SMALL MOLECULE INHIBITORS OF KRAS MUTATED PROTEINS
Compounds of Formula (I) or their pharmaceutically acceptable salts can inhibit the G12C, G12D and/or G12V 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.
1 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof
wherein
the moiety
is selected from the group consisting of:
each occurrence of R B is independently selected from the group consisting of halo, cyano, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, cyclopropyl and C 1 -C 4 cyanoalkyl;
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 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 10-membered spiroheterocycloalkyl, wherein said 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;
wherein ring X is unsubstituted or independently substituted by 1 to 3 R X2 substituents selected from the group consisting of fluoro, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 3 hydroxyalkyl, —N(H)C(O)heteroaryl, wherein heteroaryl is optionally substituted by C 1 -C 3 alkyl;
R X1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 4 cyanoalkyl;
Ring Y is selected from the group consisting of:
(i) a 8- to 10-membered bicyclic ring system, wherein the 8- to 10-membered bicyclic ring system is partially unsaturated or aromatic, and wherein the 8- to 10-membered bicyclic ring system contains 0 to 3 heteroatoms selected from the group consisting of N, S, and O;
(ii) a 13- to 14-membered tricyclic ring system, wherein the 13- to 14-membered tricyclic ring system is partially unsaturated or aromatic, and wherein the 13- to 14-membered tricyclic ring system contains 0 to 3 heteroatoms selected from the group consisting of N, S, and O; and
(iii) phenyl; and
(iv) a 6-membered heteroaryl ring containing 1 to 2 N atoms;
wherein Ring Y is unsubstituted or independently substituted by 1 to 4 R Y substituents selected from the group consisting of halo, hydroxy, amino, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkoxy, C 2 -C 3 alkynyl, C 2 -C 3 fluoroalkynyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cyclofluoroalkyl, C 3 -C 6 cycloalkoxy, C 3 -C 6 cyclofluoroalkoxy, C 2 -C 3 alkenyl, C 2 -C 3 fluoroalkenyl and cyano;
Ring Z is selected from the group consisting of:
(i) a 5- to 8-membered monocyclic- or bicyclic-heterocycloalkyl, wherein said heterocycloalkyl is saturated and contains 1 to 3 heteroatoms independently selected from the group consisting of N, S, and O, and wherein said heterocycloalkyl is unsubstituted or substituted with 1-2 substituents R ZHC selected from the group consisting of halo, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, —C(H)(OH)CF 2 H, —O—CH 2 —O—(C 1 -C 3 fluoroalkyl), and methylene(C 1 -C 3 alkyl)(C 1 -C 3 alkyl)carbamate;
(ii)
wherein M is selected from the group consisting of hydroxy, C 1 -C 3 dialkylamino, and C 1 -C 4 alkylamino, and wherein the cyclopropyl group is unsubstituted or independently substituted with up to 2 halo groups;
(iii)
wherein P is 5- to 8-membered monocyclic- or fused bicyclic- or bridged bicyclic-heterocycloalkyl, wherein said heterocycloalkyl is saturated and contains 1 to 2 heteroatoms selected from the group consisting of N and O, wherein said heterocycloalkyl is unsubstituted or substituted with 1 R P substituent selected from the group consisting of halo, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 cyanoalkyl, carbamoyl, C 1 -C 3 alkoxy, cyano, and —NHC(O)C 1 -C 3 alkyl, and wherein the cyclopropyl group is unsubstituted or independently substituted with up to 2 halo groups; and
(iv) a 4- to 8-membered monocyclic- or bicyclic-cycloalkyl, wherein said cycloalkyl is saturated and wherein said cycloalkyl is unsubstituted or independently substituted with 1-3 substituents R ZC selected from the group consisting of halo, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 hydroxyfluoroalkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cyclofluoroalkyl, C 3 -C 4 hydroxycycloalkyl, and C 3 -C 4 hydroxycyclofluoroalkyl;
subscript n is 1 or 2; and
subscript q is 0, 1 or 2.
2 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein ring X is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl is saturated and contains 0 to 1 heteroatoms selected from the group consisting of N, S, and O, in addition to the illustrated N atom.
3 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the group
is selected from the group consisting of:
4 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein
the group
is selected from the group consisting of:
5 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein
the moiety
is
6 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of naphthyl, phenyl, pyridyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, pyridopyrazolyl and benzothiophenyl.
7 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of:
8 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the group
is selected from the group consisting of:
9 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the group
is selected from the group consisting of:
10 . The compound of claim 1 selected from Examples 1-49 or the pharmaceutically acceptable salt thereof.
11 . A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12 . A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.
13 . A method of inhibiting KRAS-G12D protein comprising contacting KRAS-G12D protein with the compound of claim 1 , or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12D protein.
14 . A method of inhibiting KRAS-G12C protein comprising contacting KRAS-G12C protein with the compound of claim 1 , or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12C protein.
15 . A method of inhibiting KRAS-G12V protein comprising contacting KRAS-G12V protein with the compound of claim 1 , or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12V protein.
16 . A method of treating cancer comprising administering a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
17 . The method of claim 16 , further comprising administering an additional active agent to the subject.
18 .- 24 . (canceled)