is optionally substituted alkylene.  
     
     
         11 . The compound of  claim 6 , wherein L 2  is optionally substituted alkylene.  
     
     
         12 . The compound of  claim 10 , wherein L 2  is optionally substituted methylene.  
     
     
         13 . The compound of  claim 11 , wherein L 2  is optionally substituted methylene.  
     
     
         14 . A method to treat a condition mediated by p38-α kinase, comprising administering to a subject in need of such treatment a compound of the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein  
         A is C(O)—Y, where Y is C(O)R 2 ;  
         Ar is a phenyl group substituted with 0-5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or forms thereof containing 1-2 O, S and/or N;  
         Z 1  is CR 5  or N;  
         L 1  is C(O);  
         L 2  is optionally substituted alkylene or NR, where R is H, alkyl (1-6C), or acyl (1-6C);  
         R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         R 2  is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , CN, COOR, CONR 2 , COR, or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N, or  
         wherein R 2  is OR, NR 2 , SR, NRCONR 2 , OCONR 2 , or NRSO 2 NR 2 , wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N, and wherein two R attached to the same atom may form a 3-8 member ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined;  
         each R 3  is independently halo, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR, or NR 2 , wherein R is H, alkyl, aryl, or forms thereof containing 1-2 O, S and/or N;  
         each R 4  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or forms thereof containing 1-2 O, S and/or N;  
         R 5  is H, alkyl, OR, halo, SR, or NR 2 , where R is H or alkyl;  
         R 7  is H or is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl or heteroalkyl, said heteroalkyl containing 1-2 O, S and/or N atoms or is SOR, SO 2 R, RCO, COOR, alkyl-COR, SO 3 R, CONR 2 , SO 2 NR 2 , CN, CF 3 , NR 2 , OR, alkyl-SR, alkyl-SOR, alkyl-SO 2 R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR 2 , or R 3 Si, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         n is 0 to 3; and  
         m is 0 to 4.  
       
     
     
         15 . The method of  claim 14 , wherein the condition is selected from the group consisting of ischemia-reperfusion injury, congestive heart failure, progressive pulmonary and bronchial fibrosis, hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis, interstitial renal fibrosis, chronic scarring diseases of the eyes, bladder and reproductive tract, bone marrow dysplasia, chronic infectious or autoimmune states, and traumatic or surgical wounds.  
     
     
         16 . The method of  claim 14 , wherein the condition is an arthritic condition.  
     
     
         17 . A pharmaceutical composition, which composition comprises a therapeutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein  
         A is C(O)—Y, where Y is C(O)R 2 ;  
         Ar is a phenyl group substituted with 0-5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or forms thereof containing 1-2 O, S and/or N;  
         Z 1  is CR 5  or N;  
         L 1  is C(O);  
         L 2  is optionally substituted alkylene or NR, where R is H, alkyl (1-6C), or acyl (1-6C);  
         R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         R 2  is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , CN, COOR, CONR 2 , COR, or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N, or  
         wherein R 2  is OR, NR 2 , SR, NRCONR 2 , OCONR 2 , or NRSO 2 NR 2 , wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N, and wherein two R attached to the same atom may form a 3-8 member ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or the forms thereof containing 1-2 O, S and/or N wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined;  
         each R 3  is independently halo, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR, or NR 2 , wherein R is H, alkyl, aryl, or forms thereof containing 1-2 O, S and/or N;  
         each R 4  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or forms thereof containing 1-2 O, S and/or N;  
         R 5  is H, alkyl, OR, halo, SR, or NR 2 , where R is H or alkyl;  
         R 7  is H or is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl or heteroalkyl, said heteroalkyl containing 1-2 O, S and/or N atoms or is SOR, SO 2 R, RCO, COOR, alkyl-COR, SO 3 R, CONR 2 , SO 2 NR 2 , CN, CF 3 , NR 2 , OR, alkyl-SR, alkyl-SOR, alkyl-SO 2 R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR 2 , or R 3 Si, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         n is 0 to 3; and  
         m is 0 to 4.  
       
     
     
         18 . The pharmaceutical composition of  claim 17 , further comprising an additional therapeutic agent.  
     
     
         19 . A method to treat rheumatoid arthritis or osteoarthritis, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 10 .  
     
     
         20 . A method to treat rheumatoid arthritis or osteoarthritis, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 11.