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US 2019/0144444 A1Published application
Kras g12c inhibitors
AssigneesMirati Therapeutics, Inc., Array BioPharma Inc.
InventorsJames F. Blake, Laurence E. Burgess, Mark Joseph Chicarelli, James Gail Christensen, Adam Cook, Jay Bradford Fell, John P. Fischer, Matthew Arnold Marx, Macedonio J. Mejia, Pavel Savechenkov, Guy P.A. Vigers, Christopher Ronald Smith, Martha E. Rodriguez
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Abstract
The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.
Claims58
A compound of formula (II):
- or a pharmaceutically acceptable salt thereof:
- wherein:
- X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R8;
- Y is a bond, O, S or NR5;
- R1 is —C(O)C(RA)C(RB)p or —SO2C(RA)C(RB)p;
- R2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9;
- each Z is C1-C4 alkylene;
- each R3 is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl or halogen;
- L is a bond, —C(O)—, or C1-C3 alkylene;
- R4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6, R7 or R8;
- each R5 is independently hydrogen or C1-C3 alkyl;
- R6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7;
- each R7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;
- R8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR5, —C(O)N(R5)2, —N(R5)2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR5, —N(R5)2, or heteroaryl;
- each R9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;
- each R10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;
- R11 is haloalkyl;
- RA is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R5)2, or hydroxyalkyl;
- each RB is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR5R11, —C(O)N(R5)2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, —CH2N(CH3)C(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7;
- or when is a double bond and p is two, one RB is hydrogen and RA and one RB and the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo;
- m is zero or an integer between 1 and 2;
- p is one or two;
- and wherein,
- when is a triple bond then RA is absent, p equals one and RB is hydroxyalkyl,
- or when is a double bond then RA is present, RB is present and p equals two, wherein when RA is hydrogen or C1-C3 alkyl, at least one RB is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR5R11, —C(O)N(R5)2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl;
- or when each RB is hydrogen, then RA is deuterium, cyano, halogen, haloalkyl, —C(O)N(R5)2, hydroxyalkyl or heteroalkyl.
23 more elements
Dependencies are inferred from the claim text.