Tubulin inhibitors

A compound of Formula (VIIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

• wherein:
• L83 is —C(R83)2C(R83)2C(R83)2—;
• E is —C(═O)NR84— or —NR84C(═O)—;
• L84 is a bond or —CR86R87—;
• Rings D8 and B8 are independently heteroaryl or C2-C8 heterocyclyl;
• each R81 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen or —ORa;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
• each R82 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
• each R83 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, (—NRaC(═O)NRcRd), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd;
• and the cycloalkyl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl-ORa, or —NRcRd;
• R84 is hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Ra, —C(═O)NRcRd, C1-C6 alkyl, C1-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
• each R85 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, (—S(═O)2Rd), —NO2, —NRcRd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
• or two R85 substituents on the same carbon are taken together to form an oxo;
• R86 and R87 are independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd.
• Ra is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
• Rb is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
• each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
• wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2;
• and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
• or Rc and Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl;
• wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
• n8 is 1-5;
• m8 is 1-4;
• and
• q8 is 1-5.