Combination of a chromene compound and a second active agent

Abstract

The present disclosure provide a combination of a chromene compound having the structure of Formula (I), or pharmaceutically acceptable salts, and a second compound that can be selected from a PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, OX-40 agonist, CD137 agonist, LAG-3 inhibitor, IDO inhibitor, bi-specific protein, EGFR inhibitor, HER2 inhibitor, and immune stimulating therapy and a method of using the combination for treating or preventing cancer.

1 . A combination comprising:
 a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and a second compound,   
       
         
           
           
               
               
           
         
         wherein M is selected from the group consisting of H and alkyl; 
         Z is selected from the group consisting of —CF 3 , —CF 2 H and —C 2 F 5 ; 
         each of R 1 , R 2 , R 3 , and R 4  is independently selected from a group consisting of H, alkyl, aralkyl, deuteroalkyl, deuteroaralkyl, deuteroalkoxy, deuterocycloalkyl, deuteron, deuteriumaryloxy, deuteroaryloxy, deuteroheteroaryloxy, deuteroarylalkoxy, deuteroheteroarylalkoxy, deuterohaloalkoxy, deuterohaloalkoxy, deuteroamino, deuterosulfamidyl, sulfamidyl, cycloalkyl, cycloalkenyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, pentafluorosulfanyl, hydroxyalkyl, trialkylsilyl, alkynyl, and alkenyl; and 
         wherein the second compound is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, OX-40 agonists, CD137 agonists, LAG-3 inhibitors, IDO inhibitors, bi-specific proteins, EGFR inhibitors, HER2 inhibitors, and immune stimulating therapies. 
       
     
     
         2 . The combination of  claim 1 , wherein at least one of R 1 , R 2 , R 3 , and R 4  of Formula (II) is selected from the group consisting of deuteron, deuteroalkyl, and deuterocycloalkyl. 
     
     
         3 . The combination of  claim 2 , wherein R 2  is not H. 
     
     
         4 . The combination of  claim 3 , wherein the compound of Formula (II) is selected from the group consisting of:
 (S)-6,8-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-8-pentadeuteroethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-chloro-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-chloro-5,7-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-bromo-5,7-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-8-chloro-6-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-8-trideuteromethyl-6-(pentafluorosulfanyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and   (S)-8-trideuteromethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid.   
     
     
         5 . The combination of  claim 2 , wherein the second compound is:
 a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12;   a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab;   a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab;   an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701;   a CD137 agonist selected from the group consisting of urelumab and utomilumab;   the LAG-3 inhibitor BMS-986016;   an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane;   an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF;   an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and   an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib.   
     
     
         6 . The combination of  claim 4 , wherein the second compound is:
 a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12;   a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, and STI-A1010, avelumab, atezolizumab, and durvalumab;   a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab;   an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701;   a CD137 agonist selected from the group consisting of urelumab and utomilumab;   the LAG-3 inhibitor BMS-986016;   an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane;   a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565;   an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF;   an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and   an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib.   
     
     
         7 . The combination of  claim 6 , wherein the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 
     
     
         8 . The combination of  claim 6 , wherein the compound of Formula (II) is (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 
     
     
         9 . The combination of  claim 8 , wherein the second compound is erlotinib, cetuximab, trastuzumab, or pertuzumab. 
     
     
         10 . The combination of  claim 8 , wherein the compound of Formula (II) is (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and the second compound is pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, or avelumab. 
     
     
         11 . The combination of  claim 9  wherein the second compound is erlotinib. 
     
     
         12 . The combination of  claim 10  wherein the second compound is pembrolizumab, nivolumab, or atezolizumab. 
     
     
         13 . The combination of  claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4  of Formula (II) is independently selected from the group consisting of H, alkyl, aralkyl, cycloalkyl, cycloalkenyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, pentafluorosulfanyl, hydroxyalkyl, trialkylsilyl, alkynyl, and alkenyl. 
     
     
         14 . The combination of  claim 13  of  claim 1 , wherein R 1  is H and R 2  is selected from the group consisting of halo, haloalkoxy, and pentafluorosulfanyl, and R 4  is selected from H, alkyl, alkenyl, alkynyl, and halo. 
     
     
         15 . The combination of  claim 14 , wherein the compound of Formula (II) is selected from the group consisting of:
 (S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-8-methyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-7-(tert-butyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-pentafluorosulfanyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,   (S)-6-pentafluorosulfanyl-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and   (S)-6-pentafluorosulfanyl-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid.   (S)-6-pentafluorosulfanyl-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid.   
     
     
         16 . The combination of  claim 13 , wherein the second compound is:
 a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12;   a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab;   a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab;   an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701;   a CD137 agonist selected from the group consisting of urelumab and utomilumab;   the LAG-3 inhibitor BMS-986016;   an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane;   a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565;   an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF;   an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and   an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib.   
     
     
         17 . The combination of  claim 15 , wherein the second compound is:
 a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12;   a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab;   a CTLA-4 inhibitor selected from the group consisting of ipilimumabor tremelimumab;   an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701;   a CD137 agonist selected from the group consisting of urelumab and utomilumab;   the LAG-3 inhibitor BMS-986016;   an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane;   a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565;   an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF;   an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and   an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib.   
     
     
         18 . The combination of  claim 17 , wherein the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 
     
     
         19 . The combination of  claim 18 , wherein the second compound is erlotinib, cetuximab, trastuzumab, or pertuzumab. 
     
     
         20 . The combination of  claim 18 , wherein the second compound is pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab. 
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of the combination of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         22 - 24 . (canceled) 
     
     
         25 . A method for treating cancer, comprising:
 administering to a subject in need thereof a therapeutically effective amount of the combination of  claim 1 .   
     
     
         26 - 38 . (canceled)