Axl kinase inhibitors

Abstract

Axl kinase inhibitory compounds are disclosed, as well as compositions and methods of using the same in the treatment of cancer and other conditions mediated by and/or associated with Axl kinase.

1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
       
       including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein:
 ring moiety A is selected from: 
 
       
         
           
           
               
               
           
         
       
       and wherein:
 L 1  is —NH—, —C(═S)NH—, —C(═S)NHS(═O) 2 —, or —C(═O)NH—; 
 R 1  is optional and if present is piperazinyl; 
 L 2 =-S(═O) 2 NH—, —S(═O) 2 — or —NH—; 
 R 2  is heterocycle, substituted heterocycle, or —C(═O)R where R is alkyl; 
 X is O, S or NH; 
 Y at each occurrence is independently halo, haloakyl or alkoxy; 
 m is 0, 1, 2 or 3; 
 R 3  is —H, halo, haloalkyl, haloalkoxy, aryl or substituted aryl; and 
 R 4  is —H, alkyl, substituted alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl. 
 
     
     
         2 . The compound according to  claim 1 , wherein L 1  is —NH—. 
     
     
         3 . The compound according to  claim 2 , wherein ring moiety A is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 2 , wherein ring moiety A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein L 1  is —C(═S)NH—. 
     
     
         6 . The compound according to  claim 5 , wherein ring moiety A is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 6 , wherein R 4  is heteroaryl or substituted heteroaryl. 
     
     
         8 . The compound according to  claim 6 , wherein R 4  is —H or alkyl. 
     
     
         9 . The compound according to  claim 1 , wherein L 1  is —C(═S)NHS(═O) 2 —. 
     
     
         10 . The compound according to  claim 9 , wherein ring moiety A is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 1 , wherein L 1  is —C(═O)NH—. 
     
     
         12 . The compound according to  claim 11 , wherein ring moiety A is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 1 , consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound according to  claim 1 , consisting of:
 4-Chloro-5-iodo-7-benzenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine   7-Benzenesulfonyl-4-chloro-5-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine   4-Piperazine-5-(4-methoxylbenzene)-7H-pyrrolo[2,3-d]pyrimidine   N-(4-(4-(5-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamido)phenylsulfonyl)acetamide   N-(4-(N-(5-ethyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)-4-(5-(4-methoxyphenyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   4-Chloro-5-(4-methoxylbenzene)-7H-pyrrolo[2,3-d]pyrimidine   4-Chloro-5-(4-trifluoromethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine   4-Piperazine-5-(4-trifluoromethylbenzene)-N-benzenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine   N-(4-(N-(5-ethyl-1,3,4-thiadiazo-2-yl)sulfamoyl)phenyl)-5-(4-trifluoromethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-4-(5-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   N-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)-4-(5-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   N-(4-(N-(5-ethyl-1,3,4-thiadiazo-2-yl)sulfamoyl)phenyl)-5-(4-trifluoromethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboamide   4-Piperazine-5-(4-trifluoromethyl-3-chlorobenzene)-N-benzenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine   N-(4-(N-(5-ethyl-1,3,4-thiadiazo-2-yl)sulfamoyl)phenyl)-5-(4-trifluoromethyl-3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   N-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl)acetamide   N-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamido)phenylsulfonyl)acetamide   4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide   N-(4-(4-(5-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamido)phenylsulfonyl)acetamide   N-(4-(N-(5-ethyl-1,3,4-thiadiazo-2-yl)sulfamoyl)phenyl)-5-(4-trifluoromethyl-3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   (S)—N-(4-(N-(5-ethyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)-4-(5-(3fluoropyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbothioamide   or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof.   
     
     
         15 . A method of treating cancer or hyperproliferative disorders by administering an effective amount of the compound according to  claim 1 . 
     
     
         16 . The method of  claim 15 , wherein the cancer is of colon, breast, stomach, prostate, pancreas, or ovarian tissue. 
     
     
         17 . A method of treating lung cancer, NSCLC (non small cell lung cancer), oat-cell cancer, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colo-rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease, hepatocellular cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer (particularly hormone-refractory), chronic or acute leukemia, solid tumors of childhood, hypereosinophilia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, pediatric malignancy, neoplasms of the central nervous system, primary CNS lymphoma, spinal axis tumors, medulloblastoma, brain stem gliomas, pituitary adenomas, Barrett's esophagus, pre-malignant syndrome, neoplastic cutaneous disease, psoriasis, mycoses fungoides, benign prostatic hypertrophy, diabetic retinopathy, retinal ischemia, and retinal neovascularization, hepatic cirrhosis, angiogenesis, cardiovascular disease, atherosclerosis, immunological disease, autoimmune disease, or renal disease by administering to one in need of such treatment an effective amount of the compound according to  claim 1 . 
     
     
         18 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient.