Heterocyclic inhibitors of igf-1r for treatment of disease

A compound of Formula (II):

• or a pharmaceutically acceptable salt thereof, wherein:
• RA is unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C3-C6 cycloalkenyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, —CN, —SF5, or —SiMe3;
• or RA is
• RA2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxyl, or C1-C4 hydroxyalkyl;
• m is 0, 1, 2, or 3;
• X3 and X4 are each independently CR5 or N;
• R3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R4 is hydrogen or C1-C6 alkyl;
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• each R is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —CHR20-(unsubstituted or substituted carbocycle), —CHR20-(unsubstituted or substituted heterocycle), —C(═O)R19, —CO2R19, or —C(═O)NHR19;
• R19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl;
• R20 is hydrogen or —CH3;
• each R21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• each R22 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• or two R22 on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more R1 groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR23, —CO2R3, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23, —S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R3 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

A compound of Formula (III):

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is CR6 or N;
• each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• Y1 is —O—, —NR11—, or —SO2—;
• R11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, —C(═O)NH2, —C(═O)R12, or —S(═O)2R12,
• R12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R7 and R8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy;
• or R7 and R8 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R9 and R10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy;
• or R9 and R10 are taken together with the carbon atom to which they are attached to form a —C(═O)—;
• or R9 and R10 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R4 is hydrogen or C1-C6 alkyl,
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a C1-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR22, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, —CHR20-(unsubstituted or substituted carbocycle), —CHR20-(unsubstituted or substituted heterocycle), —C(═O)R19, —CO2R19, or —C(═O)NHR19;
• R19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl;
• R20 is hydrogen or —CH3;
• each R21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• each R22 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• or two R22 on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more RY groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR23, —CO2R23, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23, —S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R23 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

A compound of Formula (IV):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is unsubstituted or substituted bicyclic heteroaryl;
• wherein if R1 is substituted, then it is substituted with RA and 1-3 R5;
• RA is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, —CN, —SRA1, —S(═O)RA1, —S(═O)2RA1, —ORA1, —SF5, or —SiMe3;
• RA1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl;
• each R5 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R4 is hydrogen or C1-C6 alkyl;
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —CHR20-(unsubstituted or substituted carbocycle), —CHR20-(unsubstituted or substituted heterocycle), —C(═O)R19, —CO2R19, or —C(═O)NHR19;
• R19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl;
• R20 is hydrogen or —CH3;
• each R21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• each R22 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• or two R22 on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more R groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR23, —CO2R23, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23, —S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R3 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

A compound of Formula (V):

• or a pharmaceutically acceptable salt thereof, wherein:
• RA is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, —CN, —SRA1, —S(═O)RA1, —S(═O)2RA1, —ORA1, —SF5, or —SiMe3;
• RA1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl;
• R3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R4 is hydrogen or C1-C6 alkyl;
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• R5 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —CHR20-(unsubstituted or substituted carbocycle), —CHR20-(unsubstituted or substituted heterocycle), —C(═O)R19, —CO2R19, or —C(═O)NHR19;
• R19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl;
• R20 is hydrogen or —CH3;
• each R21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• each R22 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• or two R22 on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more R groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR22, —CO2R23, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23, —S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R23 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

A compound of Formula (VI):

• or a pharmaceutically acceptable salt thereof, wherein:
• RA is unsubstituted or substituted C1-C6 alkyl;
• X3 and X4 are each independently CR or N;
• R3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R4 is hydrogen or C1-C6 alkyl;
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• each R5 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl;
• or R18 is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl;
• or R18 is unsubstituted or substituted C5-C10 bicyclic cycloalkyl;
• or R18 is unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom;
• or R18 is —CHR20-(unsubstituted or substituted carbocycle) or —CHR20-(unsubstituted or substituted heterocycle);
• R20 is hydrogen or —CH3;
• each R21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• each R22 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• or two R22 on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rs groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR23, —CO2R23, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23—S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R23 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

A compound of Formula (VII):

• or a pharmaceutically acceptable salt thereof, wherein:
• RA1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl;
• X3 and X1 are each independently CR5 or N;
• R2 is
• Rc is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, —C(═O)N(R22)2, —C(═O)R21, —C(═O)OR22, or —S(═O)2R21;
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —OC(═O)R21, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21,
• R13 and R14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR2′, —CO2R22, —N(R22)2, —C(═O)N(R2)2, or —OC(═O)R21;
• or R13 and R14 are taken together with the carbon atom to which they are attached to form a —C(═O)—;
• or R13 and R14 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• Y2 is —(CR15R16)n—, —O—, or —O—CR15R16—;
• each R15 and R16 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl;
• or R14 and one R16 on an adjacent carbon atom are taken together to form an alkene bond;
• n is 1 or 2;
• or R2 is
• X2 is CR17 or N;
• each R17 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R2′, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• R18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl;
• or R18 is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl;
• or R18 is unsubstituted or substituted C5-C10 bicyclic cycloalkyl;
• or R18 is unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl;
• or R18 is —CHR20-(unsubstituted or substituted carbocycle) or —CHR20-(unsubstituted or substituted heterocycle);
• R20 is hydrogen or —CH3;
• R3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl;
• R4 is hydrogen or C1-C6 alkyl;
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
• each R5 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, —CN, —OH, —OR21, —CO2R22, —N(R22)2, —C(═O)N(R22)2, —NR22C(═O)R21, —S(═O)2N(R22)2, or —NR22S(═O)2R21;
• each R21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• each R22 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
• or two R22 on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rs groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR2, —CO2R23, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23—S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R23 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

A compound of Formula (VIII):

• or a pharmaceutically acceptable salt thereof, wherein:
• RA is —SCF3, —S(═O)CF3, or —S(═O)2CF3;
• R3 is C2-C6 alkyl which is unsubstituted or substituted by —OH, phenyl, benzyl, C3-C6 cycloalkyl, or —CH2OH;
• and
• R4 is hydrogen or methyl;
• or R3 and R4 are taken together with the carbon atom to which they are attached to form a cyclobutyl, cyclopentyl, or cyclohexyl.

A compound of Formula (IX):

• or a pharmaceutically acceptable salt thereof, wherein:
• RA is —SRA1, —S(═O)RA1, or —S(═O)2RA1;
• RA1 is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl;
• R18 is C1-C6 alkyl which is substituted by —CN, —OH, or —OMe;
• or R18 is unsubstituted or substituted C1-C6 fluoroalkyl or unsubstituted or substituted C1-C6 heteroalkyl;
• or R18 is unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl;
• or R18 is —CHR20-(unsubstituted or substituted C3-C6 cycloalkyl), —CHR20-(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), or —CHR20-(unsubstituted or substituted 5-membered heteroaryl);
• R20 is hydrogen or —CH3;
• or R18 is —C(═O)R19, where R19 is unsubstituted or substituted 3- to 10-membered heterocycloalkyl;
• or R18 is —C(═O)NHR19, where R19 is unsubstituted or substituted C3-C10 cycloalkyl or unsubstituted or substituted 3- to 10-membered heterocycloalkyl;
• wherein each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rs groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, —CN, —OR23, —CO2R3, —C(═O)N(R23)2, —N(R23)2, —NR23C(═O)R24, —SR23—S(═O)R24, —SO2R24, or —SO2N(R23)2;
• each R23 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl;
• or two R3 groups are taken together with the N atom to which they are attached to form a 3- to 6-membered N-containing heterocycloalkyl;
• each R24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.