Substituted Oxazole Derivatives and their Use as Tyrosine Kinase Inhibitors

Abstract

The present invention relates to novel compounds selected from substituted oxazole derivatives of formula (I) that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective c-kit, bcr-abl and Fit-3 inhibitors.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         Wherein substituents A, B, B′, Q and R1-R5 in Formula I are defined as follows: 
         A and B′ is one of the following:
 i) (R6)N(CH2) n  where n is 0 or 1, 
 ii) O(CH2) n  where n is 0 or 1, 
 iii) S(CH2) n  where n is 0 or 1, 
 iv) (CH2) n  where n is 0, 1 or 2, and 
 v) C(O)(CH2) n  where n is 0 or 1; 
 or when A and B′ each are a nitrogen, they may be taken together to form a bivalent radical of formula:
   —(CH2) s —X1-(CH2) t —  (a) 
 
 
         wherein s and t each independently is 1 or 2, and X1 is O, S, NR10, N[C(═O)R10] or (CH2) n  wherein n is 0 or 1, and wherein each hydrogen in said formula (a) may be substituted with halo or C 1-4 alkyl; 
         B is one of the following:
 i) (R6)N, 
 ii) Oxygen, 
 iii) S(O) n  where n is 0, 1 or 2, 
 iv) CH(R6)(R7), 
 v) C=δ, where δ is oxygen, sulfur, NH or N—CN, 
 vi) C(R6)═C(R7), and 
 vii) N═C(R6), 
 
         wherein R6 and R7 each independently are hydrogen, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-4 hydroxyalkyl; 
         R1 is selected from:
 i) hydrogen, halogen (selected from F, Cl, Br or I), 
 ii) an alkyl 1  group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO—R, COO—R, CONH—R, SO2-R, and SO2NH—R wherein R is a linear or branched alkyl group containing 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as a cycloalkyl or aryl 1  or heteroaryl 1  group optionally substituted by a pendant basic nitrogen functionality, 
 iii) an aryl 1  group defined as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as 
 halogen (selected from I, F, Cl or Br); 
 an alkyl 1  group; 
 a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality; 
 trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(alkyl 1 )(alkyl 1 ), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; 
 NHCO—R or NHCOO—R or NHCONH—R or NHSO2-R or NHSO2NH—R or CO—R or COO—R or CONH—R or SO2-R or SO2NH—R wherein R corresponds to hydrogen, alkyl 1 , aryl or heteroaryl, 
 iv) a heteroaryl 1  group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, benzoxazole, benzothiazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as 
 halogen (selected from F, Cl, Br or I); 
 an alkyl 1  group; 
 a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality, 
 trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(alkyl 1 )(alkyl 1 ), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; 
 NHCO—R or NHCOO—R or NHCONH—R or NHSO2-R or NHSO2NH—R or CO—R or COO—R or CONH—R or SO2-R or SO2NH—R wherein R corresponds to hydrogern, alkyl 1 , 
 v) an O-aryl 1 , or NH-aryl 1 , or O-heteroaryl 1  or NH-heteroaryl 1  group, 
 vi) trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(alkyl 1 )(alkyl 1 ), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality, and 
 vii) NHCO—R or NHCOO—R or NHCONH—R or NHSO2-R or NHSO2NH—R or CO—R or COO—R or CONH—R or SO2-R or SO2NH—R wherein R corresponds to hydrogen, alkyl 1 , aryl or heteroaryl 
 R2, R3, R4 and R5 each independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, C 1-6 alkyloxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, carboxyl, cyano, nitro, formyl, hydroxy, and CO—R, COO—R, CONH—R, SO2-R, and SO2NH—R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; 
 
         Q is selected from:
 i) Alkyl 1 , 
 ii) Aryl 1 , and 
 iii) Heteroaryl 1 . 
 
       
     
     
         2 . The compound according to  claim 1  of formula II: 
       
         
           
           
               
               
           
         
         Wherein Y is oxygen, sulfur, NH or N—CN, Z is oxygen, sulfur, N(R6) or (CH2) n  where n is 0, 1 or 2, L is selected from Alkyl 1 , Aryl 1  or Heteroaryl 1  and R1, R2, R3, R4, R5 and R6 as defined in  claim 1 . 
       
     
     
         3 . The compound according to  claim 1  of formula III: 
       
         
           
           
               
               
           
         
         Wherein 
         n is an integer of 0, 1 or 2; 
         M is oxygen, sulfure or (CH2) n  where n is 0, 1 or 2; 
         P is selected from N(R8)(R9), Alkyl 1 , Aryl 1  or Heteroaryl 1 ; 
         wherein R8 and R9 each independently is hydrogen, Alkyl 1 , Aryl or Heteroaryl 1 ; 
         R8 and R9 may be taken together to form a bivalent radical of formula:
   —(CH2) v —X2-(CH2) w —  (b) 
 
         wherein v and w each independently is 1 or 2 and X2 being CH2, O, S, NR10 or N[C(═O)R10] and wherein each hydrogen in said formula (b) maybe substituted with halo or C 1-4 alkyl; 
         R10 is hydrogen, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-4 hydroxyalkyl; 
         R1, R2, R3, R4 and R5 have the meaning described above. 
       
     
     
         4 . The compound according to  claim 1  of formula IV: 
       
         
           
           
               
               
           
         
         Wherein 
         G is oxygen, sulfur, N(R11) or (CH2) n  where n is 1 or 2; 
         H is oxygen, N(R11) or (CH2) n  where n is 1 or 2; 
         J is selected from N(R12)(R13), Alkyl 1 , Aryl 1  or Heteroaryl 1 ; 
         wherein R12 and R13 each independently is hydrogen, Alkyl 1 , Aryl 1  or Heteroaryl 1 ; 
         R12 and R13 maybe taken together to form a bivalent radical of formula:
   —(CH2) v —X2-(CH2) w —  (c) 
 
         wherein v and w each independently is 1 or 2 and X2 being CH2, O, S, NR14 or N[C(═O)R14] and wherein each hydrogen in said formula (c) maybe substituted with halo or C 1-4 alkyl; 
         R11 and R14 each independently is hydrogen, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-4 hydroxyalkyl; 
         R1, R2, R3, R4 and R5 have the meaning described above. 
       
     
     
         5 . The compound as claimed in  claim 1  selected from: 
       N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-C-phenyl-methane sulfonamide, 
       4-{2-[5-(Benzooxazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzonitrile, 
       4-{2-[5-(Benzooxazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzonitrile, 
       4-{2-[5-(Benzothiazol-2-ylammo)-2-methyl-phenylamino]-oxazol-5-yl}-benzonitrile, 
       N1-Benzooxazol-2-yl-4-methyl-N3-(5-pyridin-3-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       N-(5-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       N1-(6-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       N1-(5-Ethanesulfonyl-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       4-Methyl-N1-(5-methyl-benzooxazol-2-yl)-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       N1-Fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       N1-(6-Fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine, 
       4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile, 
       4-(2-{5-[3-(3-cyano-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile, 
       4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzamide, 
       1-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-imidazolidin-2-one, 
       1-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-(3-trifmoromethyl-phenyl)-imidazolidin-2-one, 
       1-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-tetrahydro-pyrimidin-2-one, 
       1-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-phenyl-propan-1-one, 
       4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile, 
       4-(2-{5-[3-(4-Fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile. 
       4-{2-[2-Methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitrile. 
       4-(2-{5-[3-(3-Fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile 
       4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzamide. 
       1-(4-Fluoro-phenyl)-2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenylamino]-ethanone, 
       1-(4-Fluoro-phenyl)-2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-ethanone, 
       4-({Methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-acetyl)-benzonitrile 
       2-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylammo)-phenylamino]-1-phenyl-ethanone, 
       4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile, 
       4-(2-{5-[2-(4-Cyano-phenyl)-2-oxo-ethylamino]-2-chloro-phenylamino}-oxazol-5-yl)-benzonitrile, 
       N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzyl]-benzamide, and 
       2-{Methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-1-phenyl-ethanone. 
     
     
         6 . The compound according to  claim 1 , wherein R1 is pyridyl or benzonitril which may additionally bear any combination, at any one ring position, of one or more substituents such as
 hydrogen;   halogen (selected from F, Cl, Br or I);   an alkyl group;   an aryl 1  group;   trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(alkyl 1 )(alkyl 1 ), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; and   NHCO—R or NHCOO—R or NHCONH—R or NHSO2-R or NHSO2NH—R or CO—R or COO—R or CONH—R or SO2-R or SO2NH—R wherein R corresponds to hydrogen, alkyl 1  aryl 1  group.   
     
     
         7 . A pharmaceutical composition comprising a compound according to  claim 1 . 
     
     
         8 . A pharmaceutical composition according to  claim 7  comprising a pharmaceutically acceptable carrier suitable for oral or topical administration. 
     
     
         9 . A pharmaceutical composition according to  claim 7  formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, and suspensions. 
     
     
         10 . A cosmetic composition for topical administration comprising a compound according to  claim 1 . 
     
     
         11 - 16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 5 , and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating a neoplastic disease comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the neoplastic disease is mastocytosis, canine mastocytoma, solid tumor, human gastrointestinal stromal tumor (“GIST”), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumor, testicular cancer, glioblastomas, or astrocytomas. 
     
     
         20 . A method of treating an allergic disease comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the allergic disease is asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation, or blood sucking parasitic infestation. 
     
     
         22 . A method of treating an inflammatory disease comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the inflammatory disease is rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, or other arthritic conditions. 
     
     
         24 . A method of treating an autoimmune disease comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 . 
     
     
         25 . The method of  claim 24 , wherein the autoimmune disease is multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, or proliferative glomerulonephritis. 
     
     
         26 . A method of treating a graft-versues-host disease or graft-rejection in an organ transplantation, comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 . 
     
     
         27 . The method of  claim 26 , wherein the organ is a kidney, pancreas, liver, heart, lung, or bone marrow. 
     
     
         28 . A method of treating a neoplastic disease, an allergic disease, an inflammatory disease, an autoimmune disease, a graft-versues-host disease, or graft-rejection in an organ transplantation, comprising administering to a subject in need thereof an effective amount of the compound according to  claim 5 .