Combination Therapy with AXL Inhibitor and Immune Checkpoint Modulator or Oncolytic Virus

Abstract

The present invention concerns an Axl inhibitor and one or more immune checkpoint (activity) modulators and/or one or more oncolytic viruses, for use in the prevention, treatment or management of cancer, wherein the Axl inhibitor and the one or more immune checkpoint (activity) modulators and/or the one or more oncolytic viruses are administered concurrently, separately or sequentially; compositions containing such components in combination; and methods of treating cancer in a patient by administering such components in combination.

1 - 33 . (canceled) 
     
     
         34 . A method of controlling cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of an Axl inhibitor in concurrent, separate, or sequential combination with a therapeutically effective amount of one or more immune checkpoint (activity) modulators;
 wherein the Axl inhibitor is a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R 8 , —C(O)N(R 6 )R 7 , and —C(═NR 6 )N(R 6 )R 7 ; 
         R 2  and R 3  are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —R 9 —OR 8 , —R 9 —O—R 10 —OR 8 , —R 9 —O—R 10 —O—R 10 —OR 8 , —R 9 —O—R 10 —CN, —R 9 —O—R 10 —C(O)OR 8 , —R 9 —O—R 10 —C(O)N(R 6 )R 7 , —R 9 —O—R 10 —S(O) p R 8  (where p is 0, 1 or 2), —R 9 —O—R 10 —N(R 6 )R 7 , —R 9 —O—R 10 —C(NR 11 )N(R 11 )H, —R 9 —OC(O)—R 8 , —R 9 —N(R 6 )R 7 , —R 9 —C(O)R 8 , —R 9 —C(O)OR 8 , —R 9 —C(O)N(R 6 )R 7 , —R 9 —N(R 6 )C(O)OR 8 , —R 9 —N(R 6 )C(O)R 8 , —R 9 —N(R 6 )S(O) t R 8  (where t is 1 or 2), —R 9 —S(O) t OR 8  (where t is 1 or 2), —R 9 —S(O) p R 8  (where p is 0, 1 or 2), and —R 9 —S(O) t N(R 6 )R 7  (where t is 1 or 2); 
         or R 2  is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R 3  is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 13 —OR 12 , —R 13 —OC(O)—R 12 , —R 13 —O—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 ) 2 , —R 13 —C(O)R 12 , —R 13 —C(O)OR 12 , —R 13 —C(O)N(R 12 ) 2 , —R 13 —C(O)N(R 12 )—R 14 —N(R 12 )R 13 , —R 13 —C(O)N(R 12 )—R 14 —OR 12 , —R 13 —N(R 12 )C(O)OR 12 , —R 13 —N(R 12 )C(O)R 12 , —R 13 —N(R 12 )S(O) t R 12  (where t is 1 or 2), —R 13 —S(O) t OR 12  (where t is 1 or 2), —R 13 —S(O) p R 12  (where p is 0, 1 or 2), and —R 13 —S(O) t N(R 12 ) 2  (where t is 1 or 2); 
         or R 3  is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R 2  is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 13 —OR 12 , —R 13 —OC(O)—R 12 , —R 13 —O—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 ) 2 , —R 13 —C(O)R 12 , —R 13 —C(O)OR 12 , —R 13 —C(O)N(R 12 ) 2 , —R 13 —C(O)N(R 12 )—R 14 —N(R 12 )R 3 , —R 3 —C(O)N(R 12 )—R 14 —OR 12 , —R 3 —N(R 12 )C(O)OR 12 , —R 3 —N(R 12 )C(O)R 12 , —R 3 —N(R 12 )S(O) t R 12  (where t is 1 or 2), —R 13 —S(O) t OR 12  (where t is 1 or 2), —R 13 —S(O) p R 12  (where p is 0, 1 or 2), and —R 13 —S(O) t N(R 12 ) 2  (where t is 1 or 2); 
         each R 6  and R 7  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 10 —OR 8 , —R 10 —CN, —R 10 —NO 2 , —R 10 —N(R 8 ) 2 , —R 10 —C(O)OR 8  and —R 10 —C(O)N(R 8 ) 2 , or any R 6  and R 7 , together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; 
         each R 8  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; 
         each R 9  is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; 
         each R 10  is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; 
         each R 11  is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and —OR 8 ; 
         each R 12  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 10 —OR 8 , —R 10 —CN, —R 10 —NO 2 , —R 10 —N(R 8 ) 2 , —R 10 —C(O)OR 8  and —R 10 —C(O)N(R 8 ) 2 , or two R 12′s , together with the common nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; 
         each R 13  is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and 
         each R 14  is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; 
         as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof; and 
         wherein the one or more immune checkpoint (activity) modulators are selected from the group consisting of anti-PD-1 antibodies and anti-PD-L1 antibodies. 
       
     
     
         35 . The method according to  claim 34 , wherein the Axl inhibitor is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method according to  claim 34 , wherein one or more of the immune checkpoint (activity) modulators is an anti-PD-1 antibody. 
     
     
         37 . The method according to  claim 36 , wherein the anti-PD-1 antibody is pembrolizumab or nivolumab. 
     
     
         38 . The method according to  claim 36 , wherein the anti-PD-1 antibody is pembrolizumab. 
     
     
         39 . The method according to  claim 34 , wherein the Axl inhibitor and the one or more immune checkpoint (activity) modulators are administered separately or sequentially. 
     
     
         40 . The method according to  claim 34 , wherein the cancer is:
 (i) a solid cancer tumor;   (ii) selected from the group consisting of: breast, renal, endometrial, bladder, ovarian, thyroid, and non-small cell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma;   (iii) a leukemia or a lymphoma;   (iv) selected from the group consisting of: breast cancer, renal cancer, lung cancer, bladder cancer, prostate cancer, melanoma and/or lymphomas, and metastatic cancers;   (v) selected from the group consisting of: non-small cell lung cancer, melanoma, and mesothelioma; or   (vi) non-small cell lung cancer.   
     
     
         41 . The method according to  claim 34 , wherein the cancer is non-small cell lung cancer. 
     
     
         42 . A method of controlling lung cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of an Axl inhibitor in concurrent, separate, or sequential combination with a therapeutically effective amount of an anti-PD-1 antibody or anti-PD-L1 antibody;
 wherein the Axl inhibitor is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof.   
     
     
         43 . The method of  claim 42 , wherein the Axl inhibitor is administered in combination with an anti-PD-1 antibody. 
     
     
         44 . The method of  claim 42 , wherein the Axl inhibitor is administered in combination with pembrolizumab. 
     
     
         45 . The method of  claim 42 , wherein the cancer is non-small cell lung cancer. 
     
     
         46 . A pharmaceutical composition comprising an Axl inhibitor, one or more immune checkpoint (activity) modulators, and a pharmaceutically acceptable excipient,
 wherein the Axl inhibitor is a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R 8 , —C(O)N(R 6 )R 7 , and —C(═NR 6 )N(R 6 )R 7 ; 
         R 2  and R 3  are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —R 9 —OR 8 , —R 9 —O—R 10 —OR 8 , —R 9 —O—R 10 —O—R 10 —OR 8 , —R 9 —O—R 10 —CN, —R 9 —O—R 10 —C(O)OR 8 , —R 9 —O—R 10 —C(O)N(R 6 )R 7 , —R 9 —O—R 10 —S(O) p R 8  (where p is 0, 1 or 2), —R 9 —O—R 10 —N(R 6 )R 7 , —R 9 —O—R 10 —C(NR 11 )N(R 11 )H, —R 9 —OC(O)—R 8 , —R 9 —N(R 6 )R 7 , —R 9 —C(O)R 8 , —R 9 —C(O)OR 8 , —R 9 —C(O)N(R 6 )R 7 , —R 9 —N(R 6 )C(O)OR 8 , —R 9 —N(R 6 )C(O)R 8 , —R 9 —N(R 6 )S(O) t R 8  (where t is 1 or 2), —R 9 —S(O) t OR 8  (where t is 1 or 2), —R 9 —S(O) p R 8  (where p is 0, 1 or 2), and —R 9 —S(O) t N(R 6 )R 7  (where t is 1 or 2); 
         or R 2  is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R 3  is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 13 —OR 12 , —R 13 —OC(O)—R 12 , —R 13 —O—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 ) 2 , —R 13 —C(O)R 12 , —R 13 —C(O)OR 12 , —R 13 —C(O)N(R 12 ) 2 , —R 13 —C(O)N(R 12 )—R 14 —N(R 12 )R 13 , —R 13 —C(O)N(R 12 )—R 14 —OR 12 , —R 13 —N(R 12 )C(O)OR 12 , —R 13 —N(R 12 )C(O)R 12 , —R 13 —N(R 12 )S(O) t R 12  (where t is 1 or 2), —R 13 —S(O) t OR 12  (where t is 1 or 2), —R 13 —S(O) p R 12  (where p is 0, 1 or 2), and —R 13 —S(O) t N(R 12 ) 2  (where t is 1 or 2); 
         or R 3  is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R 2  is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 13 —OR 12 , —R 13 —OC(O)—R 12 , —R 13 —O—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 )—R 14 —N(R 12 ) 2 , —R 13 —N(R 12 ) 2 , —R 13 —C(O)R 12 , —R 13 —C(O)OR 12 , —R 13 —C(O)N(R 12 ) 2 , —R 13 —C(O)N(R 12 )—R 14 —N(R 12 )R 13 , —R 13 —C(O)N(R 12 )—R 14 —OR 12 , —R 13 —N(R 12 )C(O)OR 12 , —R 13 —N(R 12 )C(O)R 12 , —R 13 —N(R 12 )S(O) t R 12  (where t is 1 or 2), —R 3 —S(O) t OR 12  (where t is 1 or 2), —R 13 —S(O) p R 12  (where p is 0, 1 or 2), and —R 13 —S(O) t N(R 12 ) 2  (where t is 1 or 2); 
         each R 6  and R 7  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 10 —OR 8 , —R 10 —CN, —R 10 —NO 2 , —R 10 —N(R 8 ) 2 , —R 10 —C(O)OR 8  and —R 10 —C(O)N(R 8 ) 2 , or any R 6  and R 7 , together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; 
         each R 8  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; 
         each R 9  is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; 
         each R 10  is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; 
         each R 11  is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and —OR 8 ; 
         each R 12  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 10 —OR 8 , —R 10 —CN, —R 10 —NO 2 , —R 10 —N(R 8 ) 2 , —R 10 —C(O)OR 8  and —R 10 —C(O)N(R 8 ) 2 , or two R 12′s , together with the common nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; 
         each R 13  is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and 
         each R 14  is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; 
         as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof; and 
       
       wherein the one or more immune checkpoint (activity) modulators are selected from the group consisting of anti-PD-1 antibodies and anti-PD-L1 antibodies. 
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein the Axl inhibitor is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The pharmaceutical composition of  claim 46 , wherein the one or more immune checkpoint (activity) modulator is an anti-PD-1 antibody. 
     
     
         49 . The pharmaceutical composition of  claim 46 , wherein the anti-PD-1 antibody is pembrolizumab.