Substituted Imidazo[1,2-a]-pyridines as IRAK 1/4 and FLT3 Inhibitors

Abstract

Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)) and compositions (e.g., pharmaceutical compositions) which can be used for treating, for example, certain diseases. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as head and neck squamous cell carcinoma (HNSCC), cancer, blood disorders, etc.). Additional embodiments provide synergistic combinations of a BCL2 inhibitor with an IRAK inhibiting compound, and methods of using same.

1 .- 61 . (canceled) 
     
     
         62 . A method of treating a disease or disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of:
 (i) a B-cell lymphoma 2 (BCL2) inhibitor selected from:
 navitoclax, 
 venetoclax, 
 obatoclax, 
 gossypol, 
 apogossypol, 
 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (AT-737), 
 ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), 
 5-[3-[4-(aminomethyl)phenoxy]propyl]-2-[8-[2-(2-benzothiazolyl)hydrazinylidene]-5,6,7,8-tetrahydro-2-naphthalenyl]-4-thiazolecarboxylic acid (WEHI-539), 
 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(dimethylamino)prop-1-yn-1-yl)-2-fluorophenoxy)propyl)thiazole-4-carboxylic acid (A-1155463), 
 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW37), 
 1-oxo-6-thiomorpholino-1H-phenalene-2,3-dicarbonitrile (S1), 
 (2R,3 S,6 S,7R, 8R)-8-butyl-3 -(3 -formamido-2-methoxybenzamido)-2,6-dimethyl-4,9-dioxo-1,5-dioxonan-7-yl3-methylbutanoate (2-methoxy antimycin A3), 
 1,1′,6,6′, 7,7′-hexahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-8,8′-dicarbaldehyde (AT-101), 
 (E)-3-((9-amino-7-ethoxyacridin-3-yl)diazenyl)pyridine-2,6-diamine (BXI-61), 
 2′-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-1H, 1′H-2,5′-bibenzo[d]imidazole (BXI-72), 
 4-((E)-(((Z)-2-(cyclohexylimino)-4-methylthiazol-3(2H)-yl)imino)methyl)benzene-1,2,3-triol (MIM1), and 
 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetic acid (UMI-77); and 
   (ii) an interleukin receptor-associated kinase (IRAK) and/or FLT3 inhibitor of Formula (I)   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, 
       wherein in Formula (I):
 R 1  is H, halogen, C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, OH, or C 1 -C 6  alkoxy, wherein the C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, or C 1 -C 6  alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, SO 3 H, and morpholinyl; 
 R 2  is H, halogen, CN, C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C(O)H, C(O)OH, OH, C 1 -C 6  alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C(O)H, C(O)OH, C 1 -C 6  alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, C 1 -C 3  alkyl, C 1 -C 3  perfluorinated alkyl, C≡CH, CH 2 C≡CH, C≡CCH 3 , C(O)H, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)OH, C(O)-morpholin-4-yl, NH 2 , N(CH 3 ) 2 , OH, C 1 -C 3  alkoxy, SO 3 H, heterocyclyl, aryl, and heteroaryl;
 R 3  is H, halogen, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, OH, or C 1 -C 2  alkoxy, wherein the C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, or C 1 -C 2  alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H; 
 
 R 4  is H, halogen, CN, NO 2 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C(0)H, C(O)OH, OH, C 1 -C 3  alkoxy or SO 3 H, wherein the C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, or C 1 -C 3  alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , CCH, C(O)H, C(O)OH, OH, and SO 3 H; 
 R 5  is H, halogen, CN, NO 2 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C(O)H, C(O)OH, OH, C 1 -C 3  alkoxy, or SO 3 H, wherein the C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, or C 1 -C 3  alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H; 
 R 6  is H, halogen, CN, NO 2 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C(O)H, C(O)OH, OH, C 1 -C 3  alkoxy, or SO 3 H, wherein the C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, or C 1 -C 3  alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , CCH, C(O)H, C(O)OH, OH, and SO 3 H; 
 R 7  is 
 
       
         
           
           
               
               
           
         
         R 8  is H, CN, NO 2 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C(O)H, C(O)CH 3 , C(O)CH 2 CN, C(O)-phenyl, C(O)OH, or phenyl—CH 3 ; 
         Y is —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N[CH(CH 3 ) 2 ]—, or —O—; 
         m is 0, 1, 2, 3, 4, or 5; 
         n is 0, 1, 2, 3, 4, or 5; and 
         wherein the sum of m and n is at least 1. 
       
     
     
         63 . The method of  claim 62 , wherein
 R 1  is selected from H, halogen, C 1 -C 7  alkyl, and C 1 -C 6  alkoxy, wherein C 1 -C 6  alkoxy is optionally substituted with morpholinyl;   R 2  is selected from H, halogen, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, CN, C(O)-morpholin-4-yl, C(O)N(CH 3 ) 2 , C(O)NH 2 , heterocyclyl, and heteroaryl, wherein heterocyclyl or heteroaryl are each independently optionally substituted with one or more substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  alkoxy, and morpholinyl;   R 3  is selected from H and C 1 -C 2  alkoxy;   R 4 , R 5 , and R 6  are each independently selected from H, halogen, C 1 -C 3  alkyl, and C 1 -C 2  alkoxy;   R 7  is   
       
         
           
           
               
               
           
         
         R 8  is selected from H, C(O)CH 3 , C(O)-phenyl, and C(O)CH 2 CN; and 
         Y is selected from —O—, —NH—, and —N(CH 3 )—. 
       
     
     
         64 . The method of  claim 62 , wherein R 1  is selected from Cl, CH 3 , OCH 3 , and OCH 2 CH 2 -morpholinyl. 
     
     
         65 . The method of  claim 62 , wherein R 2  is selected from Cl, Br, CN, C≡CH, OCH 3 , C(O)-morpholin-4-yl, C(O)N(CH 3 ) 2 , C(O)NH 2 , 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, pyrazol-3-yl, 1H-pyrazol-4-yl, 1-methylpyrazol-4-yl, 1-(morpholin-4-yl)pyrazol-4-yl, 3,5-dimethylpyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, tetrazol-5-yl, pyridin-3-yl, pyridin-4-yl, 2-methoxypyridin-5-yl, 4-ethylpiperazin-1-yl, and 
       
         
           
           
               
               
           
         
       
     
     
         66 . The method of  claim 62 , wherein R 3  is OCH 3 . 
     
     
         67 . The method of  claim 62 , wherein at least one of (i)-(v) applies:
 (i) R 4 , R 5 , and R 6  are each H;   (ii) R 4  and R 6  are each F and R 5  is H;   (iii) R 4  is CH 3  and each of R 5  and R 6  is H;   (iv) R 4  and R 6  are each H and R 5  is selected from CH 3 , OCH 3 , and Br;   (v) R 4  and R 5  are each H and R 6  is CH 3 .   
     
     
         68 . The method of  claim 62 , wherein R 7  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         69 . The method of  claim 62 , wherein R 8  is selected from (O)CH 3 , C(O)-phenyl, and C(O)CH 2 CN. 
     
     
         70 . The method of  claim 62 , wherein R 8  is H. 
     
     
         71 . The method of  claim 62 , wherein at least one applies:
 (i) n is 1, 2, or 3; or   (ii) m is 1, 2, or 3.   
     
     
         72 . The method of  claim 62 , wherein the IRAK and/or FLT3 inhibitor, or a stereoisomer thereof, is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         73 . The method of  claim 62 , wherein
 R 1 , R 3 , R 4 , R 5 , and R 6  are each H;   R 2  is selected from H, F, Br, I, C 2 -C 7  alkynyl, C 2 -C 6  alkoxy, C(O)-morpholin-4-yl, C(O)N(CH 3 ) 2 , C(O)NH 2 , heterocyclyl, and heteroaryl, wherein heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  alkoxy, and mornholinvl:   R 7  is   
       
         
           
           
               
               
           
         
         R 8  is H; 
         m is 0, 1, 2, 3, 4, or 5; 
         n is 0, 1, 3, 4, or5; 
         Y is —NH—; and 
       
       wherein the sum of m and n is at least 1. 
     
     
         74 . The method of  claim 62 , wherein venetoclax comprises a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         75 . The method of  claim 62 , wherein the IRAK and/or FLT3 inhibitor is administered to the individual in a therapeutically effective amount of 0.005 mg/kg to 50 mg/kg body weight. 
     
     
         76 . The method of  claim 62 , wherein the IRAK and/or FLT3 inhibitor is administered to the individual via parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. 
     
     
         77 . The method of  claim 62 , wherein the disease or disorder is a cancer or a blood disorder. 
     
     
         78 . The method of  claim 77 , wherein the cancer is selected from head and neck squamous cell carcinoma, acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, and Waldenstrom's macroglobulinemia. 
     
     
         79 . The method of  claim 78 , wherein the cancer is acute myeloid leukemia. 
     
     
         80 . The method of  claim 77 , wherein the blood disorder is myelodysplastic syndrome (MDS). 
     
     
         81 . The method of  claim 80 , wherein the MDS is selected from MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, and MDS with a mutation in isocitrate dehydrogenase 2. 
     
     
         82 . The method of  claim 62 , wherein the BCL2 inhibitor and the IRAK inhibitor are administered to the individual in one or more administrations. 
     
     
         83 . The method of  claim 62 , wherein the disease or disorder is associated with a FLT3 mutation, an IRAK4 mutation, or an IRAK1 mutation. 
     
     
         84 . The method of  claim 83 , wherein the FLT3 mutation comprises a mutation in the juxtamembrane region of FLT3, a mutation in the kinase domain of FLT3, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation.