Pharmaceutical composition administered in combination with substituted dihydropyrrolopyrazole compound and immunotherapeutic agent

Abstract

The present invention provides a pharmaceutical composition comprising a compound represented by the formula (I) or a pharmacologically acceptable salt thereof:wherein two R moieties each independently are a C1-3 alkyl group or are groups bonded to each other to form a C2-5 alkylene group; A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group; and R1, R2 and R3 each independently are an optionally substituted linear or branched C1-4 alkyl group, wherein the pharmaceutical composition is administered in combination with an immunotherapeutic agent.

What is claimed is: 
     
         1 . A method for treating cancer in a human in need thereof, the method comprising administering to the human an effective amount of:
 (i) an immunotherapeutic agent, and   (ii) a compound of formula (I) or a pharmacologically acceptable salt thereof:   
       
         
           
           
               
               
           
         
         
           wherein two R moieties each independently are a C 1-3  alkyl group or are groups bonded to each other to form a C 2-5  alkylene group; A is an optionally substituted C 6-10  aryl group or an optionally substituted heteroaryl group; and R 1 , R 2  and R 3  each independently are an optionally substituted linear or branched C 1-4  alkyl group. 
         
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) is a compound represented by formula (II) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein A is phenyl optionally substituted with halogen or C 1-4  alkyl group; or A is benzofuranyl optionally substituted with halogen or C 1-4  alkyl group; and R 1 , R 2  and R 3  are each independently a linear C 1-4  alkyl group. 
       
     
     
         3 . The method of  claim 2 , wherein R 1 , R 2  and R 3  are each methyl. 
     
     
         4 . The method of  claim 2 , wherein A is phenyl substituted with halogen or methyl; or A is benzofuranyl substituted with halogen. 
     
     
         5 . The method of  claim 2 , wherein the compound of formula (II) is N-(2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, 6-dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)-cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(5-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(2,5-dimethyl phenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(2-chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane-carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-arboxamide, N-(2-fluoro-3,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)-cyclobutanecarboxami do]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-dihydropyrrolo[3-c]pyrazole-5(1H)-carboxamide, N-(6-fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, or a pharmacologically acceptable salt of one of the foregoing. 
     
     
         6 . The method of  claim 2 , wherein the compound of formula (II) is N-(2-chloro-6-methylphenyl)-6-6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 
     
     
         7 . The method of  claim 2 , wherein the compound of formula (II) is N-(2,5-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 
     
     
         8 . The method of  claim 2 , wherein the compound of formula (II) is N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 
     
     
         9 . The method of  claim 1 , wherein the immunotherapeutic agent is an agent that inhibits an immune checkpoint selected from the group consisting of TIM-3, KIR, LAG-3, VISTA, and BTLA. 
     
     
         10 . The method of  claim 1 , wherein the immunotherapeutic agent is an agent that activates immunity selected from the group consisting of OX40, IL-10R, GITR, CD27, CD28, CD137 and ICOS. 
     
     
         11 . The method of  claim 1 , wherein the immunotherapeutic agent is tremelimumab, pidilizumab, JNJ-63723283, BMS-936559, LY3300054, or FAZ053. 
     
     
         12 . The method of  claim 1 , wherein the immunotherapeutic agent is AM0010, GSK3174998, MOXR0916, PF-04518600, MEDI0562, TRX518, MEDI1873, varlilumab, urelumab, utomilumab, or MEDI-570. 
     
     
         13 . The method of  claim 1 , wherein the cancer is breast cancer. 
     
     
         14 . The method of  claim 1 , wherein the cancer is urinary bladder cancer, colorectal cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovary cancer, pancreatic cancer, gastric cancer, cervical cancer, endometrial cancer, thyroid gland cancer, cancer of the nose, head and neck cancer, prostate cancer, skin cancer, a hematopoietic organ tumor of the lymphatic system, a hematopoietic organ tumor of the myeloid system, follicular carcinoma of thyroid, a mesenchymal tumor, a tumor of the central or peripheral nervous system, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular carcinoma of thyroid, or Kaposi's sarcoma.