Methods of inhibiting protein tyrosine kinase activity

Abstract

This invention relates to methods for inhibiting kinase activity and/or inhibiting angiogenesis and/or treating a disease responsive to inhibition of kinase activity and/or treating a cell proliferative disease and/or treating an ophthalmic disease, condition or disorder treating cell proliferative diseases and conditions and opthalmological diseases, disorders and conditions comprising administering novel compounds that inhibit protein tyrosine kinase activity.

What is claimed is: 
     
         1 . A method of inhibiting angiogenesis and/or treating a disease responsive to inhibition of kinase activity and/or treating a cell proliferative disease and/or treating an opthalmic disease, condition or disorder in patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein, 
         D is selected from the group consisting of an aromatic, heteroaromatic, cycloalkyl or heterocyclic ring system, each of which is substituted with 1 to 5 independently selected R 38 ; 
         M is 
       
       
         
           
           
               
               
           
         
         wherein 
         * represents the point of attachment to D; and 
         † represents the point of attachment to Z; 
         Z is —O—; 
         Ar is a 5 to 7 membered aromatic ring system, which is optionally substituted with 0 to 4 R 2  groups; and 
         G is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein 
         each R 38  is —C 1 -C 6 alkyl-heterocycle, wherein said heterocycle is optionally substituted with halo, hydroxy, oxo, nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups, and; 
         R 2  at each occurrence is independently selected from —H and halogen; 
         each R 3  is independently selected from the group consisting of —H and R 4 ; 
         R 4  is (C 1 -C 6 )alkyl; 
         each R 13  is independently selected from the group consisting of —H, —C(O)NR 3 R 3  and C 1 -C 6  alkyl; 
         Q is a three- to ten-membered ring system, optionally substituted with between zero and four of R 20 ; 
         each R 20  is independently selected from the group consisting of —H, halogen, trihalomethyl, —OR 3 , —S(O) 0-2 R 3 , —S(O) 2 NR 3 R 3 , —C(O)OR 3 , —C(O)NR 3 R 3 , —(CH 2 ) 0-5 (heteroaryl), C 1 -C 6  alkyl, —(CH 2 ) n P(═O)(C 1 -C 6 alkyl) 2 , wherein n is an integer ranging from 0 to 6. 
       
     
     
         2 . The method according to  claim 1 , wherein D is an aromatic or heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R 38  groups. 
     
     
         3 . The method according to  claim 1 , wherein D is a 5- or 6-membered heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R 38  groups. 
     
     
         4 . The method according to  claim 1 , wherein D is a 6-membered aromatic or 6-membered heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R 38  groups. 
     
     
         5 . The method according to  claim 1 , wherein D is a 6-membered aromatic ring system, substituted with 1 or 2 independently selected R 38  groups. 
     
     
         6 . The method according to  claim 1 , wherein D is a 6-membered heteroaromatic ring system, substituted with 1 or 2 independently selected R 38  groups. 
     
     
         7 . The method according to  claim 1 , wherein D is a 5-membered heteroaromatic ring system, substituted with 1 or 2 R 38  groups. 
     
     
         8 . The method according to  claim 1 , wherein D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R 38  groups. 
     
     
         9 . The method according to  claim 1 , wherein Ar is selected from the group consisting of phenyl, pyrazine, pyridazine, pryimidine and pyridine, wherein each of said phenyl, pyrazine, pyridazine, pryimidine and pyridine is optionally substituted with 0 to 4 R 2  groups. 
     
     
         10 . The method according to  claim 1 , wherein G is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method according to  claim 1 , wherein Q is selected from the group consisting of phenyl, cyclopropyl, isoxazolyl, cyclohexyl, thiazolyl, tetrahydrofuran, pyrazolyl, cyclobutyl and cyclopentyl, optionally substituted with between zero and two R 20 . 
     
     
         12 . The method according to  claim 1 , wherein each R 20  is independently selected from the group consisting of —P(═O)(Me) 2 , methyl, halo (for example F), trihalomethyl, methoxy, —C(O)NH 2 , heteroaryl, —COOH, —SO 2 HN 2 , —C(O)NH 2 , —COOMe, —C(O)N(H)(Me), —C(O)N(Me) 2  and —SO 2 Me. 
     
     
         13 . The method according to  claim 1 , wherein
 D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R 38  groups;   and   Ar is phenyl optionally substituted with 0 to 4 halo.   
     
     
         14 . The method according to  claim 1 , wherein
 D is pyridyl substituted with C 1 -C 6 alkyl-heterocycle, wherein said heterocycle is substituted with one oxo;   Ar is phenyl optionally substituted with one F; and   G is   
       
         
           
           
               
               
           
         
       
     
     
         15 . The method according to  claim 1 , wherein Ar is phenyl optionally substituted with 0 to 4 F; and
 Q is phenyl optionally substituted with 1 or 2 independently selected R 20 , wherein each R 20  is independently selected from the group consisting of —P(═O)(Me) 2 , methyl, halo, trihalomethyl, methoxy, —C(O)NH 2 , heteroaryl, —COOH, —SO 2 HN 2 , —C(O)NH 2 , —COOMe, —C(O)N(H)(Me), —C(O)N(Me) 2  and —SO 2 Me, or Q is pyrazolyl substituted with methyl, or Q is cyclopropyl, cyclobutyl or tetrahydrofuran.   
     
     
         16 . The method according to  claim 1 , wherein
 D is pyridyl substituted with —C 1 -C 6 alkyl-(heterocycle substituted with one oxo);   Ar is phenyl optionally substituted with one F;   G is   
       
         
           
           
               
               
           
         
         wherein 
         R 13  is H; and 
         Q is cyclopropyl. 
       
     
     
         17 . The method according to  claim 1 , wherein D is pyridyl;
 Ar is phenyl optionally substituted with one F;   G is   
       
         
           
           
               
               
           
         
         wherein 
         R 13  is H; and 
         Q is cyclopropyl. 
       
     
     
         18 . The method according to  claim 1 , wherein D is pyridyl substituted with —C 1 -C 6 alkyl-(heterocycle optionally substituted with one or two oxo);
 Ar is phenyl optionally substituted with one F; 
 G is 
 
       
         
           
           
               
               
           
         
         wherein 
         R 13  is H; and 
         Q is cyclopropyl. 
       
     
     
         19 . The method according to  claim 1 , wherein
 D is pyridyl substituted with   
       
         
           
           
               
               
           
         
         Ar is phenyl optionally substituted with 0 to 4 R 2  groups; 
         G is 
       
       
         
           
           
               
               
           
         
         wherein 
         R 13  is H; and 
         Q is cyclopropyl.