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US 12,410,160 B2Granted
KHK inhibitors
AssigneeGilead Sciences, Inc.
InventorsJames L. Bachman, Daniel H. Byun, Christopher T. Clark, Petr Jansa, Joshua A. Kaplan, Zachary A. Kasun, Jennifer R. Lo, Megan E. Neubig, Nathaniel H. Stanley, Kirk L. Stevens
Life of this patent
Estimating the term…
Abstract
Compounds of formula: wherein the variable substituents are defined herein.
Claims38
A compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein m is 0-4;
- each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, OR1b, CH2OH, CO2R12, halogen, oxo, CONH2, CN, NH2, NHR11, C1-6 alkyl-NHSO2R13, C1-6 alkyl-NHCOR13, C1-6 alkoxy or C1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R1c, alternatively two R1a can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring;
- R1b is H, or C1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens, CN, or OH;
- each R1c is independently OH, OR11, halogen, oxo, SOR13, SO2R13, SR13, SO2NH2, CONH2, C1-6 alkoxy, C6-10 aryl, C6-10 aryloxy, 5-11 membered heteroaryl, or C3-7 cycloalkyl;
- R2 is C6-10 aryl, or a 6-14 membered heteroaryl, wherein the aryl, or heteroaryl are optionally substituted with up to eight R2a, and wherein R2 is attached to the core through a carbon atom of R2;
- each R2a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, SO2R2c, SOR2c, SO2NH2, CONH2, COR2c, CONHR2e, CON(R2c)2, halogen, oxo, OH, CN, NH2, NHR2c, N(R2c)2, NHCOR2c, N(R2c) COR2c, NO2, SO2NHR2c, SO2N(R2c)2, NHSO2R2c, N(R2c) SO2R2c, S(O)(NH) R2c, S(O)(NH) NH2, NHS(O)(NH) R2c, NS(O) (NH2) R2c, NS(O) (R2c)2, S(O)(NR2c) R2c, S(O)(NR2c) NH2, S(O)(NH) NHR2c, S(O)(NR2c) NH(R2c), OR2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl, or 5-11 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are substituted with up to seven R2b, and wherein the cycloalkyl can be fused or spiro to the heteroaryl, or the cycloalkyl can be fused to the aryl;
- alternatively two R2a can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
- each R2b is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, OH, halogen, oxo, CONH2, NHCOR2c, N(R2c) COR2c, NHCO2R2c, NH2, N(R2c)2, NHR2c, S(O)(NH) R2c, S(O)(NH) NH2, NHS(O)(NH) R2c, NS(O) (NH2) R2c, NS(O) (R2c)2, S(O)(NR2c) R2c, S(O)(NR2c) NH2, S(O)(NH) NHR2c, S(O)(NR2c) NH(R2c), OR2c, NHSO2R2c, N(R2c) SO2R2c, C1-6 alkyl-CO2R12, C1-6 alkyl-CONH2, C1-6 alkyl-NHSO2R2c, CN, COR2c, NHCO2R2c, SO2NH2, SO2NHR2c, SO2R2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl or 5-11 membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl can be optionally substituted with up to four R2d;
- alternatively two R2b can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
- each R2c is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C6-10 aryl, 5-11 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl or heterocyclyl are optionally substituted with up to four R2d;
- each R2d is independently OH, halogen, NH2, C1-6 alkoxy, CONH2, SO2NH2, NHCOR13, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-NH2, C1-6 alkyl-CO2R12, oxo, or CN;
- R2e is C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, C1-6 alkyl-C6-10 aryl, 4-7 membered heterocyclyl, or 5-11 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl or heteroaryl are optionally substituted with up to three R10;
- R3, R4, R5, R6, R7, R8 are independently H, C1-6 alkyl, halogen, or C3-7 cycloalkyl;
- alternatively R3, R4, R5, R6, R7 or R8 can be combined with the atoms to which they are attached to form a 3-6 membered spiro, bridged or fused ring;
- each R10 is independently C1-6 alkoxy, CN, halogen, OH, NH2, NHR11, CONH2, SO2NH2, or NHCO2—C1-6 alkyl;
- R11 is H, C1-6 alkyl, or C1-6 haloalkyl;
- R12 is C1-6 alkyl, C1-6 haloalkyl, 3-7 cycloalkyl, 4-7 heterocyclyl, C6-10 aryl, or 5-11 heteroaryl;
- and
- R13 is C1-6 alkyl, or C1-6 haloalkyl.
16 more elements
A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of Formula VI
- wherein m is 0-4:
- each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, OR1b, CH2OH, CO2R12, halogen, oxo, CONH2, CN, NH2, NHR11, C1-6 alkyl-NHSO2R13, C1-6 alkyl-NHCOR13, C1-6 alkoxy or C1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R1c;
- alternatively two Rla can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring;
- R1b is H, or C1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens, CN, or OH;
- each R1c is independently OH, OR11, halogen, oxo, SOR13, SO2R13, SR13, SO2NH2, CONH2, C1-6 alkoxy, C6-10 aryl, C6-10 aryloxy, 5-11 membered heteroaryl, or C3-7 cycloalkyl;
- wherein R2 is
- wherein
- Y2 is a 5 membered heteroaryl, wherein Y2 is attached to the core through a carbon atom of Y2;
- p is 0, or 1;
- s is 0, 1, or 2;
- and
- W2 is O, CF2, CHF, SO, SO(NH), SO(NR2c), CH2O, CH2OCH2, OCH2O, CH2SO2, CH2SO2CH2, or SO2;
- each R2a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl SO2R2c, SOR2c, SO2NH2, CONH2, COR2c, CON(R2c)2, halogen, oxo, OH, CN, NH2, NHR2c, N(R2c)2, NHCOR2c, N(R2c)COR2c, NO2, SO2NHR2c, SON(R2c)2, NHSO2R2c N(R2c)SO2R2c, S(O)(NH)R2c, S(O)(NH)NH2, NHS(O)(NH)R2c, NS(O)(NH2)R2c, NS(O)(R2c)2, S(O)(NR2c)R2c, S(O)(NR2c)NH2, S(O)(NH)NHR2cS(O)(NR2c)NH(R2c), OR2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl, or 5-11 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are substituted with up to seven R2b, and wherein the cycloalkyl can be fused or spiro to the heteroaryl;
- alternatively two R2a can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring:
- each R2b is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, OH, halogen, oxo, CONH2, NHCOR2c, N(R2c)COR2c, NHCO2R2c, NH2, N(R2c)2, NHR2c, S(O)(NH)R2c, S(O)(NH)NH2, NHS(O)(NH)R2c, NS(O)(NH2)R2c, NS(O)(R2c)2, S(O)(NR2c)R2c, S(O)(NR2c)NH2, S(O)(NH)NHR2c, S(O)(NR2c)NH(R2c), OR2c, NHSO2R2c, N(R2c)SO,R2c, C1-6 alkyl-CO-R12, C1-6 alkyl-CONH2, C1-6 alkyl-NHSO2R2c, CN, COR2c, NHCOR2c, SO2NH2, SO2NHR2c, SO2R2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl or 5-11 membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl can be optionally substituted with up to four R2d, alternatively two R2b can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
- each R2c is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C6-10 aryl, 5-11 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl or heterocyclyl are optionally substituted with up to four R2d;
- each R2d is independently OH, halogen, NH2, C1-6 alkoxy, CONH2, SO2NH2, NHCOR13, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-NH2, C1-6 alkyl-CO2R12, oxo, or CN;
- R2e is C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, C1-6 alkyl-C6-10 aryl, 4-7 membered heterocyclyl, or 5-11 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl or heteroaryl are optionally substituted with up to three R10;
- R3, R4, R5, R6, R7, R8 are independently H, C1-6 alkyl, halogen, or C3-7 cycloalkyl;
- alternatively R3, R4, R5, R6, R7, R8 can be combined with the atoms to which they are attached to form a 3-6 membered spiro, bridged or fused ring;
- each R10 is independently C1-6 alkoxy, CN, halogen, OH, NH2, NHR11, CONH2, SO2NH2, or NHCO2—C1-6 alkyl;
- R11 is H, C1-6 alkyl, or C1-6 haloalkyl;
- R12 is C1-6 alkyl, C1-6 haloalkyl, 3-7 cycloalkyl, 4-7 heterocyclyl, C6-10 aryl, or 5-11 heteroaryl;
- and
- R13 is C1-6 alkyl, or C1-6 haloalkyl.
22 more elements
A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula VI
- wherein m is 0-4;
- each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, OR1b, CH2OH, CO2R12, halogen, oxo, CONH2, CN, NH2, NHR11, C1-6 alkyl-NHSO2R13, C1-6 alkyl-NHCOR13, C1-6 alkoxy or C1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R1c;
- alternatively two R1a can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring;
- R1b is H, or C1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens, CN, or OH;
- each R1c is independently OH, OR11, halogen, oxo, SOR13, SO2R13, SR13, SO2NH2, CONH2, C1-6 alkoxy, C6-10 aryl, C6-10 aryloxy, 5-11 membered heteroaryl, or C3-7 cycloalkyl;
- wherein R2 is
- R3, R4, R5, R6, R7, R8 are independently H, C1-6 alkyl, halogen, or C3-7 cycloalkyl:
- alternatively R3, R4, R5, R6, R7 or R8 can be combined with the atoms to which they are attached to form a 3-6 membered spiro, bridged or fused ring.
5 more elements
A pharmaceutical composition comprising a pharmaceutically effective amount of a
- wherein m is 0-4;
- each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, OR1b, CH2OH, CO2R12, halogen, oxo, CONH2, CN, NH2, NHR11, C1-6 alkyl-NHSO2R13, C1-6 alkyl-NHCOR13, C1-6 alkoxy or C1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R1c;
- alternatively two R1a can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring;
- R1b is H, or C1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens, CN, or OH;
- each R1c is independently OH, OR11, halogen, oxo, SOR13, SO2R13, SR13, SO2NH2, CONH2, C1-6 alkoxy, C6-10 aryl, C6-10 aryloxy, 5-11 membered heteroaryl, or C3-7 cycloalkyl;
- wherein
- Y2 is a 5 membered heteroaryl, wherein Y2 is attached to the core through a carbon atom of Y2;
- p is 0, or 1;
- s is 0, 1, or 2;
- and
- W2 is O, CF2, CHF, SO, SO(NH), SO(NR2c), CH2O, CH2OCH2, OCH2O, CH2SO2, CH2SO2CH2, or SO2;
- each R2a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, SO2R2c, SOR2, SO2NH2, CONH2, COR2c, CONHR2e, CON(R2c)2, halogen, oxo, OH, CN, NH2, NHR2, N(R2c)2, NHCOR2c, N(R2c)COR2c, NO2, SO2NHR2c, SO2N(R2c)2, NHSO2R2c, N(R2c)SO2R2c, S(O)(NH)R2c, S(O)(NH)NH2, NHS(O)(NH)R2c, NS(O)(NH2)R2c, NS(O)(R2c)2, S(O)(NR2c)R2c, S(O)(NR2c)NH2, S(O)(NH)NHR2c, S(O)(NR2c)NH(R2c), OR2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl, or 5-11 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are substituted with up to seven R2b, and wherein the cycloalkyl can be fused or spiro to the heteroaryl;
- alternatively two R2a can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
- each R2b is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, OH, halogen, oxo, CONH2, NHCOR2c, N(R2c)COR2c, NHCO2R2c, NH2, N(R2c)2, NHR2c, S(O)(NH)R2c, S(O)(NH)NH2, NHS(O)(NH)R2c, NS(O)(NH2)R2c, NS(O)(R2c)2, S(O)(NR2c)R2c, S(O)(NR2c)NH2, S(O)(NH)NHR2c, S(O)(NR2c)NH(R2c), OR2c, NHSO2R2c, N(R2c)SO2R2c, C1-6 alkyl-CO2R12, C1-6 alkyl-CONH2, C1-6 alkyl-NHSO2R2c, CN, COR2c, NHCO2R2c, SO2NH2, SO2NHR2c, SO2R2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl or 5-11 membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl can be optionally substituted with up to four R2d;
- alternatively two R2b can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
- each R2c is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C6-10 aryl, 5-11 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl or heterocyclyl are optionally substituted with up to four R2d;
- each R2d is independently OH, halogen, NH2, C1-6 alkoxy, CONH2, SO2NH2, NHCOR13, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-NH2, C1-6 alkyl-CO2R12, oxo, or CN;
- R2e is C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, C1-6 alkyl-C6-10 aryl, 4-7 membered heterocyclyl, or 5-11 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl or heteroaryl are optionally substituted with up to three R10;
- R3, R4, R5, R6, R7, R8 are independently H, C1-6 alkyl, halogen, or C3-7 cycloalkyl;
- alternatively R3, R4, R5, R6, R7 or R8 can be combined with the atoms to which they are attached to form a 3-6 membered spiro, bridged or fused ring;
- each R10 is independently C1-6 alkoxy, CN, halogen, OH, NH2, NHR11, CONH2, SO2NH2, or NHCO2-C1-6 alkyl;
- R11 is H, C1-6 alkyl, or C1-6 haloalkyl;
- R12 is C1-6 alkyl, C1-6 haloalkyl, 3-7 cycloalkyl, 4-7 heterocyclyl, C6-10 aryl, or 5-11 heteroaryl;
- and
- R13 is C1-6 alkyl, or C1-6 haloalkyl;
- or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
23 more elements
A pharmaceutical composition comprising a pharmaceutically effective amount of a compound having the structure of Formula VI
- wherein m is 0-4;
- each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, OR1b, CH2OH, CO2R12, halogen, oxo, CONH2, CN, NH2, NHR11, C1-6 alkyl-NHSO2R13, C1-6 alkyl-NHCOR13, C1-6 alkoxy or C1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R1c;
- alternatively two R1a can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring;
- R1b H, or C1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens, CN, or OH;
- each R1c is independently OH, OR11, halogen, oxo, SOR13, SO2R13, SR13, SO2NH2, CONH2, C1-6 alkoxy, C6-10 aryl, C6-10 aryloxy, 5-11 membered heteroaryl, or C3-7 cycloalkyl;
- wherein R2 is
- R3, R4, R5, R6, R7, R8 are independently H, C1-6 alkyl, halogen, or C3-7 cycloalkyl;
- alternatively R3, R4, R5, R6, R7 or R8 can be combined with the atoms to which they are attached to form a 3-6 membered spiro, bridged or fused ring;
- or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
6 more elements
Dependencies are inferred from the claim text.