Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described, wherein the compounds have formula Ia: In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC kinase protein. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC, including rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastoma, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors.

What is claimed is: 
     
         1 . A method for treating a subject with a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, chronic pain, acute pain, inflammatory pain, neuropathic pain, bone pain, pain associated with cancer, surgery, or bone fracture, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, non-small cell lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors, said method comprising administering to the subject in need thereof an effective amount of a compound of Formula Ia: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein:
 Y 2  is —N═ and R 15  is hydrogen; or Y 2  is —C(H)═ and R 15  is fluoro or chloro; 
 L 2  is —CH 2 — or —C(O)—; 
 Cy 2  is cycloalkyl optionally substituted with one or more R 16 ; 
 R 14  is —N(R 9a )(R 9b ); 
 R 9a  is H and R 9b  is selected from the group consisting of (i) H, lower alkyl, lower alkyl substituted with one or more substituents independently selected from fluoro, lower alkyl substituted with lower alkoxy, and lower alkyl substituted with hydroxyl, and (ii) cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with one to three members independently selected from lower alkyl, haloalkyl, lower alkoxy, and fluoro; or 
 R 9a  and R 9b  together with the nitrogen to which they are attached form a 5- or 6-membered ring having from 0 to 1 additional heteroatom selected from O, N, or S, each of which is optionally substituted with one to three members independently selected from lower alkyl, haloalkyl, lower alkoxy, and fluoro; and 
 each R 16  is independently selected from the group consisting of fluoro, —OH, lower alkyl optionally substituted with one or more substituents independently selected from fluoro, and lower alkoxy optionally substituted with one or more fluoro. 
 
       
     
     
         2 . The method of  claim 1 , wherein L 2  is —C(O)—. 
     
     
         3 . The method of  claim 2 , wherein Y 2  is —C(H)═. 
     
     
         4 . The method of  claim 1 , wherein Cy 2  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopentyl, each of which is optionally substituted with from 1 to 3 R 16 . 
     
     
         5 . The method of  claim 1 , wherein each R 16  is F. 
     
     
         6 . The method of  claim 1 , wherein R 9b  is lower alkyl. 
     
     
         7 . The method of  claim 1 , wherein R 9b  is lower alkyl substituted with one or more fluoro. 
     
     
         8 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         9 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         10 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         11 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         12 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         13 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         14 . The method according to any of the preceding claims, wherein the disease or condition is chronic pain, acute pain, inflammatory pain, neuropathic pain, or bone pain. 
     
     
         15 . The method according to  claim 14 , wherein the disease or condition is inflammatory pain. 
     
     
         16 . The method according to  claim 1 , wherein the disease or condition is pain associated with cancer, surgery, or bone fracture. 
     
     
         17 . The method according to  claim 1 , wherein the disease or condition is pancreatic cancer. 
     
     
         18 . The method according to  claim 1 , wherein the disease or condition is gastrointestinal stromal tumors. 
     
     
         19 . The method according to  claim 1 , wherein the disease or condition is non-small cell lung cancer.