Cyclic urea kras inhibitors

A compound having Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Cy1 is phenyl optionally substituted with 1, 2, 3, or 4 substituents each selected from D, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, halo, OH, C1-3 alkoxy, and C1-3 haloalkoxy;
• R1 is halo;
• R2 is selected from H, D, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, 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, 5-6 membered heteroaryl-C1-3 alkylene, halo, CN, ORa2, C(O)Rb2, C(O)NRc2Rd2, NRc2Re2, and NRc2C(O)Rb2;
• 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 R2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2A;
• wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl-C1-3 alkylene, and 4-6 membered heterocycloalkyl-C1-3 alkylene forming R2 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 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl-C1-3 alkylene, and 4-6 membered heterocycloalkyl-C1-3 alkylene forming R2 is optionally substituted by oxo to form a carbonyl group;
• and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, forming R2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2B;
• each Ra2 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 haloalkyl, 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 Ra2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2A;
• wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Ra2 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 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Ra2 is optionally substituted by oxo to form a carbonyl group;
• and wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2B;
• each Rb2, Rc2, and Rd2 is independently selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, 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 Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2A;
• the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Rb2, Rc2, and Rd2 consist of at least one carbon atom and 1, 2, 3, or4 heteroatoms selected from O, N, and S;
• wherein a ring-forming carbon atom of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Rb2Rc2, and Rd2 is optionally substituted by oxo to form a carbonyl group;
• and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl forming Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2B;
• or
• any Rc2 and Rd2 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 R2B;
• each Re2 is independently selected from C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, 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 Re2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2A;
• wherein the ring-forming atoms of the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Re2 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 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl forming Re2 is optionally substituted by oxo to form a carbonyl group;
• and wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, forming Re2 are each optionally substituted with 1, 2, or 3 substituents independently selected from R2B;
• or
• Rc2 and Re2 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 R2B;
• each R2A is independently selected from C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, and R2B, wherein the C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, forming R2A are each optionally substituted with 1, 2 or 3 substituents independently selected from R2B;
• each R2B is independently selected from C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, ORa2B, C(O)Rb2B, C(O)NRc2BRd2B, C(O)ORa2B, NRc2BRd2B, and S(O)2Rb2B;
• wherein the C1-3 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R2C;
• each R2C is independently selected from C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, ORa2C, C(O)Rb2C, C(O)NRc2CRd2C C(O)ORa2C, NRc2CRd2C, and S(O)2Rb2C;
• each Ra2B, Rb2B, Rc2B and Rd2B is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• each Ra2C, Rb2C, Rc2C and Rd2C is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• each R3 is independently selected from H, D, halo, C1-3 alkyl, ORa3, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl;
• optionally, two R3 attached to the same carbon atom, together with the carbon atom to which they are both attached, form a spiro C3-6 cycloalkyl ring;
• or, optionally, two other R3 attached to adjacent carbon atoms, together with the carbon atoms to which they are each attached, form a fused C3-6 cycloalkyl ring;
• each Ra3 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• Cy2 is selected from C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl;
• wherein the C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C6-10 aryl, and 5-10 membered heteroaryl forming Cy2 are 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, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, CN, ORaCy21, oxo, SRaCy21, C(O)RbCy21, C(O)NRCy21RdCy21, C(O)ORaCy21, OC(O)RbCy21, OC(O)NRCy21RdCy21, NRcCy21RdCy21, NRcCy21C(O)RbCy21, NRcCy21C(O)NRcCy21RaCy21, NRcCy21C(O)ORaCy21, C(═NReCy21)NRcCy21RdCy21, NRcCy21C(═NReCy21)NRcCy21RdCy21, S(O)RbCy21, S(O)NRcCy21RdCy21, S(O)2RbCy21, NReCy21S(O)2RbCy21, and S(O)2NRCy21RdCy21;
• wherein the C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl 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 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 C1-3 alkyl, 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)NRcCy21RdCy21, 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)2NRcCy21RdCy21;
• RaCy21, RbCy21, RcCy21, and RdCy21 are each independently selected from H, C1-3 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)NRcCy22RaCy22, C(O)ORaCy22, OC(O)RbCy22, OC(O)NRcCy22RaCy22, NRcCy22RaCy22, NRcCy22C(O)RbCy22, NRcCy22C(O)NRcCy22RaCy22, NRcCy22C(O)ORaCy22, C(═NReCy22)NRcCy22RaCy22, NRcCy22C(═NReCy22)NRcCy22RaCy22, S(O)RbCy22, S(O)NRcCy22RaCy22, S(O)2RbCy22, NRcCy22S(O)2RbCy22, and S(O)2NRcCy22RaCy22;
• 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-C1-3alkyl, 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)NRcCy22RdCy22, C(O)ORaCy22, OC(O)RbCy22, OC(O)NRcCy22RdCy22, NRcCy22RaCy22, NRcCy22C(O)RbCy22, NRcCy22C(O)NRCy22RaCy22, NRcCy22C(O)ORaCy22, C(═NReCy22)NRCy22RaCy22, NRcCy22C(═NReCy22)NRcCy22RaCy22, S(O)RbCy22, S(O)NRcCy22RaCy22, S(O)2RbCy22, NRcCy22S(O)2RbCy22, and S(O)2NRcCy22RaCy22;
• 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-C1-3alkyl forming RaCy22, RbCy22, RcCy22, and ReCy22 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, C1-3alkyl, 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-C1-3alkyl, and 4-10 membered heterocycloalkyl-C1-3alkyl 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.