Novel heterocyclic carboxamides as modulators of kinase activity

Abstract

The invention provides novel heterocyclic carboxamide compounds according to Formula (I) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

1 - 13 . (canceled) 
     
     
         14 . A method for treating hyperproliferative diseases, comprising administering to a subject a compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein
 X is N, or C—R 4 ; 
 Y is N—R 5 , O, or absent; 
 R 1  is L 1 -R 6 , or L 1 -R 6 -L 2 -R 7 ; 
 R 2  is H, Hal, OH, OA, CN, NH 2 , or NHA; 
 R 3  is H, CH 3 , or C(Hal) 3 ; 
 R 4  is H, Hal, OH, COOH, NH 2 , or CN; 
 R 5  is H, LA or monocyclic alkyl having 3, 4, 5, 6, or 7 ring atoms, wherein one or two CH 2  groups may be replaced by a —NH— group, or 
 R 5 , R 1  together form a monocyclic alkyl ring having 3, 4, 5, 6, or 7 ring atoms, wherein one or two CH 2  groups may be replaced by an O atom and/or an —NH—, —NA-, —N(L 1 -R 6 )—, —CHA-, —CA 2 -, CH(L 1 -R 6 )— or —CO— group, and wherein the monocyclic alkyl ring may be substituted by NH 2 ; 
 L 1 , L 2  are each independently a single bond, or unbranched or branched alkyl having 1, 2, 3, 4 or 5 C atoms, which may be unsubstituted, or mono- or disubstituted with Hal, OH, NH 2 , NH(LA), N(LA) 2 , and wherein one or two CH 2  groups may be replaced by an O atom or by a —CO—, —NH—, —N(LA)-, —CONH—, —N(LA)COO— or —NHCO— group; 
 R 6 , R 7  are each independently Ar or a monocyclic alkyl ring having 3, 4, 5, 6, or 7 ring atoms, wherein one or two CH 2  groups may be replaced by an O atom and/or an —NH—, —NA-, —CHA-, —CO— or —CONHA- group; 
 each Ar is independently a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 8, 9, or 10 skeleton atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, A, OA, OH, NH 2 , or NHA; 
 each A is independently an unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5 or 6 C atoms, wherein one or two CH 2  groups may be replaced by an O atom and/or an —NH—, —NHCOAr or —CONHAr group wherein 1-3 H atoms may be replaced by Hal, and wherein one or two CH 3  groups may be replaced by NH 2 , OH, NH(LA) or N(LA) 2  group; 
 each LA is independently an unbranched or branched, linear alkyl having 1, 2, 3, or 4 C atoms wherein 1, 2 or 3 H atoms may be replaced by Hal; and 
 each Hal is independently F, Cl, Br or I. 
 
     
     
         15 . The method according to  claim 14 , wherein X is N and Y is N—R 5 . 
     
     
         16 . The method according to  claim 14 , wherein X is N; Y is N—R 5 ; and R 5 , R 1  together form monocyclic alkyl having 3, 4, 5, 6, or 7 ring atoms, wherein one or two CH 2  groups may be replaced by an —NH—, —NA-, —N(L 1 -R 6 )—, —CHA-, —CA 2 -, CH(L 1 -R 6 )— or —CO— group, and wherein monocyclic alkyl may be substituted by NH 2 . 
     
     
         17 . The method according to  claim 14 , wherein X is N; Y is N—R 5 ; and R 5 , R 1  together form monocyclic alkyl having 4, 5 or 6 ring atoms, wherein one CH 2  group is replaced by an —N(L 1 -R 6 )— group, and wherein monocyclic alkyl may be substituted by NH 2 . 
     
     
         18 . The method according to  claim 14 , wherein X is N; Y is N—R 5 ; R 5 , R 1  together form monocyclic alkyl having 4, 5 or 6 ring atoms, wherein one CH 2  group is replaced by an —N(L 1 -R 6 )— group, and wherein monocyclic alkyl may be substituted by NH 2 ; and L 1  is a bond, —CONH—, —NHCO—, —CONHCH 2 —, or CH 2 CONH—. 
     
     
         19 . The method according to  claim 14  wherein X is N; Y is N—R 5 ; R 5 , R 1  together form monocyclic alkyl having 4, 5 or 6 ring atoms, wherein one CH 2  group is replaced by an —N(L 1 -R 6 )— group, and wherein monocyclic alkyl may be substituted by NH 2 ; and R 6  is phenyl, which is unsubstituted, or independently mono-, di- or trisubstituted by Hal, C(Hal) 3 , CH 3 , or C(Hal) 3 O. 
     
     
         20 . The method according to  claim 14 , wherein X is N; Y is N—R 5 ; R 5 , R 1  together form monocyclic alkyl having 4, 5 or 6 ring atoms, wherein one CH 2  group is replaced by an —N(L 1 -R 6 )— group, and wherein monocyclic alkyl may be substituted by NH 2 ; L 1  is a bond, —CONH—, —NHCO—, —CONHCH 2 —, or CH 2 CONH—; and R 6  is phenyl, which is unsubstituted, or independently mono-, di- or trisubstituted by Hal, C(Hal) 3 , CH 3 , CH 3 O, or C(Hal) 3 O. 
     
     
         21 . The method according to  claim 14 , wherein X is N; Y is NH; R 1  is L 1 -R 6 -L 2 -R 7 ; L 1  and L 2  are a bond; R 6  is monocyclic alkyl having 4, 5 or 6 ring atoms, wherein one CH 2  group is replaced by an —NH—, group; and R 7  is phenyl, which is unsubstituted, or independently mono-, di- or trisubstituted by Hal, C(Hal) 3 , CH 3 , CH 3 O, or C(Hal) 3 O. 
     
     
         22 . The method according to  claim 14 , wherein X is N; Y is NH; R 1  is L 1 -R 6 -L 2 -R 7 ; L 1  and L 2  are a bond; R 6  is piperidyl or pyrrolidinyl; and R 7  is phenyl, which is mono- or disubstituted by Hal, C(Hal) 3 , CH 3 , CH 3 O, or C(Hal) 3 O. 
     
     
         23 . The method according to  claim 14 , wherein X is N; Y is NH; R 1  is L 1 -R 6 -L 2 -R 7 ; L 1  and L 2  are a bond; R 6  is 
       
         
           
           
               
               
           
         
       
       and R 7  is phenyl, which is mono- or disubstituted by Hal, C(Hal) 3 , CH 3 , CH 3 O, or C(Hal) 3 O. 
     
     
         24 . The method according to  claim 14 , wherein X is N; Y is NH; R 1  is L 1 -R 6 ; and R 6  is phenyl, which is unsubstituted, or independently mono-, di- or trisubstituted by Hal, C(Hal) 3 , CH 3 , CH 3 O, or C(Hal) 3 O. 
     
     
         25 . The method according to  claim 14 , wherein the compound is selected from:
 5-((4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide (trans_racemic),   5-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide (trans_racemic),   5-((4-(3-fluoro-4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic),   5-((-4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide (trans_racemic)   5-((4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide,   5-((4-(4-chloro-3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide,   5-((4-(3-chloro-4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide,   5-(((3R,4R)-4-(3-chloro-4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide, and   5-((4-(4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide,   or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.   
     
     
         26 . The method according to  claim 14 , wherein the hyperproliferative disease is selected from cancer, inflammation, pancreatitis, kidney diseases, pain, benign hyperplasia of the skin, restenosis, prostate diseases related to vasculogenesis or angiogenesis, tumor angiogenesis, psoriasis, eczema, sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, and Kaposi's sarcoma.