Pyrrolotriazine compounds and methods of inhibiting tam kinases

Abstract

Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments comprising such compounds, and methods of using such compounds to treat cancer.

1 .- 30 . (canceled) 
     
     
         31 . A method of treating a patient who has cancer, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, wherein
 the cancer is resistant to treatment with a checkpoint inhibitor; cells of the cancer overexpress one or more TAM kinases; the cancer is associated with elevated myeloid infiltration relative to a comparable biological sample or reference standard; and/or the cancer is a breast cancer, ovarian cancer, glioblastoma, pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, leukemia, lymphoma, gastric cancer, prostate cancer, pituitary adenoma, melanoma, or rhabdomyosarcoma and   the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of structural formula II   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, where:
 R 1  is pyridin-3-yl, pyridin-4-yl, pyrazol-4-yl, cyclohexyl, or 8-azabicyclo[3.2.1]oct-2-ene-3-yl, wherein R 1  is optionally substituted with up to four independently selected substituents; 
 R 2  is cyclohexyl substituted with hydroxy and optionally substituted with one or two additional substituents independently selected from C 1 -C 4  alkyl and fluoro, or is 4,5,6,7-tetrahydro-1H-indazolyl optionally substituted with one to three substituents independently selected from C 1 -C 4  alkyl and fluoro; and 
 R 3  is —C 3 -C 8  alkyl, —(C 2 -C 6  alkylene)-O—(C 1 -C 6  alkyl), C 3 -C 6  cycloalkyl, or —(C 2 -C 6  alkylene)-C 3 -C 6  cycloalkyl, wherein R 3  is optionally substituted with 1-5 substituents independently selected from deuterium, halo, and —OH. 
 
     
     
         32 . The method of  claim 31 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 1  is optionally substituted with up to four substituents independently selected from halo, hydroxy, —CN, —(C 1 -C 4  alkyl optionally substituted with one or more substituents selected from cyano, hydroxy and halo), —C(O)NH 2 , —COOH, —(C 0 -C 3  alkylene)-C(O)—(C 1 -C 4  alkyl), —(C 0 -C 3  alkylene)-C(O)—NH—(C 1 -C 4  alkyl), —(C 0 -C 3  alkylene)-C(O)—NH—S(O) 2 —(C 1 -C 4  alkyl), —(C 0 -C 3  alkylene)-C(O)—O—(C 1 -C 4  alkyl), —(C 0 -C 3  alkylene)-COOH, —(C 0 -C 4  alkylene)-S(O) 2 —(C 1 -C 3  alkyl), —(C 1 -C 3  alkylene)-O—(C 1 -C 4  alkyl), —S(O)(═NH)—(C 1 -C 4  alkyl), S(O) 2 —NH—(C 1 -C 4  alkyl), -(cyclopropyl)-(cyano-substituted C 1 -C 3  alkyl), -(cyclopropyl)-C(O)—NH—(C 1 -C 4  alkyl), —(C 0 -C 3  alkylene)-C(O)-heterocyclyl, —C(O)—(C 0 -C 3  alkylene)-heterocyclyl, -(cyclopropyl)-C(O)-heterocyclyl, —(C 0 -C 4  alkylene)-heterocyclyl, —(C 0 -C 3  alkylene)-C(O)—NH— heterocyclyl, —(C 0 -C 4  alkylene)-aryl, and —(C 0 -C 4  alkylene)-heteroaryl, wherein the heterocyclyl or heteroaryl portion of the R 1  substituent is optionally further substituted. 
     
     
         33 . The method of  claim 31 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 1  is 1-((1-oxetan-3-ylcarbonyl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(1-trifluoromethylcyclopropylcarbonyl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(2,2,2-trifluoroethan-1-yl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(2,2-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(2,6-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(3,3,3-trifluoropropan-1-yl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(azetidin-1-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(ethan-2-ylsulfonyl)-3-(cyanomethyl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(hexahydro-1H-furo[3,4-c]pyrrol-5-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(isopropylaminocarbonyl)cyclopropyl)pyrazol-4-yl, 1-(1-(morpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(morpholin-4-ylcarbonyl)cyclopropyl)pyrazol-4-yl, 1-(1-(pyrrolidin-1-ylcarbonyl)cyclopropyl)pyrazol-4-yl, 1-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazol-4-yl, 1-(1,3-dimethylpyrazol-5-yl)pyrazol-4-yl, 1-(1-acetylazetidin-3-yl)pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)pyrazol-4-yl, 1-(1-cyanocyclopropylmethyl)pyrazol-4-yl, 1-(1H-pyrazol-4-ylmethyl)pyrazol-4-yl, 1-(1-hydroxy-3-chloropropan-2-yl)pyrazol-4-yl, 1-(1-hydroxylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-methoxycarbonylazetidin-3-yl)pyrazol-4-yl, 1-(1-methyl-2(1H)-pyridinon-5-ylmethyl)pyrazol-4-yl, 1-(1-methyl-2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl, 1-(1-methylaminocarbonyl-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl, 1-(1-t-butoxycarbonylpyrrolidin-3-yl)pyrazol-4-yl, 1-(2-(1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-methyl-1,3,4-oxadiazol-5-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3,5-dimethylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxy-3-methylazetidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxy-3-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxy-3-methylpyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxypyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(4-cyano-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4yl, 1-(2-(4-hydroxy-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(4-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(4-methylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-(morpholin-4-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-difluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(methyl)-2-(morpholin-4-yl)propan-3-yl)pyrazol-4-yl, 1-(2-(methyl)-3-(morpholin-4-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(pyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-cyanoethyl)pyrazol-4-yl, 1-(2-hydroxy-2-methylpropan-1-yl)pyrazol-4-yl, 1-(2-methoxyethyl)pyrazol-4-yl, 1-(2-methyl-3-hydroxypropan-2-yl)pyrazol-4-yl, 1-(2-methylpropyl)pyrazol-4-yl, 1-(2-methylsulfonylethan-1-yl)pyrazol-4-yl, 1-(2-morpholin-4-ylethyl)pyrazol-4-yl, 1-(2-oxopyrrolidin-3-yl)pyrazol-4-yl, 1-(2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl, 1-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)pyrazol-4-yl, 1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl, 1-(4-methylpiperazin-1-ylcarbonylmethyl)pyrazol-4-yl, 1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl, 1-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)pyrazol-4-yl, 1-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)pyrazol-4-yl, 1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl, 1-(5-oxopyrrolidin-2-ylmethyl)pyrazol-4-yl, 1-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)pyrazol-4-yl, 1-(6-methylpyrazin-2-ylmethyl)pyrazol-4-yl, 1-(ethoxycarbonylmethyl)pyrazol-4-yl, 1-(hexahydrofuro[2,3-b]furan-3-yl)pyrazol-4-yl, 1-(hydroxycarbonylmethyl)pyrazol-4-yl, 1-(isopropylaminocarbonylmethyl)pyrazol-4-yl, 1-(isopropylcarbonylmethyl)pyrazol-4-yl, 1-(methylaminocarbonylmethyl)pyrazol-4-yl, 1-(methylsulfonylaminocarbonylmethyl)pyrazol-4-yl, 1-(methylsulfonylmethyl)pyrazol-4-yl, 1-(morpholin-4-ylcarbonylmethyl)pyrazol-4-yl, 1-(oxetan-2-ylmethyl)pyrazol-4-yl, 1-(oxetan-3-ylmethyl)pyrazol-4-yl, 1-(pyrazin-2-ylmethyl)pyrazol-4-yl, 1-(pyridazin-4-ylmethyl)pyrazol-4-yl, 1-(pyridin-3-ylmethyl)pyrazol-4-yl, 1-(pyrrolidin-1-ylcarbonylmethyl)pyrazol-4-yl, 1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl, 1-(tetrahydrofuran-3-yl)pyrazol-4-yl, 1-(tetrahydrofuran-3-ylaminocarbonylmethyl)pyrazol-4-yl, 1-(tetrahydropyran-4-yl)pyrazol-4-yl, 1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, 1-difluoromethylpyrazol-4-yl, 1H-pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-oxetan-3-ylpyrazol-4-yl, 1-t-butylpyrazol-4-yl, 2-(1,1-dioxothiomorpholin-4-yl)pyridin-4-yl, 2-(1-methylpiperidin-3-yloxy)pyridin-4-yl, 2-(1-methylpiperidin-4-yloxy)pyridin-4-yl, 2-(1-methylpyrrolidin-3-yloxy)pyridin-4-yl, 2-(2-methoxyethan-1-yloxy)pyridin-4-yl, 2-(3-oxopiperazin-1-yl)pyridin-4-yl, 2-(4-acetylpiperazin-1-yl)pyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-(4-methylsulfonylpiperazin-1-yl)pyridin-4-yl, 2-(morpholin-4-yl)pyridin-4-yl, 2-(oxetan-3-yloxy)pyridin-4-yl, 2-(piperidin-3-yloxy)pyridin-4-yl, 2-(piperidin-4-yloxy)pyridin-4-yl, 2-(pyrrolidin-3-yloxy)pyridin-4-yl, 2,6-dimethylpyridin-4-yl, 2-isopropoxypyridin-4-yl, 2-isopropylaminopyridin-4-yl, 2-methylaminocarbonyl-6-methylpyridin-4-yl, 2-methylaminocarbonylpyridin-4-yl, 2-methylaminopyridin-4-yl, 2-methylpyridin-4-yl, 2-morpholin-4-ylpyridin-4-yl, 2-pyrrolidin-1-ylpyridin-4-yl, 4-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclohexyl, 4-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)cyclohexyl, 4-(4,4-difluoropiperidin-1-ylcarbonyl)cyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(morpholin-4-ylcarbonyl)cyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-methylpyridin-3-yl, 5-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl, 5-(morpholin-4-ylmethyl)pyridin-3-yl, 5-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl, 5-(S-imino(methyl)sulfinyl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl, 5-cyanopyridin-3-yl, 5-dimethylaminocarbonylpyridin-3-yl, 5-fluoropyridin-3-yl, 5-hydroxycarbonylpyridin-3-yl, 5-methylaminocarbonylpyridin-3-yl, 5-methylaminosulfonylpyridin-3-yl, 5-methylpyridin-3-yl, 5-methylsulfonylpyridin-3-yl, 6-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-yl)pyridin-4-yl, 6-(1-methylpiperazin-4-yl)pyridin-3-yl, 6-(2-(2-hydroxypropan-2yl)morpholin-4-yl)pyridin-4-yl, 6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-4-yl, 6-(2-hydroxypropan-2-yl)pyridin-4-yl, 6-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-yl)pyridin-4-yl, 6-(2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-5-yl)pyridin-4-yl, 6-(2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-5-yl)pyridin-4-yl, 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl, 6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-4-yl, 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl, 6-(2-oxo-oxazol-3-yl)pyridin-4-yl, 6-(3-methyl-3-hydroxyazetidin-1-yl)pyridin-4-yl, 6-(3-methyl-3-hydroxypyrrolidin-1-yl)pyridin-4-yl, 6-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl, 6-(3-oxomorpholin-4-yl)pyridin-4-yl, 6-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(N-isopropyl-N-ethylaminocarbonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-ylcarbonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-yloxycarbonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-methoxycarbonylpiperazin-1-yl)pyridin-4-yl, 6-(4-methyl-4-hydroxypiperidin-1-yl)pyridin-4-yl, 6-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl, 6-(4-methylpiperazin-1-ylmethyl)pyridin-4-yl, 6-(4-trifluoromethylsulfonylpiperazin-1-yl)pyridin-4-yl, 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl, 6-(hexahydro-1H-furo[3,4-c]pyrrol-5-yl)pyridin-4-yl, 6-(isopropylaminocarbo-nyl)pyridin-3-yl, 6-(methylaminocarbonyl)pyridin-3-yl, 6-(morpholin-4-yl)pyridin-4-yl, 6-(morpholin-4-ylcarbonyl)pyridin-3-yl, 6-(morpholin-4-ylmethyl)pyridin-3-yl, 6-(oxetan-3-yl)pyridin-4-yl, 6-(piperazin-1-yl)pyridin-4-yl, 6-(pyridin-3-yloxy)pyridin-4-yl, 6-(S-imino(methyl)sulfinyl)pyridin-4-yl, 6-(S-methyl-S-iminosulfinyl)pyridin-3-yl, 6-(tetrahydro-pyran-3-ylamino)pyridin-4-yl, 6-(tetrahydropyran-4-ylamino)pyridin-4-yl, 6-fluoropyridin-4-yl, 6-methylaminosulfonylpyridin-3-yl, 6-methylpyridin-3-yl, 6-methylpyridin-4-yl, or 6-methylsulfonylpyridin-3-yl. 
     
     
         34 . The method of  claim 31 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 2  is 4-hydroxycyclohexyl optionally substituted with one to three substituents selected from —CH 3  and fluoro, or is 4,5,6,7-tetrahydro-1H-indazol-5-yl. 
     
     
         35 . The method of  claim 31 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 3  is isopropyl, n-butanyl, heptan-2-yl, propan-2-yl, 3-methoxypropan-2-yl, 3,3-(difluoromethoxy)propan-2-yl, 3,3-difluoropropan-2-yl, 3-cyclopropylpropan-2-yl, 4,4,4-trifluorobutan-2-yl, 4-fluorobutan-2-yl, 4,4-difluorobutan-2-yl, 2-methoxyethan-1-yl, 2-cyclopropanylethan-1-yl, or 3,3,3-trifluoropropan-1-yl. 
     
     
         36 . The method of  claim 31 , wherein, the compound has structural Formula IV 
       
         
           
           
               
               
           
         
       
       or structural Formula V 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof, wherein:
 R 8  is —(C 0 -C 4  alkylene)-S(O) 2 —(C 1 -C 3  alkyl), —C(O)—NH—(C 1 -C 4  alkyl), —C 1 -C 4  alkyl optionally substituted with one or more of halo, hydroxy and cyano, —NH—(C 1 -C 4  alkyl), —O—(C 1 -C 3  alkylene)-O—(C 1 -C 4  alkyl), —O—(C 1 -C 4  alkyl), —S(O)(═NH)—(C 1 -C 4  alkyl), —S(O) 2 —NH—(C 1 -C 4  alkyl), —(C 0 -C 3  alkylene)-C(O)-heterocyclyl, —(C 0 -C 3  alkylene)-NH-heterocyclyl, —(C 0 -C 4  alkylene)-heterocyclyl, —O-heteroaryl, or —O-heterocyclyl, wherein any heterocyclyl, or heteroaryl portion of R 8  is optionally further substituted; 
 R 7  is —O—C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, or —O—C 1 -C 3  haloalkyl; 
 R 12  is hydrogen or C 1 -C 4  alkyl; and 
 each of R 13a  and R 13b  is independently selected from hydrogen and fluoro. 
 
     
     
         37 . The method of  claim 36 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 8  is —CH 3 , —C(O)NHCH 3 , —C(O)NHCH(CH 3 ) 2 , —NHCH(CH 3 ) 2 , —NHCH 3 , —S(═O)(═NH)—CH 3 , —S(═O) 2 —CH 3 , —S(═O) 2 —NH—CH 3 , 1,1-dioxothiomorpholin-4-yl, 1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl, 1-methylpiperidin-3-yloxy, 1-methylpiperidin-4-yloxy, 1-methylpyrrolidin-3-yloxy, 1-oxa-7-azospiro[3.5]nonan-7-yl, 2-(2-hydroxypropan-2-yl)morpholin-4-yl, 2,5-dioxa-8-azospiro[3.5]nonan-8-yl, 2-methoxyethan-1-yloxy, 2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl, 2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, 2-oxa-6-azospiro[3.3]heptan-6-yl, 2-oxa-6-azospiro[3.5]octan-6-yl, 2-oxa-7-azospiro[3.5]nonan-7-yl, 2-oxo-oxazolidin-3-yl, 3-oxomorpholin-4-yl, 3-oxopiperazin-1-yl, 4-(N-ethyl-N-isopropylaminocarbonyl)piperazin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 4-(oxetan-3-ylmethyl)piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-cyclopropylsulfonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-methyl piperazin-1-ylmethyl, 4-sulfonylmethylpiperazin-1-yl, 4-trifluoromethylsulfonylpiperazin-1-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, isopropyloxy, morpholin-4-carbonyl, morpholin-4-yl, morpholin-4-ylmethyl, oxetan-3-yl, oxetan-3-yloxy, piperazin-1-yl, piperidin-3-yloxy, piperidin-4-yloxy, pyridin-3-yloxy, pyrrolidin-1-yl, pyrrolidin-3-yloxy, tetrahydro-1H-furo[3,4-c]pyrrol-5-yl, tetrahydrofuran-3-ylamino, or tetrahydropyran-4-yl. 
     
     
         38 . The method of  claim 36 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 8  is morpholin-4-yl, —S(═O)(═NH)—CH 3 , or —S(═O) 2 —CH 3 . 
     
     
         39 . The method of  claim 36 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 7  is —OCH 3 , —CF 3 , or —OCHF 2 . 
     
     
         40 . The method of  claim 36 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 12  is hydrogen or —CH 3 . 
     
     
         41 . The method of  claim 40 , wherein, in the compound or the pharmaceutically acceptable salt thereof, each of R 12 , R 13a  and R 13b  is hydrogen and the compound has structural formula IVa 
       
         
           
           
               
               
           
         
       
       or structural formula Va 
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 31 , wherein the compound has structural Formula VI 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof, wherein:
 R 7  is —O—C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, or —O—C 1 -C 3  haloalkyl; 
 each of R 9a  and R 9b  are —CH 3 , or R 9a  and R 9b  are taken together with the carbon atom to which they are bound to form cyclopropyl; 
 R 9  is C 1 -C 3  alkyl, C 1 -C 3  hydroxyalkyl, —COOH, —C(O)NH—C 1 -C 4  alkyl, —CH 2 -heterocyclyl, —C(═O)-heterocyclyl or a 5-membered heteroaryl, wherein the heterocyclyl or heteroaryl portion of R 9  is optionally substituted with up to two substituents independently selected from oxo, cyclopropyl, —OH, —CN, —C 1 -C 3  alkyl, and —C 1 -C 3  hydroxyalkyl; and 
 R 12  is hydrogen or C 1 -C 4  alkyl; and 
 each of R 13a  and R 13b  is independently selected from hydrogen and fluoro. 
 
     
     
         43 . The method of  claim 42 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 7  is —OCH 3 , —CF 3 , or —OCHF 2 . 
     
     
         44 . The method of  claim 42 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 9  is —CH 3 , —CH 2 OH, —COOH, —C(O)NHCH 3 , —C(O)NHCH(CH 3 ) 2 , 1,1-dioxothiomorpholin-4-ylcarbonyl, 2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl, 2,2-dimethylmorpholin-4-ylcarbonyl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, 2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl, 2-oxa-6-azaspiro [3.4]octan-6-ylcarbonyl, 3-hydroxpyrrolidin-1-ylcarbonyl, 4-cyano-4-methylpiperidin-1-ylcarbonyl, 4-hydroxy-4-methylpiperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl, azetidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, morpholin-4-ylmethyl, pyrrolidin-1-ylcarbonyl, or tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylcarbonyl. 
     
     
         45 . The method of  claim 44 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 9  is morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 2-oxa-6-azaspiro [3.3]heptan-6-ylcarbonyl, 3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl. 
     
     
         46 . The method of  claim 42 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 12  is hydrogen or —CH 3 . 
     
     
         47 . The method of  claim 46 , wherein, in the compound or the pharmaceutically acceptable salt thereof, each of R 12 , R 13a  and R 13b  is hydrogen and the compound has structural formula VIa 
       
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 31 , wherein the compound has structural Formula VII 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof, wherein:
 R 7a  is C 1 -C 4  alkyl, —O—C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, or —O—C 1 -C 3  haloalkyl; 
 R 9  is —COOH, —C(═O)-heterocyclyl or a 5-membered heteroaryl, wherein R 9  is optionally substituted with up to two substituents independently selected from oxo, —OH and —C 1 -C 3  alkyl; and 
 R 12  is hydrogen, or C 1 -C 4  alkyl; and 
 each of R 13a  and R 13b  is independently selected from hydrogen and fluoro. 
 
     
     
         49 . The method of  claim 48 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 7a  is —(CH 2 ) 3 CH 3 , —OCH 3 , —CF 3 , or —OCHF 2 . 
     
     
         50 . The method of  claim 49 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 7a  is —(CH 2 ) 3 CH 3 , —OCH 3 , or —CF 3 . 
     
     
         51 . The method of  claim 47 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 9  is —COOH, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl, 3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, or 1,1-dioxothiomorpholin-4-ylcarbonyl. 
     
     
         52 . The method of  claim 51 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 9  is morpholin-4-ylcarbonyl. 
     
     
         53 . The method of  claim 47 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 12  is hydrogen or —CH 3 . 
     
     
         54 . The method of  claim 48 , wherein, in the compound or the pharmaceutically acceptable salt thereof, each of R 12 , R 13a  and R 13b  is hydrogen and the compound has structural formula VIIa: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 31 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt of any of the foregoing compounds. 
     
     
         56 . The method of  claim 31 , wherein the compound or the pharmaceutically acceptable salt thereof demonstrates a Ki against MERTK at least two times lower than its Ki against FLT3.