US 2024/0390340 A1 · PYRROLIDINE KRAS INHIBITORS

Abstract

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting KRAS activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with KRAS activity such as cancer.

A compound having Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Cy1 is C6-10 aryl or 6-10 membered heteroaryl;
wherein the ring-forming atoms of the 6-10 membered heteroaryl forming Cy1 consist of at least one ring-forming carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of the 5-6 membered heteroaryl forming Cy1 is optionally substituted by oxo to form a carbonyl group;
and wherein the C6-10 aryl and 6-10 membered heteroaryl forming Cy1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RcCy1;
each RCy1 is independently selected from D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, CN, ORaCy1, C(O)RbCy1, C(O)NRcCy1RdCy1, C(O)ORaCy1, NRcCy1RdCy1, and S(O)2RbCy1,
each RaCy1, RbCy1, RcCy1, and RdCy1 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R1 is H or D;
R2 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, CN, and ORa2;
wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R2 are each optionally substituted with 1 or 2 substituents independently selected from R2A;
each R2A is independently selected from D, halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino;
each Ra2 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R3 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, cyclopropyl, halo, CN, and ORa3;
wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R3 are each optionally substituted with 1 or 2 substituents independently selected from R3A;
and wherein the cyclopropyl forming R3 is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, and R3A;
each Ra3 is independently selected from H, C1-3 alkyl, and C1-3haloalkyl;
each R3A is independently selected from D, halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino;
R4 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-5 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl-C1-3 alkylene, 4-6 membered heterocycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 membered heteroaryl-C1-3 alkylene, halo, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, NRc4Re4, and NRc4C(O)Rb4;
wherein the C3-5 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl-C1-3 alkylene, 4-6 membered heterocycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, and 5-6 membered heteroaryl-C1-3 alkylene forming R4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4A;
wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C1-3 alkylene, and 5-6 membered heteroaryl-C1-3 alkylene forming R4 consist of at least one ring-forming carbon atom and 1, 2, or 3 heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C1-3 alkylene, and 5-6 membered heteroaryl-C1-3 alkylene forming R4 is optionally substituted by oxo to form a carbonyl group;
and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4B;
each R4A is independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, and R4B;
wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R4A are each optionally substituted with 1, 2, or 3 substituents each independently selected from R4B;
each R4B is independently selected from D, C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, ORa4B, C(O)Rb4B, C(O)NRc4BRd4B, C(O)ORa4B, NRc4BRd4B, and S(O)2Rb4B;
wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming R4B consist of at least one ring-forming carbon atom and 1, 2, or 3 heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, forming R4B is optionally substituted by oxo to form a carbonyl group;
and wherein the C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl forming R4B are each optionally substituted with 1, 2, or 3 substituents independently selected from R4C;
each R4C is independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, ORa4C, C(O)Rb4C, C(O)NRc4CRd4C, C(O)ORa4C, NRc4CRd4C, and S(O)2Rb4C;
wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming R4C consist of at least one ring-forming carbon atom and 1, 2, or 3 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming R4C is optionally substituted by oxo to form a carbonyl group;
each Ra4 is independently selected from C1-6 alkyl, C1-3 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl;
wherein the C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl forming Ra4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4A;
wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4B;
wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Ra4 consist of at least one ring-forming carbon atom and 1, 2, or 3 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, forming Ra4 is optionally substituted by oxo to form a carbonyl group;
each Rb4, Rc4, and Rd4 is independently selected from H, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl;
and wherein the C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl forming Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4A;
wherein the C1-3 alkyl, C1-3 haloalkyl, O2-3 alkenyl, and C2-3 alkynyl, forming Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4B;
wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Rb4, Rc4 and Rd4 consist of at least one ring-forming carbon atom and 1, 2, or 3 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Rb4, Rc4 and Rd4 is optionally substituted by oxo to form a carbonyl group;
or
any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R4A,
each Re4 is independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl;
wherein the C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl forming Re4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4A;
wherein the C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl forming Re4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R4B;
wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Re4 consist of at least one ring-forming carbon atom and 1, 2, or 3 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, forming Re4 is optionally substituted by oxo to form a carbonyl group;
or
Rc4 and Re4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R4A,
each Ra4B, Rb4B, Rc4B, and Rd4B is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
each Ra4C, Rb4C, Rc4C, and Rd4C is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl,
R5 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, cyclopropyl, halo, CN, and ORa5;
wherein the C1-3 alkyl, C2-3 alkenyl and C2-3 alkynyl forming R5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R5A;
and wherein the cyclopropyl forming R5 is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, and R5A;
each R5A is independently selected from D, OH, CN, halo, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino;
Ra5 is selected from H, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl,
R6 is selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, OR6A, and NR6BR6C;
wherein the C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl C1-3 alkyl forming R6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R6D;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl forming R6 consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S;
wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl forming R6 is optionally substituted by oxo to form a carbonyl group;
and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R6E;
R6A is selected from C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl;
wherein the C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl C1-3 alkyl forming R6A are each optionally substituted with 1, 2, or 3 substituents independently selected from R6D;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming R6A consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S;
wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl forming R6A is optionally substituted by oxo to form a carbonyl group;
and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R6A are each optionally substituted with 1, 2, or 3 substituents independently selected from R6E;
R6B is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl;
wherein the C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl forming R6B are each optionally substituted with 1, 2, or 3 substituents independently selected from R6D;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl forming R6B consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S;
wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl forming R6B is optionally substituted by oxo to form a carbonyl group;
and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R6B are each optionally substituted with 1, 2, or 3 substituents independently selected from R6E;
R6C is selected from H, C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl;
wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R6C are each optionally substituted with 1, 2, or 3 substituents independently selected from R6E;
or
R6B and R6C, together with the N atom to which they are both attached, optionally form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, or 3 substituents independently selected from independently selected from R6D;
each R6D is independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, and R6E;
wherein each of the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming R6D is optionally substituted with 1, 2, or 3 substituents independently selected from R6E;
each R6E is independently selected from D, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, and S(O)2NRc6Rd6;
Ra6, Rb6, Rc6, and Rd6 are each independently selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C6-10 aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl;
wherein the C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, CN, ORa6A, SRa6AC(O)Rb6A, C(O)NRc6ARd6A, C(O)ORa6A, OC(O)Rb6A, OC(O)NRc6ARd6A, NRc6ARd6A, NRc6AC(O)Rb6A NRc6AC(O)NRc6ARd6A, NRc6AC(O)ORa6A, C(═NRe6A)NRc6ARd6A, NRc6AC(═NRe6A)NRc6ARd6A S(O)Rb6A, S(O)NRc6ARd6A, S(O)2Rb6A, NRc6AS(O)2Rb6A, and S(O)2NRc6ARd6A;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra6, Rb6, Rc6, and Rd6 consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S;
wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra6, Rb6, Rc6, and Rd6 is optionally substituted by oxo to form a carbonyl group;
or
Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, CN, ORa6A, SRa6A, C(O)Rb6A, C(O)NRc6ARd6AC(O)ORa6A, OC(O)Rb6A, OC(O)NRc6ARd6A, NRc6ARd6A, NRc6AC(O)Rb6A, NRc6AC(O)NRc6ARd6A, NRc6AC(O)ORa6A, C(═NRe6A)NRc6ARd6A, NRc6AC(═NRe6A)NRc6ARd6A, S(O)Rb6A, S(O)NRc6ARd6A, S(O)2Rb6A, NRc6AS(O)2Rb6A, and S(O)2NRc6ARd6A;
Ra6A, Rb6A, Rc6A, and Rd6A are each independently selected from H, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl;
wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra6A, Rb6A, Rc6A, and Rd6A are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra6A, Rb6A, Rc6A, and Rd6A consist of at least one carbon atom, and 1, 2, 3, or 4 heteroatoms selected from O, N, and S;
wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra6A, Rb6A, Rc6A, and Rd6A is optionally substituted by oxo to form a carbonyl group;
or
Rc6A and Rd6A attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
Re6 and Re6A are each, independently, H, CN or NO2;
each R7 is independently selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, OH, C1-3 alkoxy, and C1-3 alkyl-C1-3 alkoxy, provided that if one R7 is OH, the other R7 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl;
or
two R7 together with the carbon atom to which they are both attached, form a spiro C3-5 cycloalkyl ring;
R8 is H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, or halo;
each R9 is independently selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, OH, and C1-3 alkoxy, provided that if one R9 is OH, the other R9 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl;
or
two R9 together with the carbon atom to which they are both attached, form a spiro C3-5 cycloalkyl ring;
X is O or a bond directly connecting the groups to which X is attached;
and
Y is C1-3 alkylene or a bond directly connecting the groups to which Y is attached;
wherein the C1-3 alkylene forming Y is optionally substituted by 1, 2, 3, 4, 5, or 6 D, or 1, 2, or 3 halo, or oxo;
or
the moiety X—Y is a bond directly connecting the groups to which X and Y are attached;
Cy2 is selected from C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl;
and wherein the C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl forming Cy2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming Cy2 consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl forming Cy2 is optionally substituted by oxo to form a carbonyl group;
each RCy2 is independently selected from D, C1-4 alkyl, C1-4 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halo, CN, ORaCy21, SRaCy21, C(O)RbCy21, C(O)NRcCy21RaCy21, C(O)ORaCy21, OC(O)RbCy21, OC(O)NRcCy21RaCy21, NRcCy21RaCy21, NRcCy21C(O)RbCy21, NRcCy21C(O)NRcCy21RdCy21, NRcCy21C(O)ORaCy21, C(═NReCy21)NRcCy21RdCy21, NRcCy21C(═NReCy21)NRcCy21RdCy21, S(O)RbCy21, S(O)NRcCy21RdCy21, S(O)2RbCy21, NRcCy21S(O)2RbCy21, and S(O)2NRcCy21RaCy21;
wherein the C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, and 5-10 membered heteroaryl-C1-3 alkylene forming RCy2 are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RCy2A;
wherein the ring-forming atoms of the 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1-3 alkylene, and 5-10 membered heteroaryl-C1-3 alkylene forming RCy2 consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl forming RCy2 is optionally substituted by oxo to form a carbonyl group;
and wherein the C1-4 alkyl, C1-4 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl forming RCy2 are each optionally substituted by 1, 2, or 3 substituents independently selected from RCy2B;
each RCy2A is independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, and RCy2B;
wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming RCy2A are each optionally substituted by 1, 2, or 3 substituents independently selected from RCy2B,
each RCy2B is independently selected from D, halo, CN, ORaCy21, SRaCy21, C(O)RbCy21, C(O)NRCy21RdCy21, C(O)ORaCy21, OC(O)RbCy21, OC(O)NRcCy21RdCy21, NRcCy21RdCy21 NReCy21C(O)RbCy21, NRcCy21C(O)NRcCy21RdCy21, NRcCy21C(O)ORaCy21, C(═NReCy21)NRcCy21RdCy21, NRcCy21C(═NReCy21)NRcCy21RdCy21, S(O)RbCy21, S(O)NRcCy21RdCy21, S(O)2RbCy21, NRcCy21S(O)2RbCy21, and S(O)2NRCy21RdCy21;
RaCy21, RbCy21, RcCy21, and RdCy21 are each independently selected from H, C1-4 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl;
wherein the C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming RaCy21, RbCy21, RcCy21, and RdCy21 are each optionally substituted with 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, CN, ORaCy22, SRaCy22, C(O)RbCy22, C(O)NRcCy22RdCy22, C(O)ORaCy22, OC(O)RbCy22, OC(O)NRcCy22RdCy22, NRcCy22RdCy22, NRcCy22C(O)RbCy22, NRcCy22C(O)NRcCy22RdCy22, NRcCy22C(O)ORaCy22, C(═NReCy22)NRcCy22RdCy22, NRcCy22C(═NReCy22)NRcCy22RdCy22, S(O)RbCy22, S(O)NRCy22RdCy22, S(O)2RbCy22, NRcCy22S(O)2RbCy22, and S(O)2NRCy22RdCy22;
wherein the ring-forming atoms each of the 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming RaCy21, RbCy21, RcCy21, and RdCy21 consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming RaCy21, RbCy21, RcCy21, and RdCy21 is optionally substituted by oxo to form a carbonyl group;
or RcCy21 and RdCy21 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, CN, ORaCy22, SRaCy22, C(O)RbCy22, C(O)NReCy22RdCy22, C(O)ORaCy22, OC(O)RbCy22, OC(O)NRcCy22RdCy22, NRcCy22RdCy22, NRcCy22C(O)RbCy22, NRcCy22C(O)NRcCy22RdCy22, NRcCy22C(O)ORaCy22, C(═NReCy22)NRcCy22RdCy22, NRcCy22C(═NReCy22)NRcCy22RdCy22, S(O)RbCy22, S(O)NRcCy22RdCy22, S(O)2RbCy22, NRcCy22S(O)2RbCy22, and S(O)2NRcCy22RdCy22;
RaCy22, RbCy22, RcCy22, and ReCy22 are each independently selected from H, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl;
wherein the C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming RaCy22, RbCy22, RcCy22, and RdCy22 are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, NH(C1-3 alkyl), N(C1-3 alkyl)2, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;
wherein the ring-forming atoms each of the 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming RaCy22, RbCy22, RcCy22, and RdCy22 consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;
and wherein a ring-forming carbon atom of the 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl forming RaCy22, RbCy22, RcCy22, and RdCy22 is optionally substituted by oxo to form a carbonyl group;
or
RcCy22 and RdCy22 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;
and
ReCy21 and ReCy22 are each, independently, H, CN or NO2.

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Pyrrolidine kras inhibitors

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Pyrrolidine kras inhibitors

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Abstract

Claims62