Pyrrolotriazine compounds and methods of inhibiting TAM kinases

Patent metadata

Field	Value
Publication number	US-11040981-B2
Application number	US-201816755051-A
Country	US
Kind code	B2
Filing date	Oct 9, 2018
Priority date	Oct 10, 2017
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

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.

First claim

What is claimed is:

1. A compound of structural formula II:

or a pharmaceutically acceptable salt thereof, wherein:
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.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein 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 1 -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.

3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein 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-l-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)ppyrazol-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)ppyrazol-4-yl, 1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl, 1-(4-methylpiperazin-1-ylcarbonylmethylppyrazol-4-yl, 1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl, 1-(5-methyl -1,2,4-oxadiazol-3-ylmethylppyrazol-4-yl, 1-(5-methyl-1,3,4-oxadiazol-2-ylmethylppyrazol-4-yl, 1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl, 1-(5-oxopyrrolidin-2-ylmethylppyrazol-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-(methylsulfonylaminocarbonylmethylppyrazol-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-ylmethylppyrazol-4-yl, 1-(pyrrolidin-l-ylcarbonylmethylppyrazol-4-yl, 1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl, 1-(tetrahydrofuran-3-yl)pyrazol-4-yl, 1-(tetrahydrofuran-3-ylaminocarbonylmethylppyrazol-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-oxo

Assignees

• Syros Pharmaceuticals Inc

Inventors

• Moebius David
• Marineau Jason J
• Zhang Yi
• Chuaqui Claudio Edmundo
• Malojcic Goran
• Sinko William
• Guan Huiping Amy
• Ciblat Stephane
• James Clint
• Xolin Amandine
• Bernard Sylvain
• Doshi Malay

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title