US 2026/0176289 A1 · SMALL MOLECULE INHIBITORS OF KRAS PROTEINS

Abstract

Compounds of Formula (I) or their pharmaceutically acceptable salts can inhibit the G12C, G12D, G12V, and/or G13D mutants of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The disclosure also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

A compound of Formula (I)

wherein:
X is:
Ring X is selected from the group consisting of:
(i) a 5- to 9-membered monocyclic or fused bicyclic or bridged bicyclic heterocycloalkyl, wherein the 5- to 9-membered monocyclic or fused bicyclic or bridged bicyclic heterocycloalkyl is saturated and contains 0 to 2 heteroatom groups selected from the group consisting of N, S, S(O), S(O)2 and O, in addition to the illustrated N atom;
and
(ii) an 8- to 12-membered spiroheterocycloalkyl, wherein the 8- to 12-membered spiroheterocycloalkyl is saturated and contains 0 to 2 heteroatom groups selected from the group consisting of N, S, S(O), S(O)2 and O, in addition to the illustrated N atom;
each RX is independently selected from the group consisting of fluoro, cyano, hydroxy, oxo, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C1-C6 cyanoalkyl, and C1-C6 hydroxyalkyl;
X1 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, C3-C6 cycloalkyl, and C3-C6 fluorocycloalkyl;
X2 is H or —(CRa2)p—CX, wherein CX is:
(i) a 3- to 10-membered monocyclic or fused bicyclic or bridged bicyclic cycloalkyl or an 8- to 10-membered spirocycloalkyl;
(ii) a 3- to 10-membered monocyclic or fused bicyclic or bridged bicyclic heterocycloalkyl or an 8- to 10-membered spiroheterocycloalkyl, wherein the 3- to 10-membered monocyclic or fused bicyclic or bridged bicyclic heterocycloalkyl or the 8- to 10-membered spiroheterocycloalkyl is saturated and contains 1 to 3 heteroatom groups independently selected from the group consisting of N, S, S(O), S(O)2 and O;
wherein CX is unsubstituted or substituted by 1 to 2 RCX substituents independently selected from the group consisting of fluoro, hydroxy, oxo, cyano, C1-C6 alkyl, C1-C6 acyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, and C3-C6 fluorocycloalkyl;
each Ra is independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C1-C6 cyanoalkyl, C1-C6 fluorocyanoalkyl, C3-C6 cycloalkyl, and C3-C6 fluorocycloalkyl;
XA, XB, and XC, are independently selected from the group consisting of N, C(H), and C(R1);
XD is selected from the group consisting of N and C;
each R1 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, halo, hydroxy, oxo, cyano, C1-C3 alkylamino, C1-C3 dialkylamino, and CB;
wherein CB is selected from the group consisting of:
(i) a monocyclic, saturated heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O;
(ii) a monocyclic 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O;
wherein CB is unsubstituted or substituted by 1 to 2 RCB substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, C3-C6 cycloalkyl, and C3-C6 fluorocycloalkyl;
WA is selected from the group consisting of N(RW1), C(RW2)2, O, S, Se, and C(RW3);
RW1 is selected from the group consisting of C1-C3 alkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, and C3-C6 fluorocycloalkyl;
each RW2 is independently selected from the group consisting of fluoro, C1-C3 alkyl, C1-C3 fluoroalkyl, and hydroxy;
or alternatively, the two RW2, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl or C3-C6 fluorocycloalkyl;
RW3 is selected from the group consisting of H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 fluoroalkyl, C1-C3 fluoroalkoxy, C3-C6 cycloalkyl, and C3-C6 fluorocycloalkyl;
WB is C or N, wherein when:
WB is C, then WA is N(RW1), C(RW2)2, O, or S;
and
WB is N, then WA is C(RW3);
Y is selected from the group consisting of C1-C6 alkyl, C1-C6 fluoroalkyl, and CY;
CY is:
(i) an aryl selected from the group consisting of phenyl and naphthyl:
(ii) an indanyl or fused indanyl group of the formula:
(iii) a 5- to 6-membered monocyclic heteroaryl, wherein the 5- to 6-membered monocyclic heteroaryl contains 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O;
or
(iv) a 9- to 10-membered fused, bridged or spiro-bicyclic heteroaryl, wherein the 9- to 10-membered fused, bridged or spiro-bicyclic heteroaryl contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S;
or
(v) a 12- to 17-membered fused, bridged or spiro-tri- or tetracyclic heterocycloalkyl, where at least 2 of the rings of the 12- to 17-membered fused, bridged or spiro-tri- or tetracyclic heterocycloalkyl are aromatic, the third ring is partially unsaturated or aromatic, and the fourth ring, if present, is saturated, wherein the 12- to 17-membered fused, bridged or spiro-tri- or tetracyclic heterocycloalkyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, S, and O;
wherein CY is unsubstituted or substituted by 1 to 5 RY substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C6 alkyl, C2-C6 alkynyl, C2-C7 alkenyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 fluoroalkynyl, C2-C7 fluoroalkenyl, C1-C3 fluoroalkenylenyl, C1-C6 alkylthio, C1-C6 fluoroalkylthio, amino, C1-C6 alkylamino, C1-C6 dialkylamino, tri (C1-C6 alkyl) silyl, cyano, C1-C6 cyanoalkyl, C1-C6 fluorocyanoalkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C6 alkoxycarbonyl, C1-C6 acyl, methylenyl, and Rya;
wherein Rya is:
(a) a 3- to 9-membered monocyclic or fused bicyclic or bridged bicyclic cycloalkyl;
(b) a 3- to 9-membered monocyclic or fused bicyclic or bridged bicyclic cycloalkenyl;
(c) a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O;
or
(d) a 4- to 7-membered saturated or partially saturated heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group of N, S, and O;
wherein Rya is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halo, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, C3-C6 fluorocycloalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, and C1-C3 cyanoalkyl;
Ring Z is selected from the group consisting of:
(i) a 3- to 10-membered monocyclic, fused, bridged or spiro-bicyclic, or fused, bridged or spiro-tricyclic heterocycloalkyl, wherein the 3- to 10-membered monocyclic, fused, bridged or spiro-bicyclic, or fused, bridged or spiro-tricyclic heterocycloalkyl is saturated or partially unsaturated and contains 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O;
(ii) a 3- to 10-membered monocyclic, fused, bridged or spiro-bicyclic, or fused, bridged or spiro-tricyclic cycloalkyl, wherein the 3- to 10-membered monocyclic, fused, bridged or spiro-bicyclic, or fused, bridged or spiro-tricyclic cycloalkyl is saturated or partially unsaturated;
and
(iii)
wherein ring Z is unsubstituted or independently substituted with 1 to 4 substituents RZC selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 fluoroalkenylenyl, C1-C3 hydroxyfluoroalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, C1-C3 cyanoalkyl, C3-C6 cycloalkyl, C3-C6 fluorocycloalkyl, C3-C6 hydroxycycloalkyl, C3-C6 hydroxyfluorocycloalkyl, C2-C4 fluoroalkenyl, C1-C3 alkylamino, C1-C3 dialkylamino, methylene (C1-C3 alkyl)amino, C1-C3 alkylenedi (C1-C3 alkyl)amino and methylene (C1-C3 alkyl) (C1-C3 alkyl) carbamate;
wherein ring Z is optionally substituted with 1 P or —CH2P, wherein P is a 4- to 10-membered monocyclic, fused, bridged or spiro-bicyclic, or fused, bridged or spiro-tricyclic heterocycloalkyl, wherein the 4- to 10-membered monocyclic, fused, bridged or spiro-bicyclic, or fused, bridged or spiro-tricyclic heterocycloalkyl is saturated or partially unsaturated and contains 1 to 2 heteroatoms selected from the group consisting of N, S, and O;
wherein P is unsubstituted or independently substituted with 1 to 4 RP substituents selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 hydroxyfluoroalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, C1-C3 cyanoalkyl, C3-C6 cycloalkyl, C3-C6 fluorocycloalkyl, C3-C6 hydroxycycloalkyl, C1-C3 alkoxy C1-C3 alkyl, C3-C6 hydroxyfluorocycloalkyl, carbamoyl, and —NHC(O)C1-C3alkyl;
subscript m is 0, 1, or 2;
subscript n is 0, 1, 2, or 3;
and
subscript p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.

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Small molecule inhibitors of kras proteins

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Small molecule inhibitors of kras proteins

Life of this patent

Abstract

Claims27