Claims for Patent: 11,673,898

Summary for Patent: 11,673,898

Title:	Substituted inhibitors of menin-MLL and methods of use
Abstract:	The present disclosure provides methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins with compositions of Formula (II-A). The methods are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin. Compositions of Formula (II-A) for use in these methods are also provided.
Inventor(s):	Tao Wu, Liansheng Li, Yi Wang, Pingda Ren, Jolanta Grembecka, Tomasz Cierpicki, Szymon Klossowski, Jonathan Pollock, Dmitry Borkin
Assignee:	Wellspring Biosciences LLC , University of Michigan System , Kura Oncology Inc
Application Number:	US16/944,040
Patent Claims:	1. A method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II-A): or a pharmaceutically acceptable salt thereof, wherein: C is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; L2 is selected from bond, —C(O)—, —C(O)O—, —C(O)N(R51)—, —C(O)N(R51)C(O)—, —C(O)N(R51)C(O)N(R51)—, —C(NR51)—, —S(O)2—, —S(O)O—, —S(O)—, —S(O)2O—, —S(O)2N(R51)—, —S(O)N(R51)—, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50; L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further substituted with one or more R50; R1 and R3 are each independently selected from hydrogen and R50; R2 is R50; RA, RB, and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50 is independently selected at each occurrence from: halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(—O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, and —P(O)(R52)2, or two R50 groups attached to the same carbon are taken together to form ═O, =S, or =N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51 is independently selected at each occurrence from: hydrogen, —C(O)R52, —C(O)OR52, —C(O)N(R52)2, and —C(O)NR53R54; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle; R56 is independently selected at each occurrence from: —NO2, —OR59, —SR52, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, or two R56 groups attached to the same carbon are taken together to form ═O, ═S, or ═N(R52); wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO2, —CN, —OR59, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56 optionally forms a bond to ring C; and R59 is independently selected at each occurrence from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle, wherein when R56 is —CH3, L3 is not further substituted with —OH, —NH2, or —CN; and wherein the disease or condition comprises leukemia, hematologic malignancy, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes. 2. The method of claim 1, wherein RC is selected from —C(O)R52, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, C1-3 alkyl, and C1-3 haloalkyl, or two RC groups attached to the same carbon are taken together to form ═O, or two RC groups attached to different atoms can together form a C1-3 bridge. 3. The method of claim 1, wherein C is 5- to 12-membered saturated heterocycle, wherein the heterocycle comprises at least one nitrogen atom. 4. The method of claim 1, wherein C—(RC)p is selected from: wherein R57 is selected from —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, and C1-10 alkyl, wherein the C1-10 alkyl is substituted with one or more substituents selected from —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, and —NR52S(═O)2R52. 5. The method of claim 1, wherein: R2 is selected from halogen, —OR52, —N(R52)2, —CN, C1-3 alkyl, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl; and R3 is selected from hydrogen, halogen, —OH, —N(R52)2, —CN, —C(O)OR52, C1-3 alkyl, and C1 3 haloalkyl. 6. The method of claim 1, wherein R1 is C1-3 haloalkyl. 7. The method of claim 1, wherein m is 0. 8. The method of claim 1, wherein n is an integer from 1 to 3. 9. The method of claim 1, wherein L2 is C1-4 alkylene, optionally substituted with one or more R50. 10. The method of claim 1, wherein L3 is substituted with ═O, C1-6 alkyl C1-6 haloalkyl, C1-3 alkyl(cyclopropyl), C1-3 alkyl(NR52C(O)R52), or —O(C1-6 alkyl). 11. The method of claim 1, wherein L3 is selected from 12. The method of claim 11, wherein R56 is methyl. 13. The method of claim 1, wherein: L2 is —CH2—; L3 is selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R56 and optionally further substituted with one or more R50; m is an integer from 0 to 3; n is an integer from 1 to 3; and R56 is independently selected at each occurrence from: —OR59, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, or two R56 groups attached to the same carbon are taken together to form ═O, wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO2, —CN, —OR59, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56 optionally forms a bond to ring C. 14. The method of claim 13, wherein p is 1 and RC is —S(═O)2R52, S(50 O)2N(R52)2, or —S(═O)2—NR53R54. 15. The method of claim 13, wherein the stereoisomer is provided in at least 90% enantiomeric excess. 16. The method of claim 1, wherein the disease or condition is associated with MLL fusion proteins. 17. The method of claim 1, wherein the disease or condition is mediated by chromosomal rearrangement on chromosome 11q23. 18. The method of claim 1, wherein the disease or condition is mediated by an interaction between menin and another protein. 19. The method of claim 1, wherein the compound has the structure of Formula (II-C): or a pharmaceutically acceptable salt thereof; wherein R2, C, L3, RB, RC, and p are each defined as in claim 2. 20. The method of claim 1, wherein the compound has the structure of Formula (II-F) or Formula (II-H): or a pharmaceutically acceptable salt thereof; wherein R2, RC, and R56 are each defined as in claim 2. 21. The method of claim 1, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof. 22. The method of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 23. A method of inhibiting an interaction of menin with one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication, comprising contacting menin with an effective amount of a compound of Formula (II-A): or a pharmaceutically acceptable salt thereof, wherein: C is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; L2 is selected from bond, —C(O)—, —C(O)O—, —C(O)N(R51)—, —C(O)N(R51)C(O)—, —C(O)N(R51)C(O)N(R51)—, —C(NR51)—, —S(O)2—, —S(O)O—, —S(O)—, —S(O)2O—, —S(O)2N(R51)—, —S(O)N(R51)—, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50; L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further substituted with one or more R50; R1 and R3 are each independently selected from hydrogen and R50; R2 is R50; RA, RB, and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50 is independently selected at each occurrence from: halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, and —P(O)(R52)2, or two R50 groups attached to the same carbon are taken together to form ═O, ═S, or =N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51 is independently selected at each occurrence from: hydrogen, —C(O)R52, —C(O)OR52, —C(O)N(R52)2, and —C(O)NR53R54; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle; R56 is independently selected at each occurrence from: —NO2, —OR59, —SR52, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, or two R56 groups attached to the same carbon are taken together to form ═O, ═S, or ═N(R52), wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO2, —CN, —OR59, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is optionally substituted with one or more substituents independently selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(═O)2R52, —NR52S(═O)2N(R52)2, —NR52S(═O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56 optionally forms a bond to ring C; and R59 is independently selected at each occurrence from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle, wherein when R56 is —CH3, L3 is not further substituted with —OH, —NH2, or —CN. 24. The method of claim 23, wherein the compound is: or a pharmaceutically acceptable salt thereof. 25. The method of claim 23, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof. 26. The method of claim 1, wherein the compound is 27. The method of claim 23, wherein the compound is