Quinazoline and indole compounds to treat medical disorders

Abstract

Compounds, methods of use, and processes for making inhibitors of Complement Factor B are provided.

We claim: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 D is D2; 
 E is selected from: E1 and E2; 
 F is selected from: F1 and F2; 
 D2 is selected from 
 
       
         
           
           
               
               
           
         
         wherein D2 is optionally substituted by one or more groups selected from R 55  and R 62 ; 
         R 51  is independently selected from hydrogen, halogen, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  aminoalkyl, (C 1 -C 6  alkoxy)(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)(C 1 -C 6  alkoxy), C 1 -C 6  haloalkoxy, —S(C 1 -C 6  alkyl), —S(O)(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), —CH 2 NHC(O)(C 1 -C 6  alkyl), and —OCH 2 C(O)R 57 ; 
         R 52  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  hydroxyalkyl, and halogen; 
         R 53  is selected from hydrogen; halogen; cyano; C 1 -C 6  alkyl; C 1 -C 6 haloalkyl; —CH 2 C(O)R 57 ; C 6 -C 14  aryl; and 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from nitrogen, oxygen phosphorus, sulfur, silicon, and boron, wherein the aryl and heteroaryl group is optionally substituted with C 1 -C 6  alkyl groups; 
         E1 is 
       
       
         
           
           
               
               
           
         
         E2 is 
       
       
         
           
           
               
               
           
         
         F1 is phenyl, napthyl, or heteroaryl, wherein F1 is optionally substituted by R 55  and further optionally substituted with a substituent selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, and cyanomethyl; 
         F2 is selected from 
       
       
         
           
           
               
               
           
         
       
       and a 5- to 10-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron with a R 62  substituent;
 wherein each F2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 55  and R 62 ; 
 R 54  is hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  hydroxyalkyl; 
 R 55  is selected from —C(O)R 58 , —CH 2 C(O)R 58 , R 59 , —C(O)NHSO 2 (C 1 -C 6  alkyl), —SO 2 NR 25 C(O)(C 1 -C 6  alkyl), —SO 2 N(R 25 ) 2 , —SO 2 (C 1 -C 6  alkyl), cyano, halogen, C 1 -C 6  hydroxyalkyl, and 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; 
 m is independently 0, 1, or 2; 
 n is 0, 1, 2, 3, or 4; 
 R 25  is independently selected from hydrogen and C 1 -C 4 alkyl; 
 R 56  is independently selected at each occurrence from hydrogen, hydroxy, —N(R 25 ) 2 , C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  cyanoalkyl, and C 1 -C 6  alkyoxy; 
 or C(R 56 ) 2 , taken in combination, forms a spirocyclic carbocycle having 3, 4, 5, or 6 ring atoms; 
 R 57  is hydroxy, C 1 -C 6  alkoxy, or —N(R 25 ) 2 ; 
 R 58  is hydroxy; C 1 -C 6  alkoxy; —N(R 25 ) 2 ; or 3- to 12-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron, wherein each R 58  other than hydroxy is optionally substituted with halogen, hydroxy, or C 1 -C 6  alkyl; 
 R 59  is 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron, optionally substituted with one or more C 1 -C 6  alkyl groups; 
 R 60  is halogen; 
 R 61  is independently selected at each occurrence from hydrogen, halogen, hydroxy, —N(R 25 ) 2 , C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  cyanoalkyl, and C 1 -C 6  alkyoxy; 
 R 62  is selected from 
 
       
         
           
           
               
               
           
         
       
       P(Q)R 65 R 65 , —C(O)NR 25 OR 25 , and SF 5 ;
 R 63  and R 64  are independently selected at each occurrence from hydrogen; hydroxyl; cyano; amino; C 1 -C 6  alkyl; C 1 -C 6  haloalkyl; C 1 -C 6  alkoxy; (C 3 -C 6  cycloalkyl)(C 1 -C 6  alkyl); (phenyl)C 0 -C 4 alkyl; —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl; —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl; —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl; C 6 -C 14  aryl; 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; 3- to 12-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; (C 6 -C 14  aryl)(C 1 -C 6  alkyl); (5- to 10-membered heteroaryl)(C 1 -C 6  alkyl) having 1, 2, or 3 ring atoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; and (3- to 12-membered heterocyclo)(C 1 -C 6  alkyl) having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; and 
 R 65  is independently selected at each occurrence from hydroxy; C 1 -C 6  alkoxy; C 1 -C 6  haloalkoxy; C 1 -C 6  alkyl; (C 3 -C 6  cycloalkyl)(C 1 -C 6  alkyl); C 6 -C 14  aryl; (C 6 -C 14  aryl)(C 1 -C 6  alkyl); —O-arylalkyl, —O-aryl, heterocycle, heterocycloalkyl, heteroaryl, heteroarylalkyl, O-heteroaryl, O-heterocycle, and —N(R 25 ) 2 . 
 
     
     
         2 . The compound of  claim 1 , wherein D2 is R 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein D2 is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein each R 51  is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein F is F1. 
     
     
         6 . The compound of  claim 5 , wherein F1 is phenyl; or phenyl substituted by R 55 ; and further optionally substituted with a substituent selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, and cyanomethyl. 
     
     
         7 . The compound of  claim 1 , wherein E is E1. 
     
     
         8 . The compound of  claim 7 , wherein E1 is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein m is 1. 
     
     
         10 . The compound of  claim 9 , wherein R 56  is independently selected at each occurrence from hydrogen and C 1 -C 6  alkyl. 
     
     
         11 . The compound of  claim 10 , wherein R 54  is hydrogen. 
     
     
         12 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         13 . A method for the treatment of a disorder mediated by Complement Factor B, comprising administering an effective amount of a compound of  claim 1  or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, to a human in need thereof. 
     
     
         14 . The method of  claim 13 , wherein the disorder is age-related macular degeneration (AMD), retinal degeneration, or an ophthalmic disease. 
     
     
         15 . The method of  claim 13 , wherein the disorder is rheumatoid arthritis, multiple sclerosis, or arthritis. 
     
     
         16 . The method of  claim 13 , wherein the disorder is a respiratory disease or COPD. 
     
     
         17 . The method of  claim 13 , wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH). 
     
     
         18 . The method of  claim 13 , wherein the disorder is a cardiovascular disease. 
     
     
         19 . The method of  claim 13 , wherein the disorder is atypical or typical hemolytic uremic syndrome. 
     
     
         20 . The method of  claim 13 , wherein the disorder is C3 glomerulonephritis.