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.

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 COON(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; 
       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 ; 
     
     
       
         
         
             
             
         
       
       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 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein Ar 1  is 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . A compound of the formula 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       7 . (canceled) 
   
   
       8 . (canceled) 
   
   
       9 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein Ar is
 3-aminophenyl, 3-isonicotinamido-phenyl, 5-(1H-indolyl)amino, or 4-phenoxyanilino. 
 
     
   
   
       10 . (canceled) 
   
   
       11 . A compound of the formula 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       12 . (canceled) 
   
   
       13 . (canceled) 
   
   
       14 . A method of treating hypertension, atherosclerosis, restenosis, cerebral ischemia, cerebral vasospasm, 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, or erectile dysfunction, comprising administering to a host in need thereof a compound according to  claim 5 . 
   
   
       16 . (canceled) 
   
   
       17 . (canceled) 
   
   
       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.