Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase

Abstract

This invention relates to the treatment of intimation in a patient suffering from such disorder. More specifically, the invention relates to mono- and/or bicyclic aryl or heteroaryl quinazoline compounds in the treatment of inflammation.

We claim:  
     
       1. A method for the treatment of inflammation in a patient suffering from such disorder comprising administering to said patient an effective amount of the compound of formula:                    
       wherein 
       Ar is a substituted or unsubstituted benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, 1 H-pyrazole[3,4-d]pyrimidine, pteridine, 2(1H)-quinolone, 1(2H)-isoquinoline, 1,4-binzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline;  
       X is a bond, O, S, SO, SO 2 , OCH 2 , C—C, C≡C, C—S, SCH 2 , NH, NHCH 2 , NR 4  or NR 4 CH 2 ;  
       R is independently, located at any appropriate position of Ar, hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono-alkylamido, di-alkylamido, N, N-cycloalkylamido, sulfonyl, mono-alkyl sulfonyl, di-alkyl sulfonyl, sulfamoyl, mono-alkyl sulfamoyl, di-alkyl sulfamoyl, halophenyl or benzoyl;  
       R 4  is alkyl or benzyl;  
       R 5  is hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; and  
       R 6  and R 7  are alkoxy or aralkoxy; or  
       a pharmaceutically acceptable salt thereof,  
       provided that: when R 5  is hydrogen, R 6  and R 7  are methoxy, and X is a bond, then Ar is other than R substitute phenyl wherein R is hydrogen of (mono- or di-)methoxy; or when R 5  is hydrogen, R 6  and R 7  are alkoxy, X is NHCH 2 or NR 4 , and R 4  is hydrogen, then Ar is other than R substituted Ar is phenyl wherein R is hydrogen; or when R 5  is hydrogen or methoxy, R 6  and R 7  are methoxy, and X is NHCH 2 , then Ar is other than R substituted pyridinyl wherein R is hydrogen, mono-alkyl or mono-hydroxy, or Ar is other than R substituted indol-3-yl wherein R is hydrogen. 
     
     
       2. The method according to  claim 1  wherein said compound is selected from the group consisting of: 
           4   -(   3 , 4 , 5   - trimethoxyphenylamino )-   6 , 7   - dimethoxyquinazoline    
           4   -( naphthalen -   2   - ylethynyl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   4   - hydroxyphenyl )-   6 , 7   - dimethoxyquinazoline,    
           4   -( naphthalen -   1   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -( naphthalen -   2   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -( phenylacetylenyl -   6 , 7   - dimethoxyquinazoline,    
           4   -( fluoro -   4   - methoxyphenyl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   3   - phenylphenyl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   2   - phenylethylenyl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   2   - methoxypyridin -   5   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   1   - benzyl - indol -   3   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -( indol -   3   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   1   - methylindol -   3   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   1   - methylsulphonylindol -   3   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - methyl -   3 , 4 , 5   - trimethoxyanilino )-   6 , 7   - dimethoxyquinazoline,    
       (±)-   4   -(   2   - methyl -   1 , 2 , 3 , 4   - tetrahydroquinolin -   1   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   1 , 2 , 3 , 4   - tetrahydroquinolin -   1   - yl )-   6 , 7   -dimethoxyquinazoline,  
           4   -( N - methyl -   4   - methoxyanilino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - methyl -   4   - chloroanilino )-   6 , 7   -dimethoxyquinazoline,  
           4   -(   2 , 3   - dihydroindol -   1   - yl )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - methyl -   3   - trifluoromethylanilino )-   6 , 7   -dimethoxyquinazoline,  
           4   -( N - methyl -   3   - chloroanilino )-   6 , 7   - dimethoxyquinazoline -   4   - yl ) , and    
           4   -( naphthalen -   1   - ylethynyl )-   6 , 7   - dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.   
     
     
       3. The method according to  claim 1  wherein said compound is selected from the group consisting of: 
           4   -( indazol -   5   - ylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - methylanilino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - benzylanilino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - ethyl -   3   - chloroanilino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - methyl -   4   - methylanilino )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   4   - methoxybenzylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   3 , 5   - dimethoxybenzylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   3 , 4 , 5   - trimethoxyphenoxy )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   3   - methoxythiophenoxy )-   6 , 7   - dimethoxyquinazoline,    
           4   -[ N -(   5   - indanyl ) amino] -   6 , 7   - dimethoxyquinazoline,    
           4   -(   3   - chlorothiophenoxy )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   3   - aminopyrazolyl )-   6 , 7   - dimethoxyquinazoline,    
           4   -(   1 , 4   - benzodioxan -   6   - ylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -(α- naphthylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -(β- naphthylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( cyclohexylamino )-   6 , 7   - dimethoxyquinazoline,    
           4   -( N - methylanilino )-   6 , 7   - dimethoxyquinazoline, and    
           4   -(   3   - chlorophenoxy )-   6 , 7   - dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.   
     
     
       4. The method according to  claim 1  wherein said compound is  4 -( indol -   3   - yl )-   6 , 7   - dimethoxyquinazoline.   
     
     
       5. The method according to  claim 1  wherein said compound is  4 -(α- naphthylamino )-   6 , 7   - dimethoxyquinazoline.