WDR5-MLL1 inhibitors and modulators

A compound of formula (I)

• or a pharmaceutically acceptable salt or tautomer thereof, wherein:
• Q1 is N or CR3;
• Q2 is N or CR5;
• Q3 is N or CR2;
• R1a is C1-C4alkyl, G1 or —(CRaRb)n-G1;
• n is 1, 2, or 3;
• Ra is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6carbocycle, or —C1-C3alkylene-C(O)YR20;
• Y is O, NH, or NC1-C4alkyl;
• R20 is H, C1-C4alkyl, C3-C6cycloalkyl, or —C1-C3alkylene-R30;
• R30 is C(O)C1-C4alkyl, C(O)C3-C6cycloalkyl, or phenyl, wherein the C3-C6cycloalkyl and phenyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-C4alkyl, —OC1-C4alkyl, and C1-C4haloalkyl;
• Rb is hydrogen or C1-C4alkyl;
• optionally Ra and Rb together with the carbon atom to which they are attached form a ring selected from the group consisting of a 3-8 membered saturated or partially unsaturated carbocyclic ring and a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
• optionally Ra and Rb are taken together to form an oxo group;
• R1b is hydrogen, C1-C4alkyl, C3-C6cycloalkyl, or —C1-C3alkylene-C3-C6cycloalkyl;
• G1 is 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C3-C10carbocycle optionally fused to a phenyl or to a 5- to 6-membered heteroaryl, wherein G1 is optionally substituted with 1-5 substituents independently selected from the group consisting of C1-C4hydroxyalkyl, halogen, C1-C6alkyl, C1-C6haloalkyl, oxo, —OR1c, —NR1cR1d, —SR1c, cyano, —C(O)OR1c, —C(O)NR1cR1d, —C(O)R1e, —SOR1e, —SO2R1e, —SO2NR1cR1d, —NR1cC(O)R1e, —NR1cC(O)OR1d, —NR1cC(O)NR1cR1d, —NR1cS(O)2R1e, —NR1cS(O)2NR1cR1d, C3-C8cycloalkyl, and —C1-C3alkylene-C3-C8cycloalkyl, wherein the C3-C8cycloalkyl and C1-C3alkylene-C3-C8cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of C1-C4alkyl and halogen;
• R2 is hydrogen, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
• R3 is hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, —OR3a, —NR3aR3b, —SR3a, cyano, —C(O)OR3a, —C(O)NR3aR3b, —C(O)R3c, —SOR3c, —SO2R3c, —SO2NR3aR3b, —NR3aC(O)R3c, —NR3aC(O)OR3b, —NR3aC(O)NR3aR3b, —NR3aS(O)2R3c, —NR3aS(O)2NR3aR3b, C3-C8cycloalkyl, or —C1-C3alkylene-C3-C8cycloalkyl, wherein the C3-C8cycloalkyl and —C1-C3alkylene-C3-C8cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of C1-C4alkyl and halogen;
• R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6haloalkenyl, -L-Rx, G2, -L-G2, or -L-C1-C3alkylene-G2;
• L is O, S, —NR4a—, —S(O)—, —S(O)2—, —S(O)2NR4a—, —C(O)NR4a—, —C(O)—, —NR4aC(O)—, —NR4aC(O)O—, —NR4aC(O)NR4a—, —NR4aS(O)2—, or —NR4aS(O)2NR4a—;
• Rx is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;
• G2 is a C3-C10carbocycle, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocycle, wherein G2 is optionally substituted with 1-5 substituents independently selected from the group consisting of C1-C4hydroxyalkyl, halogen, C1-C6alkyl, C1-C6haloalkyl, oxo, —OR4b, —NR4bR4c, —SR4b, cyano, —C(O)OR4b, —C(O)NR4bR4c, —C(O)R4d, —SOR4d, —SO2R4d, —SO2NR4bR4c, —NR4bC(O)R4d, —NR4bC(O)OR4c, —NR4bC(O)NR4bR4c, —NR4bS(O)2R4d, —NR4bS(O)2NR4bR4c, C3-C8cycloalkyl, and C1-C3alkylene-C3-C8cycloalkyl, wherein the C3-C8cycloalkyl and C1-C3alkylene-C3-C8cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of C1-C4alkyl and halogen;
• R5 is hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, —OR5a, —NR5aR5b, —SR5a, cyano, —C(O)OR5a, —C(O)NR5aR5b, —C(O)R5c, —SOR5c, —SO2R5c, —SO2NR5aR5b, —NR5aC(O)R5c, —NR5aC(O)OR5b, —NR5aC(O)NR5aR5b, —NR5aS(O)2R5c, —NR5aS(O)2NR5aR5b, C3-C8cycloalkyl, or —C1-C3alkylene-C3-C8cycloalkyl, wherein the C3-C8cycloalkyl and —C1-C3alkylene-C3-C8cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of C1-C4alkyl and halogen;
• G3 is
• X is O, NR or (CR6aR6b)1-2;
• R is independently hydrogen or C1-C4 alkyl;
• R6a and R6b, at each occurrence, are each independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, G3a, or —C1-C3alkylene-G3a, wherein optionally each R6a and R6b, independently, are taken together to form an oxo group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
• R7a and R7b are independently hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl, or R7a and R7b are taken together to form an oxo group;
• R9a, R9b, and R9c, are each independently hydrogen, halogen, C1-C4alkyl, C1-C4haloalkyl, or C3-C10carbocycle, wherein the C3-C10carbocycle is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4haloalkyl, OH, and —OC1-C4alkyl;
• G3a is C3-C10carbocycle, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocycle, wherein G3a is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4haloalkyl, OH, and —OC1-C4alkyl;
• and
• R1c, R1d, R1e, R3a, R3b, R3c, R4a, R4b, R4c, R4d, R5a, R5b, and R5c, at each occurrence, are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, or —C1-C6alkylene-C3-C8cycloalkyl, wherein the C3-C8cycloalkyl and —C1-C6alkylene-C3-C8cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of C1-C4alkyl and halogen, wherein alternatively R1c and R1d, R3a and R3b, R4b and R4c, and/or R5a and R5b, each together with a common nitrogen atom to which each attaches form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of C1-C4alkyl, C1-C4haloalkyl, oxo, —OH, and —OC1-C4alkyl.