Tubulin inhibitors

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

Formula (VIIIa);

wherein:

L 83 is—C(R 83 ) 2 C(R 83 ) 2 C(R 83 ) 2 —;

E is—C(═O)NR 84 — or —NR 84 C(═O)—;

L 84 is a bond or —CR 86 R 87 —;

Rings D8 is heteroaryl, wherein heteroaryl is selected from the group consisting of:

wherein:

each R 88 is independently hydrogen, S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O)NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;

B8 is heteroaryl or C 2 -C 8 heterocyclyl;

each R 81 is each R 81 is independently hydrogen, halogen, —CN, —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen or —OR a ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;

each R 82 is independently hydrogen, halogen, —CN, —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;

each R 83 is independently hydrogen, halogen, —CN, —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , (—NR a C(═O)NR c R d ), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl—OR a , or —NR c R d ;

R 84 is hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O)NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;

each R 85 is independently hydrogen, halogen, —CN, —OR a , —SR a , —S(═O)R b , (—S(═O) 2 R d ), —NO 2 , —NR c R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;

or two R 85 substituents on the same carbon are taken together to form an oxo;

R 86 and R 87 are independently hydrogen, halogen, —CN, —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d

R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;

R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;

each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;

or R c and R d , 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, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;

n8 is 0-2;

m8 is 1-4; and

q8 is 1-5.

2. The compound of claim 1 , wherein L 84 is a bond.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

Ring B8 is C 3 -C 9 heteroaryl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

Ring B8 is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvatc, or stereoisomer thereof wherein:

each R 81 is independently hydrogen, halogen, or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1, 2, or 3 halogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

n8 is 1.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

each R 82 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

m8 is 1.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

each R 83 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

R 84 is hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

each R 85 is independently hydrogen, halogen, amino, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

q8 is 1 or 2.

13. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof wherein the compound is selected from:

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

15. The compound of claim 1 , wherein R 88 is hydrogen or C 1 -C 6 alkyl.