Rho-kinase inhibitors

Abstract

Disclosed are compounds and derivatives thereof, their synthesis, and their use as Rho-kinase inhibitors. These compounds of the present invention are useful for inhibiting tumor growth, treating erectile dysfunction, and treating other indications mediated by Rho-kinase, e.g., coronary heart disease.

We claim:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 X is —(CH 2 ) x —, —O—(CH 2 ) n —, —S—(CH 2 ) n —, —NR 7 —CO—(CH 2 ) n —,  
 —NR 7 —SO 2 —(CH 2 ) n —, —NR 7 —(CH 2 ) n —, or —(O)C—NR 7 —,  
 each n is an integer which is independently 0, 1, 2 or 3,  
 x is 0-3  
 p is 0-3  
 a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —, and b is —CR 5 ═ or —N═;  
 A is H, halogen, —CO—OR 8 , —CO—R 8 , cyano, —OR 8 , —NR 8 R 9 , —CO—NR 8 R 9 , —NR 8 —CO—R 9 , —NR 8 —CO—OR 9 , —NR 8 —SO 2 —R 9 , —SR 8 , —SO 2 —R 8 , —SO 2 —NR 8 R 9 , NR 8 —CO—NHR 9 , or  
 A is cyclohexyl; or C 5-12 -aryl or C 5-12 -heteroaryl each optionally independently substituted up to 3 times by (i) C 1 -C 10  alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10  cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; (xx) NR 8 —CO—NHR 9 ; or (xxi) aryl or heteroaryl substituted by halogen, C 1-10 -alkyl, C 1-10 -alkoxyphenyl, naphthyl, —OR 10 ,  
                     
 wherein  
 each Z independently is halogen, hydroxy, hydroxy-C 1-10 -alkyl, —CN, —NO 2 , C 1-10 -alkoxycarboxyl, —NR 10 —CO—R 11  or —NR 10 —CO—OR 11 ;  
 Y is 0-3;  
 Ring B represents a fused 5- or 6-membered heterocyclic ring containing 1-2 O, N, and/or S atoms and 1-5 C atoms;  
 R 1 , and R 6 -R 11  are each independently H and C 1 - 6  alkyl;  
 R 2 -R 5  are each independently (i) C 1-10  alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, C 5-10 -heteroaryl-C 1-10 -alkoxy or halogen up to perhalo; (ii) C 3 -C 10  cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-10 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (X) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;  
 R 12  is H, C 1-6 -alkyl or C 5-10 -aryl,  
 R 13  is H, C 1-6 -alkyl or C 1-6 -alkoxy,  
 R 14  is lower alkyl or phenyl;  
 R 15  is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14  or —OCOR 14 ;  
 R 16  is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl;  
 or a pharmaceutically acceptable salt thereof,  
 with the provisos that A is not hydrogen when x is 0;  
 —X-A is not CH 3  when B represents a thieno[3,2b]fused ring, and b and c are —CR 5 ═, and a is NH;  
 and A is not phenyl when X is NH, B forms an imidazo fused ring, and -a-b-c- is —CR 5 ═N—NR 6 — or —NR 6 ═N—CR 5 —.  
 
     
     
         2 . The compound according to  claim 1 , wherein A is 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-, -3- or B5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or 5-yl, 1,3,4-thiadiazol-3- or 5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl.  
     
     
         3 . The compound according to  claim 1  wherein A is phenyl, pyridyl, pyrimidinyl, oxazolyl, furyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl or pyrazinyl, each independently substituted up to three times by halogen, C 1-10 -alkyl, C 1-10 -alkoxyphenyl, naphthyl, —OR 10 ,  
       
         
           
           
               
               
           
         
         wherein each Z independently is halogen, hydroxy, hydroxy-C 1-10 -alkyl, —CN, —NO 2 , C 1-10 -alkoxycarboxyl, —NR 10 —CO—R 11 , or —NR 10 —CO—OR 11 , and y is 0-3.  
       
     
     
         4 . The compound according to  claim 1  wherein A is  
       
         
           
           
               
               
           
         
         wherein R 15  is H; phenyl optionally substituted by C 1-10 -alkyl, C 1-10 -alkoxy, C 1-10 -alkylcarboxyl, or halogen; benzyl; pyrimidyl or pyridyl; and R 16  is H, phenyl, —COOR 10 ,  
         
           
             
             
                 
                 
             
           
         
       
     
     
         5 . The compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
       
       wherein Ar 1  is  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
         wherein R′ is 5-methyl and R″ is H or 4-oxymethyl, or R′ is 5,6 dimethyl and R″ is H or 3-oxymethyl.  
       
     
     
         8 . The compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
       
       wherein Ar is 
 3-aminophenyl, 3-isonicotinamido-phenyl, 5-(1H-indolyl)amino, or 4-phenoxyanilino.  
 
     
     
         10 . The compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 1 , of the formula  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A method of treating an indication mediated by Rho-kinase, comprising administering a compound of  claim 1 .  
     
     
         13 . A method of treating an indication mediated by Rho-kinase, comprising administering a compound of  claim 5 .  
     
     
         14 . A method of treating hypertension, atherosclerosis, restenosis, cerebral ischemia, cerebral vasospasm, neuronal degeneration, spinal cord injury, cancer of the breast, colon, prostate, ovaries, brain or lung, thrombotic disorders, asthma, glaucoma, osteoporosis or erectile dysfunction, comprising administering to host in need thereof a compound according to  claim 1 .  
     
     
         15 . A method of treating hypertension, atherosclerosis, restenosis, cerebral ischemia, cerebral vasospasm, neuronal degeneration, spinal cord injury, cancer of the breast, colon, prostate, ovaries, brain or lung, thrombotic disorders, asthma, glaucoma, osteoporosis or erectile dysfunction, comprising administering to a host in need thereof a compound according to  claim 5 .  
     
     
         16 . A process according to  claim 12 , wherein the host is a human.  
     
     
         17 . A process according to  claim 13 , wherein the host is a human.  
     
     
         18 . A process according to  claim 14 , wherein the host is a human.  
     
     
         19 . A process according to  claim 15 , wherein the host is a human.