Kif modulator compounds and methods of use

A pharmaceutical composition comprising a compound having the structure of Formula (I-1):

• or a pharmaceutically acceptable salt solvate, or isotopologue thereof, wherein:
• Y1, Y2, and Y3 are each independently CR5 or N;
• X1 and X2 are each independently CR6 or N;
• L1 is a linker comprising the structure-L1a-L1b-*, where * designates the attachment point to R1;
• L1a is a bond, —O—, —NH—, —S—, or —SO2—;
• L1b is optionally substituted C4-C5 alkenylene;
• or L1 is optionally substituted C4-C6 heteroalkylene;
• wherein the terminal atoms of the heteroalkylene are C, and the heteroalkylene comprises 1 or 2 non-adjacent heteroatoms independently selected from N, O, and S;
• R1 is a bond, —O—, —NH—, or —N(C1-C4 alkyl)-;
• each R2 is independently halogen, —CN, —(CH2)v—CN, —OR2a, —(CH2)v—OR2a, —O—(CH2)v—R2a, —N(R2a)2, —(CH2)v—N(R2a)2, —C(O)N(R2a)2, —(CH2)v—C(O)N(R2a)2, —N(R2a)C(O)NR2a, —(CH2)v—N(R2a)C(O)NR2a, —C(O)R2b, —(CH2)v—C(O)R2b, —C(O)OR2a, —(CH2)v—C(O)OR2a, —S(O)2N(R2a)2, (CH2)v—S(O)2N(R2a)2, —S(O)2R2b, —(CH2)v—S(O)2R2b, optionally substituted C1-C8 alkyl, C1-C8 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, —(CH2)v-(optionally substituted C3-C10 cycloalkyl), optionally substituted 4- to 10-membered heterocycloalkyl, —(CH2)v-(optionally substituted 4- to 10-membered heterocycloalkyl), optionally substituted phenyl, —(CH2)v-(optionally substituted phenyl), —CH(OR2a)-(optionally substituted phenyl), optionally substituted monocyclic or bicyclic heteroaryl, or —(CH2)v-(optionally substituted monocyclic heteroaryl);
• or
• two R2 are joined together to form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkyl;
• each R2a is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, or optionally substituted monocyclic heteroaryl;
• or two R2a on the same N atom are taken together with the N atom to which they are attached to form a 4- to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, oxo, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl-CN, —(O)(C1-C6 alkyl), —S(O)2 (C1-C6 alkyl), and optionally substituted C3-C6 cycloalkyl;
• each R2b is independently optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 4- to 10-membered heterocycloalkyl;
• each v is independently 1, 2, or 3;
• R3 is —N(R3a)2, —NR3a (SO2R3b), —SO2NR3aR3b, —SO(═NH)NR3aR3b, —NR3aSO2N(R3a)2, —SO2R3b, —NR3aC(O)—C(O)R3b, —NR3aC(O)OR3b, or —NR3bC(O)NR3aR3a,
• each R3a is independently hydrogen, optionally substituted C1-C6 alkyl, or C1-C6 hydroxyalkyl;
• R3b is optionally substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted (C3-C10 cycloalkyl)-(C1-C6 alkyl), optionally substituted (4- to 10-membered heterocycloalkyl)-(C1-C6 alkyl), optionally substituted (heteroaryl)-(C1-C6 alkyl), or optionally substituted monocyclic heteroaryl;
• or R3a and R3b are taken together with the intervening atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl;
• each R4 is independently halogen, —CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl;
• or two R4 on the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl;
• or two R4 on different carbon atoms are taken together with the intervening atoms to which they are attached to form a C1-C3 alkylene bridge;
• each R5 is independently hydrogen, halogen, —CN, —OR5a, —N(R5a)2, —C(O)N(R5a)2, —N(R5a)C(O)NR5a, —C(O)R5b, —C(O)OR5a, —S(O)2N(R5a)2, —S(O)2R5b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R5a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R5b is independently optionally substituted C1-C6 alkyl;
• each R6 is independently hydrogen, halogen, —CN, —OR6a, —N(R6a)2, —C(O)N(R62)2, —N(R6a)C(O)NR6a, —C(O)R6b, —C(O)OR6a, —S(O)2N(R63)2, —S(O)2R6b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R6a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R6b is independently optionally substituted C1-C6 alkyl;
• p is 0, 1, or 2;
• q is 0, 1, or 2;
• m is 0, 1, 2, or 3;
• and
• n is 0, 1, 2, 3, or 4;
• wherein if any L1, L1b, R2, R2a, R2b, R3, R3a, R3b, R5, R5a, R5b, R6, R6a, or R6b group is substituted then it is substituted by 1, 2, or 3 groups independently selected from halogen, oxo, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2 (C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O) C1-C4alkyl, and —S(═O)2C1-C4alkyl;
• or pharmaceutically acceptable salt, solvate, or isotopologue thereof, and a pharmaceutically acceptable excipient.

A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound having the structure of Formula (I-1):

• or a pharmaceutically acceptable salt solvate, or isotopologue thereof, wherein:
• Y1, Y2, and Y3 are each independently CR5 or N;
• X1 and X2 are each independently CR6 or N;
• L1 is a linker comprising the structure-L1a-L1b-*, where * designates the attachment point to R1;
• L1a is a bond, —O—, —NH—, —S—, or —SO2—;
• L1b is optionally substituted C4-C5 alkenylene;
• or L1 is optionally substituted C4-C6 heteroalkylene;
• wherein the terminal atoms of the heteroalkylene are C, and the heteroalkylene comprises 1 or 2 non-adjacent heteroatoms independently selected from N, O, and S;
• R1 is a bond, —O—, —NH—, or —N(C1-C4 alkyl)-;
• each R2 is independently halogen, —CN, —(CH2)v—CN, —OR2a, —(CH2)v—OR2a, —O—(CH2)v—R2a, —N(R2a)2, —(CH2)v—N(R2a)2, —C(O)N(R2a)2, —(CH2)v—C(O)N(R2a)2, —N(R2a)C(O)NR2a, —(CH2)v—N(R2a)C(O)NR2a, —C(O)R25, —(CH2)v—C(O)R2b, —C(O)OR2a, —(CH2)v—C(O)OR2a, —S(O)2N(R2a)2, (CH2)v—S(O)2N(R2a)2, —S(O)2R2b, —(CH2)v—S(O)2R2b, optionally substituted C1-C8 alkyl, C1-C8 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, —(CH2)v-(optionally substituted C3-C10 cycloalkyl), optionally substituted 4- to 10-membered heterocycloalkyl, —(CH2)v-(optionally substituted 4- to 10-membered heterocycloalkyl), optionally substituted phenyl, —(CH2)v-(optionally substituted phenyl), —CH(OR2a)-(optionally substituted phenyl), optionally substituted monocyclic or bicyclic heteroaryl, or —(CH2)v-(optionally substituted monocyclic heteroaryl);
• or
• two R2 are joined together to form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkyl;
• each R2a is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, or optionally substituted monocyclic heteroaryl;
• or two R2a on the same N atom are taken together with the N atom to which they are attached to form a 4- to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, oxo, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl-CN, —C(O)(C1-C6 alkyl), —S(O)2 (C1-C6 alkyl), and optionally substituted C3-C6 cycloalkyl;
• each R2b is independently optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 4- to 10-membered heterocycloalkyl;
• each v is independently 1, 2, or 3;
• R3 is —N(R3a)2, —NR3a (SO2R3b), —SO2NR3aR3b, —SO(═NH)NR3aR3b, —NR3aSO2N(R3a)2, —SO2R3b, —NR3aC(O)—C(O)R3b, —NR3aC(O)OR3b, or —NR3C(O)NR3aR3a,
• each R3a is independently hydrogen, optionally substituted C1-C6 alkyl, or C1-C6 hydroxyalkyl;
• R3b is optionally substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted (C3-C10 cycloalkyl)-(C1-C6 alkyl), optionally substituted (4- to 10-membered heterocycloalkyl)-(C1-C6 alkyl), optionally substituted (heteroaryl)-(C1-C6 alkyl), or optionally substituted monocyclic heteroaryl;
• or R3a and R3b are taken together with the intervening atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl;
• each R4 is independently halogen, —CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl;
• or two R4 on the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl;
• or two R4 on different carbon atoms are taken together with the intervening atoms to which they are attached to form a C1-C3 alkylene bridge;
• each R5 is independently hydrogen, halogen, —CN, —OR5a, —N(R5a)2, —C(O)N(R5a)2, —N(R5a)C(O)NR5a, —C(O)R5b, —C(O)OR5a, —S(O)2N(R5a)2, —S(O)2R5b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R5a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R5b is independently optionally substituted C1-C6 alkyl;
• each R6 is independently hydrogen, halogen, —CN, —OR6a, —N(R6a)2, —C(O)N(R6a)2, —N(R6a)C(O)NR6a, —C(O)R6b, —C(O)OR6a, —S(O)2N(R6a)2, —S(O)2R6b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R6a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R6b is independently optionally substituted C1-C6 alkyl;
• p is 0, 1, or 2;
• q is 0, 1, or 2;
• m is 0, 1, 2, or 3;
• and
• n is 0, 1, 2, 3, or 4;
• wherein if any L1, L1b, R2, R2a, R2b, R3, R3a, R3b, R5, R5a, R5b, R6, R6a, or R6b group is substituted then it is substituted by 1, 2, or 3 groups independently selected from halogen, oxo, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2 (C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O) C1-C4alkyl, and —S(═O)2C1-C4alkyl;
• or pharmaceutically acceptable salt, solvate, or isotopologue thereof.

A method of inhibiting KIF18A comprising contacting the enzyme with a compound having the structure of Formula (I-1):

• or a pharmaceutically acceptable salt solvate, or isotopologue thereof, wherein:
• Y1, Y2, and Y3 are each independently CR5 or N;
• X1 and X2 are each independently CR6 or N;
• L1 is a linker comprising the structure -L1a-L1b-*, where * designates the attachment point to R1;
• L1a is a bond, —O—, —NH—, —S—, or —SO2—;
• L1b is optionally substituted C4-C5 alkenylene;
• or L1 is optionally substituted C4-C6 heteroalkylene;
• wherein the terminal atoms of the heteroalkylene are C, and the heteroalkylene comprises 1 or 2 non-adjacent heteroatoms independently selected from N, O, and S;
• R1 is a bond, —O—, —NH—, or —N(C1-C4 alkyl)-;
• each R2 is independently halogen, —CN, —(CH2)v—CN, —OR2a, —(CH2)v—OR2a, —O—(CH2)v—R2a, —N(R2a)2, —(CH2)v—N(R2a)2, —C(O)N(R2a)2, —(CH2)v—C(O)N(R2a)2, —N(R2a)C(O)NR2a, —(CH2)v—N(R2a)C(O)NR2a, —C(O)R2b, —(CH2)v—C(O)R2b, —C(O)OR2a, —(CH2)v—C(O)OR2a, —S(O)2N(R2a)2, —(CH2)v—S(O)2N(R2a)2, —S(O)2R2b, —(CH2)v—S(O)2R2b, optionally substituted C1-C8 alkyl, C1-C8 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, —(CH2)v-(optionally substituted C3-C10 cycloalkyl), optionally substituted 4- to 10-membered heterocycloalkyl, —(CH2)v-(optionally substituted 4- to 10-membered heterocycloalkyl), optionally substituted phenyl, —(CH2)v-(optionally substituted phenyl), —CH(OR2a)-(optionally substituted phenyl), optionally substituted monocyclic or bicyclic heteroaryl, or —(CH2)v-(optionally substituted monocyclic heteroaryl);
• or
• two R2 are joined together to form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkyl;
• each R2a is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, or optionally substituted monocyclic heteroaryl;
• or two R2a on the same N atom are taken together with the N atom to which they are attached to form a 4- to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, oxo, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl-CN, —C(O)(C1-C6 alkyl), —S(O)2 (C1-C6 alkyl), and optionally substituted C3-C6 cycloalkyl;
• each R2b is independently optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 4- to 10-membered heterocycloalkyl;
• each v is independently 1, 2, or 3;
• R3 is —N(R3a)2, —NR3a (SO2R3b), —SO2NR3aR3b, —SO(═NH)NR3aR3b, —NR3aSO2N(R3a)2, —SO2R3b, —NR3aC(O)—C(O)R3b, —NR3aC(O)OR3b, or —NR3bC(O)NR3aR3a,
• each R3a is independently hydrogen, optionally substituted C1-C6 alkyl, or C1-C6 hydroxyalkyl;
• R3b is optionally substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted (C3-C10 cycloalkyl)-(C1-C6 alkyl), optionally substituted (4- to 10-membered heterocycloalkyl)-(C1-C6 alkyl), optionally substituted (heteroaryl)-(C1-C6 alkyl), or optionally substituted monocyclic heteroaryl;
• or R3a and R3b are taken together with the intervening atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl;
• each R4 is independently halogen, —CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl;
• or two R4 on the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl;
• or two R4 on different carbon atoms are taken together with the intervening atoms to which they are attached to form a C1-C3 alkylene bridge;
• each R5 is independently hydrogen, halogen, —CN, —OR5a, —N(R5a)2, —C(O)N(R5a)2, —N(R5a)C(O)NR5a, —C(O)R5b, —C(O)OR5a, —S(O)2N(R5a)2, —S(O)2R5b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R5a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R5b is independently optionally substituted C1-C6 alkyl;
• each R6 is independently hydrogen, halogen, —CN, —OR6a, —N(R6a)2, —C(O)N(R6a)2, —N(R6a)C(O)NR6a, —C(O)R6b, —C(O)OR6a, —S(O)2N(R6a)2, —S(O)2R6b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R6a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R6b is independently optionally substituted C1-C6 alkyl;
• p is 0, 1, or 2;
• q is 0, 1, or 2;
• m is 0, 1, 2, or 3;
• and
• n is 0, 1, 2, 3, or 4;
• wherein if any L1, L1b, R2, R2a, R2b, R3, R3a, R3b, R5, R5a, R5b, R6, R6a, or R6b group is substituted then it is substituted by 1, 2, or 3 groups independently selected from halogen, oxo, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2 (C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O) C1-C4alkyl, and —S(═O)2C1-C4alkyl;
• or pharmaceutically acceptable salt, solvate, or isotopologue thereof.

An adduct comprising a KIF18A and a compound having the structure of Formula (I-1):

• or a pharmaceutically acceptable salt solvate, or isotopologue thereof, wherein:
• Y1, Y2, and Y3 are each independently CR5 or N;
• X1 and X2 are each independently CR6 or N;
• L1 is a linker comprising the structure-L1a-L1b-*, where * designates the attachment point to R1;
• L1a is a bond, —O—, —NH—, —S—, or —SO2—;
• L1b is optionally substituted C4-C5 alkenylene;
• or L1 is optionally substituted C4-C6 heteroalkylene;
• wherein the terminal atoms of the heteroalkylene are C, and the heteroalkylene comprises 1 or 2 non-adjacent heteroatoms independently selected from N, O, and S;
• R1 is a bond, —O—, —NH—, or —N(C1-C4 alkyl)-;
• each R2 is independently halogen, —CN, —(CH2)v—CN, —OR2a, —(CH2)v—OR2a, —O—(CH2)v—R2a, —N(R2a)2, —(CH2)v—N(R2a)2, —C(O)N(R2a)2, —(CH2)v—C(O)N(R2a)2, —N(R2a)C(O)NR2a, —(CH2)v—N(R2a)C(O)NR2a, —C(O)R2b, —(CH2)v—C(O)R2b, —C(O)OR2a, —(CH2)v—C(O)OR2a, —S(O)2N(R2a)2,
• (CH2)v—S(O)2N(R2a)2, —S(O)2R2b, —(CH2)v—S(O)2R2b, optionally substituted C1-C8 alkyl, C1-C8 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, —(CH2)v-(optionally substituted C3-C10 cycloalkyl), optionally substituted 4- to 10-membered heterocycloalkyl, —(CH2)v-(optionally substituted 4- to 10-membered heterocycloalkyl), optionally substituted phenyl, —(CH2)v-(optionally substituted phenyl), —CH(OR2a)-(optionally substituted phenyl), optionally substituted monocyclic or bicyclic heteroaryl, or —(CH2)v-(optionally substituted monocyclic heteroaryl);
• or
• two R2 are joined together to form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkyl;
• each R2a is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, or optionally substituted monocyclic heteroaryl;
• or two R2a on the same N atom are taken together with the N atom to which they are attached to form a 4- to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, oxo, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl-CN, —C(O)(C1-C6 alkyl), —S(O)2 (C1-C6 alkyl), and optionally substituted C3-C6 cycloalkyl;
• each R2b is independently optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted 4- to 10-membered heterocycloalkyl;
• each v is independently 1, 2, or 3;
• R3 is —N(R3a)2, —NR3a (SO2R3b), —SO2NR3aR3b, —SO(═NH)NR3aR3b, —NR3aSO2N(R3a)2, —SO2R3b, —NR3aC(O)—C(O)R3b, —NR3aC(O)OR3b, or —NR3bC(O)NR3aR3a,
• each R3a is independently hydrogen, optionally substituted C1-C6 alkyl, or C1-C6 hydroxyalkyl;
• R3b is optionally substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted (C3-C10 cycloalkyl)-(C1-C6 alkyl), optionally substituted (4- to 10-membered heterocycloalkyl)-(C1-C6 alkyl), optionally substituted (heteroaryl)-(C1-C6 alkyl), or optionally substituted monocyclic heteroaryl;
• or R3a and R3b are taken together with the intervening atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl;
• each R4 is independently halogen, —CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl;
• or two R4 on the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl;
• or two R4 on different carbon atoms are taken together with the intervening atoms to which they are attached to form a C1-C3 alkylene bridge;
• each R5 is independently hydrogen, halogen, —CN, —OR5a, —N(R5a)2, —C(O)N(R5a)2, —N(R5a)C(O)NR5a, —C(O)R5b, —C(O)OR5a, —S(O)2N(R5a)2, —S(O)2R5b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R5a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R5b is independently optionally substituted C1-C6 alkyl;
• each R6 is independently hydrogen, halogen, —CN, —OR6a, —N(R6a)2, —C(O)N(R6a)2, —N(R6a)C(O)NR6a, —C(O)R6b, —C(O)OR6a, —S(O)2N(R6a)2, —S(O)2R6b, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl;
• each R6a is independently hydrogen or optionally substituted C1-C6 alkyl;
• each R6b is independently optionally substituted C1-C6 alkyl;
• p is 0, 1, or 2;
• q is 0, 1, or 2;
• m is 0, 1, 2, or 3;
• and
• n is 0, 1, 2, 3, or 4;
• wherein if any L1, L1b, R2, R2a, R2b, R3, R3a, R3b, R5, R5a, R5b, R6, R6a, or R6b group is substituted then it is substituted by 1, 2, or 3 groups independently selected from halogen, oxo, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2 (C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O) C1-C4alkyl, and —S(═O)2C1-C4alkyl.