Compounds modulating c-kit and c-fms activity and uses therefor

Abstract

Compounds active on the receptor protein tyrosine kinases c-kit and c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or condition and c-fms-mediated diseases or condition, and methods for the use thereof.

1 .- 35 . (canceled) 
     
     
         36 . A method for treating a subject suffering from or at risk of a c-kit or c-fms mediated disease or condition, comprising administering to the subject an effective amount of a compound having the chemical structure: 
       
         
           
           
               
               
           
         
         all salts, tautomers, and stereoisomers thereof, 
       
       wherein:
 X 1  is CR 2 , X 2  is CR 6 , Y 1  is CR 4 , and Y 2  is CR 5 ; 
 L 1  is lower alkylene; 
 L 2  is selected from the group consisting of (alk) a -S-(alk) b -, -(alk) a -O-(alk) b - and -(alk) a -NR 9 -(alk) b -, wherein alk is optionally substituted C 1-3  alkylene and a and b are independently 0 or 1; 
 R 1  is cycloalkyl or phenyl, wherein phenyl is substituted with a substituent selected from the group consisting of fluoro, chloro, methyl, methoxy and trifluoromethyl; 
 R 2  and R 6  are hydrogen; 
 one of R 4  and R 5  is selected from the group consisting of fluoro, chloro, bromo, lower alkyl optionally substituted with one or more fluoro, lower alkenyl, lower alkynyl, cycloalkyl, —CN, and lower alkoxy optionally substituted with one or more fluoro, lower alkoxy, di-alkylamino or cycloalkylamino, and the other of R 4  and R 5  is selected from the group consisting of hydrogen, fluoro, chloro, bromo, lower alkyl optionally substituted with one or more fluoro, lower alkenyl, lower alkynyl, cycloalkyl, —CN, and lower alkoxy optionally substituted with one or more fluoro, lower alkoxy, dialkylamino, or cycloalkylamino; 
 Ar 1  is a 6 membered optionally substituted heteroarylene having the structure 
 
       
         
           
           
               
               
           
         
          wherein 
       
       
         
           
           
               
               
           
         
          indicates the point of attachment of L 1  and 
       
       
         
           
           
               
               
           
         
          indicates the point of attachment of L 2 , and wherein the indicated N is either ═N— or —N═; 
         n is 1; 
         F and J are both C; 
         P is CR and is CH, wherein R is hydrogen, methyl or methoxy; 
         T is CH; 
         R 9  at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and —NR 12 R 13 , provided, however, that when R 9  is substituted lower alkyl, any substitution on the alkyl carbon bound to the —N— of —NR 9 — is fluoro; and 
         R 12  and R 13  combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio. 
       
     
     
         37 - 38 . (canceled) 
     
     
         39 . The method of  claim 36 , wherein the compound is approved for administration to a human. 
     
     
         40 . The method of  claim 39 , wherein the disease or condition is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, canine mast cell tumors, hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, Wegener's granulomatosis, Chronic Obstructive Pulmonary Disease, emphysema, atherosclerosis, insulin resistance, hyperglycemia, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, and diabetes-associated renal complications. 
     
     
         41 . (canceled) 
     
     
         42 . A kit comprising a compound having the chemical structure: 
       
         
           
           
               
               
           
         
         all salts, tautomers, and stereoisomers thereof, 
       
       wherein:
 X 1  is CR 2 , X 2  is CR 6 , Y 1  is CR 4 , and Y 2  is CR 5 ; 
 L 1  is lower alkylene; 
 L 2  is selected from the group consisting of (alk) a -S-(alk) b -, -(alk) a -O-(alk) b - and -(alk) a -NR 9 -(alk) b -, wherein alk is optionally substituted C 1-3  alkylene and a and b are independently 0 or 1; 
 R 1  is cycloalkyl or phenyl, wherein phenyl is substituted with a substituent selected from the group consisting of fluoro, chloro, methyl, methoxy and trifluoromethyl; 
 R 2  and R 6  are hydrogen; 
 one of R 4  and R 5  is selected from the group consisting of fluoro, chloro, bromo, lower alkyl optionally substituted with one or more fluoro, lower alkenyl, lower alkynyl, cycloalkyl, —CN, and lower alkoxy optionally substituted with one or more fluoro, lower alkoxy, di-alkylamino or cycloalkylamino, and the other of R 4  and R 5  is selected from the group consisting of hydrogen, fluoro, chloro, bromo, lower alkyl optionally substituted with one or more fluoro, lower alkenyl, lower alkynyl, cycloalkyl, —CN, and lower alkoxy optionally substituted with one or more fluoro, lower alkoxy, dialkylamino, or cycloalkylamino; 
 Ar 1  is a 6 membered optionally substituted heteroarylene having the structure 
 
       
         
           
           
               
               
           
         
          wherein 
       
       
         
           
           
               
               
           
         
          indicates the point of attachment of L 1  and 
       
       
         
           
           
               
               
           
         
          indicates the point of attachment of L 2 , and wherein the indicated N is either ═N— or —N═; 
         n is 1; 
         F and J are both C; 
         P is CR and is CH, wherein R is hydrogen, methyl or methoxy; 
         T is CH; 
         R 9  at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and —NR 12 R 13 , provided, however, that when R 9  is substituted lower alkyl, any substitution on the alkyl carbon bound to the —N— of —NR 9 — is fluoro; and 
         R 12  and R 13  combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; 
         wherein the compound is approved for a medical indication selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, canine mast cell tumors, hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, Wegener's granulomatosis, Chronic Obstructive Pulmonary Disease, emphysema, atherosclerosis, insulin resistance, hyperglycemia, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, and diabetes-associated renal complications. 
       
     
     
         43 . The method of  claim 36 , wherein L 1  is CH 2 . 
     
     
         44 . The method of  claim 36 , wherein L 2  is selected from the group consisting of —O—CH 2 —, NH—CH 2 —, —NH—CH(CH 3 )— and —NH—C(O). 
     
     
         45 . The method of  claim 36 , wherein L 1  is CH 2  and L 2  is selected from the group consisting of —O—CH 2 —, NH—CH 2 —, —NH—CH(CH 3 )— and —NH—C(O). 
     
     
         46 . The method of  claim 36 , wherein Y 1  is CH and Y 2  is CR 5 . 
     
     
         47 . The method of  claim 46 , wherein R 5  is fluoro, chloro, lower alkyl or lower alkoxy. 
     
     
         48 . The method of  claim 46 , wherein R 5  is chloro or methoxy. 
     
     
         49 . The method of  claim 36 , wherein Y 2  is CH and Y 1  is CR 4 . 
     
     
         50 . The method of  claim 49 , wherein R 4  is fluoro, chloro, lower alkyl or lower alkoxy. 
     
     
         51 . The method of  claim 49 , wherein R 4  is chloro or methoxy. 
     
     
         52 . The method of  claim 40 , wherein the disease or condition is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer and canine mast cell tumors. 
     
     
         53 . The method of  claim 40 , wherein the disease or condition is selected from the group consisting of hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, Wegener's granulomatosis, Chronic Obstructive Pulmonary Disease, emphysema, atherosclerosis, insulin resistance, hyperglycemia, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis and diabetes-associated renal complications. 
     
     
         54 . The method of  claim 45 , wherein the disease or condition is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer and canine mast cell tumors. 
     
     
         55 . The method of  claim 45 , wherein the disease or condition is selected from the group consisting of hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, Wegener's granulomatosis, Chronic Obstructive Pulmonary Disease, emphysema, atherosclerosis, insulin resistance, hyperglycemia, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis and diabetes-associated renal complications. 
     
     
         56 . The kit of  claim 42 , wherein the compound is approved for a medical indication selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer and canine mast cell tumors. 
     
     
         57 . The kit of  claim 42 , wherein the compound is approved for a medical indication selected from the group consisting of hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, Wegener's granulomatosis, Chronic Obstructive Pulmonary Disease, emphysema, atherosclerosis, insulin resistance, hyperglycemia, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, and diabetes-associated renal complications.