WDR5 inhibitors and modulators

A compound of formula (I)

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is G1 or —(CRaRb)p-G1;
• p is 1, 2, or 3;
• G1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C3-10carbocycle 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 halogen, C1-6alkyl, C1-6haloalkyl, oxo, —OR1a, —N(R1a)2, —SR1a, cyano, —C(O)OR1a, —C(O) N(R1a)2, —C(O)R1a, —SOR1b, —SO2R1b, —SO2N(R1a)2, —NR1aC(O)R1a, —NR1aC(O)OR1b, —NR1aC(O)N(R1a)2, —NR1aS(O)2R1b, —NR1aS(O)2N(R1a)2, and -L1-G1a;
• L is —(CR2aR2b)n—, wherein is a single bond and X is O, NR3, or S;
• or L is —C(R2c):
• wherein is a double bond and X is N;
• n is 1, 2, or 3;
• R1a, at each occurrence, is independently hydrogen, C1-6alkyl, C1-6haloalkyl, —C2-4alkylene-Y, G1a, or —C1-6alkylene-G1a, wherein two R1a, together with a common nitrogen atom to which the R1a attach 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 C1-4alkyl, C1-4haloalkyl, oxo, —OH, and —OC1-4alkyl;
• Y, at each occurrence, is independently —OH, —OC1-4alkyl, —NH2, —NHC1-4alkyl, or —N(C1-4alkyl)2,
• R1b, at each occurrence, is independently C1-6alkyl, C1-6haloalkyl, G1a, or —C1-6alkylene-G1a;
• L1 is a bond or C1-3alkylene;
• G1a, at each occurrence, is independently C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein G1a is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, oxo, —OR1c, —N(R1c)2, —SR1c, cyano, —C(O)OR1c, —C(O)N(R1c)2, —C(O)R1c, —SOR1d, —SO2R1d, —SO2N(R1c)2, —NR1cC(O)R1c, —NR1cC(O)OR1d, —NR1cC(O)N(R1c)2, —NR1cS(O)2R1d, and —NR1cS(O)2N(R1d)2;
• Ra, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4haloalkyl, —C1-6alkylene-Raa, G1b, or —C1-6alkylene-G1b, wherein each C1-6alkylene is optionally substituted with 1-4 halogen;
• Raa, at each occurrence, is independently —OR1e, —N(R1e)2, —SR1e, cyano, —C(O)OR1e, —C(O)N(R1e)2, —C(O)R1e, —SOR1f, —SO2R1f, —SO2N(R1e)2, —NR1eC(O)R1e, —NR1eC(O)OR1f, —NR1eC(O)N(R1e)2, —NR1eS(O)2R1f, or —NR1eS(O)2N(R1e)2;
• G1b, at each occurrence, is independently a C3-6carbocycle or a 4- to 10-membered heterocyclyl, wherein the C3-6carbocycle and 4- to 10-membered heterocyclyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, oxo, —OR1e, —N(R1e)2, —SR1e, cyano, —C(O)OR1e, —C(O)N(R1e)2, —C(O)R1e, —SOR1f, —SO2R1f, —SO2N(R1e)2, —NR1eC(O)R1e, —NR1eC(O)OR1f, —NR1eC(O)N(R1e)2, —NR1eS(O)2R1f, and —NR1eS(O)2N(R1e)2;
• Rb is hydrogen or C1-4alkyl;
• or alternatively one Ra and one Rb together with the carbon atom to which they are attached form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;
• or alternatively one Ra and one Rb are taken together to form an oxo group;
• R2a and R2b, at each occurrence, are independently hydrogen, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, or —C1-3alkylene-C3-6cycloalkyl;
• or alternatively one R2a and one R2b are taken together with the atom or atoms to which they attach to form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring that is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, and —OC1-4alkyl;
• or alternatively one R2a and one R2b are taken together to form an oxo group;
• R2c is hydrogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, or —C1-3alkylene-C3-6cycloalkyl;
• R3 is hydrogen or C1-6alkyl;
• R4 is halogen, C1-6haloalkyl, C1-6haloalkenyl, —OR4a, —SR4a, —N(R4a)2, —S(O)R4b, —S(O)2R4b, —S(O)2N(R4a)2, —C(O)N(R4a)2, —C(O)R4a, —NR4aC(O) R4a, —NR4aC(O)OR4b, —NR4aC(O)N(R4a)2, —NR4aS(O)2R4b, —NR4aS(O)2N(R4a)2, or G2;
• R4a at each occurrence, is independently hydrogen, C1-6alkyl, C1-6haloalkyl, G2, or —C1-3alkylene-G2;
• R4b is C1-6alkyl, C1-6haloalkyl, G2, or —C1-3alkylene-G2;
• G2, at each occurrence, is independently a C3-10carbocycle, 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 halogen, C1-6alkyl, C1-6haloalkyl, oxo, —OR4c, —N(R4c)2, —SR4c, cyano, —C(O)OR4c, —C(O)N(R4c)2, —C(O)R4c, —SOR4d, —SO2R4d, —SO2N(R4c)2, —NR4cC(O)R4c, —NR4cC(O)OR4d, —NR4cC(O)N(R4c)2, —NR4cS(O)2R4d, —NR4cS(O)2N(R4c)2, C3-8cycloalkyl, and —C1-3alkylene-C3-8cycloalkyl, wherein each C3-8cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl and halogen;
• R1c, R1e, and R4c, at each occurrence, are independently hydrogen, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, or —C1-6alkylene-C3-8cycloalkyl, wherein each C3-8cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl and halogen, wherein alternatively two R1c, two R1e, and/or two R4c, together with a common nitrogen atom to which the R1c, R1e, and/or R4c attach 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 C1-4alkyl, C1-4haloalkyl, oxo, —OH, and —OC1-4alkyl;
• R1d, R1f, and R4c, at each occurrence, are independently C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, or —C1-6alkylene-C3-8cycloalkyl, wherein each C3-8cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl and halogen;
• R5 and R6 are each independently hydrogen, halogen, C1-4alkyl, C1-4haloalkyl, or —OC1-4alkyl;
• R7a and R7b are independently selected from the group consisting of hydrogen, halogen, C1-4alkyl, and C1-4haloalkyl, or R7a and R7b are taken together to form an oxo group;
• R8 is
• indolyl, pyrrolopyridinyl, or imidazolyl, wherein the indolyl, pyrrolopyridinyl, and imidazolyl are optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, and —C1-3alkylene-C3-8cycloalkyl, wherein each C3-8cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, OH, and —OC1-4alkyl;
• wherein X1 is NR13, O, or S;
• R10a and R10b are independently hydrogen, halogen, C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, or —C1-3alkylene-C3-8cycloalkyl;
• R12, at each occurrence, is independently halogen, C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, or —C1-3alkylene-C3-8cycloalkyl;
• R13 is hydrogen, C1-4alkyl, C1-4haloalkyl, C3-8cycloalkyl, or —C1-3alkylene-C3-8cycloalkyl;
• wherein each cycloalkyl in R10a, R10b, R12, and R13 is further optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, OH, and —OC1-4alkyl;
• and
• t is 0, 1, 2, 3, or 4;
• wherein R30, at each occurrence, is independently halogen, C1-4alkyl, C1-4haloalkyl, or C3-6cycloalkyl;
• and
• X2 is CH2, O, or NH.