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

Abstract

This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, cell inflammatory response, the control of abnormal cell growth and cell reproduction. More specifically, this invention relates to the use of mono- and/or bicyclic aryl or heteroaryl quinazoline compounds in inhibiting cell proliferation, including compounds which are useful protein tyrosine kinase (PTK) inhibitors. The method of treating cell proliferation and/or differentiation or mediator release using said quinazoline compounds and their use in pharmaceutical compositions is described.

What is claimed:  
     
         1 . A method for the treatment of bone disease in a patient suffering from such disorder comprising administering to said patient an effective amount of a composition having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O, and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R;  
 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 independently includes hydrogen, alkyl, 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- and di-alkylamido, and N,N-cycloalkylamido, sulfonyl, mono- and di-alkyl sulfonyl, sulfamoyl, mono- and di-alkyl sulfamoyl, halophenyl, or benzoyl, and R and R together may also form a ketone group;  
 R 4  is alkyl, —CH2—CH2— or —CH2—CH2—CH2—; and  
 R5, R6, and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A method for the treatment of inflammation in a patient suffering from such disorder comprising administering to said patient an effective amount of a composition having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O, and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R;  
 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 independently includes hydrogen, alkyl, 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- and di-alkylamido, and N,N-cycloalkylamido, sulfonyl, mono- and di-alkyl sulfonyl, sulfamoyl, mono- and di-alkyl sulfamoyl, halophenyl, or benzoyl, and R and R together may also form a ketone group;  
 R 4  is alkyl, —CH2—CH2— or —CH2—CH2—CH2—; and  
 R5, R6, and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A method of inhibiting cell proliferation, differentiation, or mediator release in a patient suffering from a disorder characterized by such proliferation and/or differentiation and/or mediator release comprising administering to a patient a composition selected from: 
 4-(naphthalen-2-ylethynyl)-6,7-dimethoxyquinazoline,    4-(4-hydroxyphenyl)-6,7-dimethoxyquinazoline hydrochloride    4-phenylacetylenyl-6,7-dimethoxyquinazoline,    4-(2-phenylphenyl)-6,7-dimethoxyquinazoline,    4-(1-methylindol-3-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(4-phenylpiperidin-1-yl)-6,7-dimethoxyquinazoline,    4-[4-(3-chlorophenyl)piperazin-1-yl]-6,7-dimethoxyquinazoline,    (±)-4-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-methoxyanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-chloro-anilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-trifluoromethylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-chloroanilino)quinazoline hydrochloride and    4-(naphthalen-1-ylethynyl)-6,7-dimethoxyquinazoline; or    a pharmaceutically acceptable salt thereof.    
     
     
         4 . The method of  claim 3  where said composition administered is selected from: 
 4-(indazol-5-ylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-benzylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methylanilino)-6-chloroquinazoline,  
 4-(N-ethyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methyl-4-methylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-benzylamino)-6,7-dimethoxyquinazoline,  
 4-(4-methoxybenzylamino)-6,7-dimethoxyquinazoline,  
 4-(3,5-dimethoxybenzylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methylanilino)quinazolin-4-yl) hydrochloride,  
 4-(4-morpholin-4-ylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline,  
 4-[N-(5-indanyl)amino]-6,7-dimethoxyquinazoline hydrochloride,  
 4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline,  
 4-(3-aminopyrazolyl)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(1,4-benzodioxan-6-ylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(α-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(β-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(cyclohexylanilino)-6,7-dimethoxyquinazoline,  
 4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride, and  
 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         5 . A pharmaceutical composition for effectively inhibiting CSF-1R tyrosine kinase activity by exhibiting inhibition of cell proliferation and/or differentiation and/or mediator release comprising a CSF-1R receptor inhibiting effective amount of a compound selected from: 
 4-(naphthalen-2-ylethynyl)-6,7-dimethoxyquinazoline,    4-(4-hydroxyphenyl)-6,7-dimethoxyquinazoline hydrochloride    4-phenylacetylenyl-6,7-dimethoxyquinazoline,    4-(2-phenylphenyl)-6,7-dimethoxyquinazoline,    4-(1-methylindol-3-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(4-phenylpiperidin-1-yl)-6,7-dimethoxyquinazoline,    4-[4-(3-chlorophenyl)piperazin-1-yl]-6,7-dimethoxyquinazoline,    (±)-4-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-methoxyanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-chloro-anilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-trifluoromethylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-chloroanilino)quinazoline hydrochloride and    4-(naphthalen-1-ylethynyl)-6,7-dimethoxyquinazoline; or    a pharmaceutically acceptable salt thereof.    
     
     
         6 . The pharmaceutical composition of  claim 5  where said composition is selected from: 
 4-(indazol-5-ylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-benzylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methylanilino)-6-chloroquinazoline,  
 4-(N-ethyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methyl-4-methylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-benzylamino)-6,7-dimethoxyquinazoline,  
 4-(4-methoxybenzylamino)-6,7-dimethoxyquinazoline,  
 4-(3, 5-dimethoxybenzylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(N-methylanilino)quinazolin-4-yl) hydrochloride,  
 4-(4-morpholin-4-ylanilino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline,  
 4-[N-(5-indanyl)amino]-6,7-dimethoxyquinazoline hydrochloride,  
 4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline,  
 4-(3-aminopyrazolyl)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(1,4-benzodioxan-6-ylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(α-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(β-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride,  
 4-(cyclohexylanilino)-6,7-dimethoxyquinazoline,  
 4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride, and  
 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         7 . A compound selected from: 
 4-(indazol-5-ylamino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-benzylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methylanilino)-6-chloroquinazoline,    4-(N-ethyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-methylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-benzylamino)-6,7-dimethoxyquinazoline,    4-(4-methoxybenzylamino)-6,7-dimethoxyquinazoline,    4-(3,5-dimethoxybenzylamino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methylanilino)quinazolin-4-yl) hydrochloride,    4-(4-morpholin-4-ylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline,    4-[N-(5-indanyl)amino]-6,7-dimethoxyquinazoline hydrochloride,    4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline,    4-(3-aminopyrazolyl)-6,7-dimethoxyquinazoline hydrochloride,    4-(3,6-dioxananilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(α-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride,    4-(β-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride,    4-(cyclohexylanilino)-6,7-dimethoxyquinazoline,    4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride, and    4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline; or    a pharmaceutically acceptable salt thereof.    
     
     
         8 . A compound selected from: 
 4-(naphthalen-2-ylethynyl)-6,7-dimethoxyquinazoline,    4-(4-hydroxyphenyl)-6,7-dimethoxyquinazoline hydrochloride    4-phenylacetylenyl-6,7-dimethoxyquinazoline,    4-(2-phenylphenyl)-6,7-dimethoxyquinazoline,    4-(1-methylindol-3-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(4-phenylpiperidin-1-yl)-6,7-dimethoxyquinazoline,    4-[4-(3-chlorophenyl)piperazin-1-yl]-6,7-dimethoxyquinazoline,    (±)-4-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-methoxyanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-4-chloro-anilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-trifluoromethylanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride,    4-(N-methyl-3-chloroanilino)quinazoline hydrochloride and    4-(naphthalen-1-ylethynyl)-6,7-dimethoxyquinazoline; or    a pharmaceutically acceptable salt thereof.