Methods for treating hematological malignancies and Ewing's sarcoma

Abstract

Methods for treating hematological malignancies and Ewing's sarcoma are provided. Compositions for use in these methods are also provided. A method of treating a subject with acute myeloid leukemia or acute lymphoblastic leukemia, comprising: (a) screening a subject for the presence of an MLL rearrangement, an MLL partial tandem duplication, or an elevated MEIS1 expression level; (b) administering a menin inhibitor to the subject if one or more of MLL rearrangement, MLL partial tandem duplication, or elevated MEIS1 expression level is determined to be present.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 476,710, filed March 24, 2017; U.S. Provisional Patent Application No. 61 / 561,119, filed September 20, 2017; U.S. Provisional Patent Application No. 62 / 577,640, filed October 26, 2017; and U.S. Provisional Patent Application No. 62 / 635,256, filed February 26, 2018, each of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The above ASCII copy, created on March 19, 2018, is named 47535727601_SL.txt and is 15,924 bytes in size. [Background technology]

[0003] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase important for epigenetic regulation of gene transcription. Protein-protein interactions between MLL and menin have been shown to play an important role in the development of many diseases. Menin protein, encoded by the multiple endocrine neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein involved in DNA processing and repair proteins, chromatin modification proteins, and interactions with many transcription factors (Non-Patent Document 1). Menin binds to the N-terminus of MLL proteins, including MLL1, MLL2, and MLL fusion proteins.

[0004] Abnormal expression of HOX genes is implicated in many diseases, including hematological malignancies such as acute myeloid leukemia (AML) and Ewing's sarcoma. Certain hematological malignancies are characterized by the presence of specific genetic abnormalities or mutations, including nucleoporin 98 (NUP98) gene fusions (NPL 2), mutations in the nucleophosmin (NPM1) gene (NPL 3), mutations in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene (NPL 4), or mixed lineage leukemia (MLL) gene amplification (NPL 5). Ewing's sarcoma exhibits abnormal overexpression of posterior HOXD genes, particularly the HOXD13 gene. Ewing's sarcoma tumors and cell lines express high levels of menin and MLL1, which are required for tumor maintenance and progression, and HOXD13 is a downstream target of MLL1 (NPL 6). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Agarwal,et al.;Horm Metab Res,2005,37(6):369-374 [Non-patent document 2] Xu et al.;Cancer Cell. 2016 Dec 12;30(6):863-878. [Non-patent document 3] Kuehn et al.;Cancer Discov. 2016 Oct;6(10):1166-1181. [Non-patent document 4] Spencer et al.;Leukemia. 2015 Jun;29(6):1279-89. [Non-patent document 5] Tang et al.;Hum Pathol. 2015 Jan;46(1):65-73. [Non-patent document 6] Svoboda et al.; Oncotarget. 2017 Jan 3;8(1):458-471. Summary of the Invention

[0006] New therapeutic strategies are urgently needed to treat these diseases. Small molecule inhibitors that block the menin-MLL interaction are therefore valuable targets for treating hematological malignancies and Ewing's sarcoma.

[0007] The present disclosure addresses a need in the art by providing compositions and methods for treating hematological malignancies, such as acute myeloid leukemia, or Ewing's sarcoma, using menin inhibitors. Menin inhibitors can inhibit the protein-protein interaction of menin with MLL proteins (e.g., MLL1, MLL2, or MLL fusion proteins). The compositions and methods described herein may be useful for treating diseases, such as hematological malignancies or Ewing's sarcoma, that are affected by the activity of menin, MLL1, and / or MLL2.

[0008] In one aspect, the present disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a nucleoporin 98 (NUP98) gene fusion, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, or mixed lineage leukemia (MLL) gene amplification, the method comprising administering a menin inhibitor to a subject in need thereof. In some embodiments, the subject exhibits a nucleoporin 98 (NUP98) gene fusion. In some embodiments, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a homeodomain partner gene. In some embodiments, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 and a non-homeodomain partner gene. In some embodiments, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 with a partner gene selected from HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23, JARID1A, NSD1, NSD3, MLL, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAP1GDS1, ADD3, DDX10, TOP1, TOP2B, LNP1, RARG, ANKRD28, and POU1F1. In some embodiments, the subject exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene. In some embodiments, the mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene is an R882 mutation. In some embodiments, the mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene is not an R882 mutation. In some embodiments, the mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene is a frameshift deletion, a missense mutation, a nonsense mutation, a splice site substitution, a splice site deletion, or a whole gene deletion. In some embodiments, the subject presents with mixed lineage leukemia (MLL) gene amplification.

[0009] In one aspect, the disclosure provides a method of treating a subject having acute myeloid leukemia or acute lymphoblastic leukemia, the method comprising: (a) screening the subject for the presence of an MLL rearrangement, a partial tandem duplication of MLL, or an elevated MEIS1 expression level; and (b) administering a menin inhibitor to the subject if one or more of an MLL rearrangement, a partial tandem duplication of MLL, or an elevated MEIS1 expression level is determined to be present.

[0010] In some embodiments, the menin inhibitor is a compound of formula (IA):

[0011] [ka] or a pharmaceutically acceptable salt or prodrug thereof, H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; C is a 3-12 membered heterocycle; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )-CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Two R's attached to either the same atom or different atoms 50 the groups may together optionally form a bridge or a ring; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups may together optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54, -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54, -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12optionally substituted by a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 57 is selected from: Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR52 )2, =S, =N(R 52 ); and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is —NO, —CN, —SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, and, =N(R 52), each occurrence of which is substituted with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl; R 58 is hydrogen; and, C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IA), C is azetidinylene, piperidinylene, or piperazinylene; and R 57 But -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 When: p is an integer from 1 to 6; and / or L 3 is one or more R 50 where L 3 is not -CHCH(OH)-.

[0012] In some embodiments, the menin inhibitor is a compound of formula (IB):

[0013] [ka] or a pharmaceutically acceptable salt thereof, H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A, B, and C are 3-12 independently selected from carbocycle and 3-12 membered heterocycle; L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 is replaced by; R A , R B , and R Care R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52)2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54, -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52, -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52)2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen is used; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 56 appears, -NO2, -OR 59 , -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from carbocycles, and 3- to 12-membered heterocycles; R 56 Each C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is independently selected from halogen, -NO2, -CN, -OR 59 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52, -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from Furthermore, where R 56 optionally forms a single bond to Ring C; and R 59 independently, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12Carbocycles and 3- to 12-membered heterocycles, each of which may be selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IB), R 56 When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0014] In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is C 1-3 Crosslinks can be formed.

[0015] In some embodiments, the menin inhibitor is a compound of formula (II):

[0016] [ka] or a pharmaceutically acceptable salt or prodrug thereof, H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; R A , R B , and R C are each independently, R 50 from each occurrence, or two R A group or two R Bthe groups together can optionally form a bridge or a ring; m and n are each independently an integer of 0 to 6; W 1 is one or more R 50 optionally substituted with C 1-4 is alkylene; W 2 is a single bond; and one or more R 50 C optionally substituted with 1-4 alkylene; W 3 is absent; and one or more R 50 C optionally substituted with 1-4 alkylene; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52)2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 2-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 and forming a heterocycle optionally substituted with, for a compound or salt of formula (II), W 3 When does not exist: W 1 is C1 alkylene, and W 2 is a single bond, and L 3 is not a single bond; W 1 is C 2-4 alkylene, W 2 is a single bond; or W 1 and W 2 are each C1 alkylene, and L 3is not a single bond, and wherein each C alkylene is independently one or more R 50 is optionally substituted with

[0017] In some embodiments, the menin inhibitor is a compound of formula (III):

[0018] [ka] or a pharmaceutically acceptable salt or prodrug thereof, H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0019] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 Each of -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the groups is -C(O)- or -C(R A1 )(R A2 )-C(O)-; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; C is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is R 50are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R C is hydrogen and R 50 are independently selected for each occurrence, or two R C the groups together can optionally form a bridge or a ring; R A1 and R A2 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, p is an integer from 1 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0020] In some embodiments, the menin inhibitor is a compound of formula (IV):

[0021] [ka] or a pharmaceutically acceptable salt or prodrug thereof,

[0022] [ka] is a fused thienyl or fused phenyl group; Ga is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from -E 1 -R 4a and optionally one or more R 50 Further substituted with; R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl; R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; X a -Y a is -N(R 52 )-C(=O)-, -C(=O)-O-, -C(=O)-N(R 52 )-, -CHN(R 52 )-CH2-, -C(=O)N(R 52 )-CH2-, -CH2CH2-N(R 52 )-, -CHN(R 52 )—C(═O)—, and —CH2OCH2—; or X a and Y a does not form a chemical bond, where: X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and Y a is cyano, hydroxy, and -CHR 50 Selected from; E 1 does not exist or -C(=O)-, -C(=O)N(R 52 )-, -[C(R 14a )2] 1-5 O-, -[C(R 14a )2] 1-5 NR 52 -, -[C(R14a )2] 1-5 -, -CH2(=O)-, and -S(=O)2-; R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; R 14a is selected from hydrogen and alkyl; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52)2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50Forms a heterocycle optionally substituted with

[0023] In some embodiments, the menin inhibitor is a compound of formula (VI):

[0024] [ka] or a pharmaceutically acceptable salt or prodrug thereof, wherein H2 is C 3-12 selected from carbocycles and 3-12 membered heterocycles; H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0025] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 each independently represents -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2 )—C(O)—, and —N═C(NH2)—; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the following is -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(RA1 )(R A2 )—C(O)— or —N═C(NH2)—; Z 5 and Z 6 is -C(R A3 )- and -N- independently selected; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 4 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51)-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 4 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is hydrogen and R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R H2 is R 50 are independently selected for each occurrence, or two R H2 the groups together can optionally form a bridge or a ring; R A1 , R A2 , and R A3 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, r is an integer from 1 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52)2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52)2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0026] In one aspect, the disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, said method comprising administering to a subject a compound of formula (IA):

[0027] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject in need thereof; H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; C is a 3-12 membered heterocycle; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54, -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 57 is selected from: Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, =N(R 52 ); and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10alkynyl, each of which independently is —NO, —CN, —SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, and, =N(R 52 ), each occurrence of which is substituted with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl; R58 is hydrogen; and, C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IA), C is azetidinylene, piperidinylene, or piperazinylene; and R 57 But -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 When: p is an integer from 1 to 6; and / or L 3 is one or more R 50 where L 3 is not -CHCH(OH)-.

[0028] In one aspect, the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the FMS-like tyrosine kinase-3 (FLT3) gene, the isocitrate dehydrogenase 1 (IDH1) gene, the isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, comprising administering to a subject in need thereof a compound of formula (IA).

[0029] In one aspect, the disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, said method comprising administering to a subject a compound of formula (IB):

[0030] [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof; H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A, B, and C are 3-12 independently selected from carbocycle and 3-12 membered heterocycle; L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 is replaced by; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52, -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52)(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54, -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 56 appears, -NO2, -OR 59 , -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52, -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from carbocycles, and 3- to 12-membered heterocycles; R 56 Each C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is independently selected from halogen, -NO2, -CN, -OR 59 , -SR 52 , -N(R 52 )2, -NR 53 R54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; R 56 Each C in 3-12The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from Furthermore, where R 56 optionally forms a single bond to Ring C; and R 59 independently, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 Carbocycles and 3- to 12-membered heterocycles, each of which may be selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IB), R 56 When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0031] In one aspect, the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the FMS-like tyrosine kinase-3 (FLT3) gene, the isocitrate dehydrogenase 1 (IDH1) gene, the isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, comprising administering to a subject in need thereof a compound of formula (IB).

[0032] In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is C 1-3 Crosslinks can be formed.

[0033] In one aspect, the disclosure provides a method of treating acute myeloid leukemia in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the method comprising administering to a subject a compound of formula (II):

[0034] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject; H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; R A , R B , and R C are each independently, R 50 from each occurrence, or two R A group or two R B the groups together can optionally form a bridge or a ring; m and n are each independently an integer of 0 to 6; W 1 is one or more R 50 optionally substituted with C 1-4 is alkylene; W 2 is a single bond; and one or more R 50 C optionally substituted with 1-4 alkylene; W 3 is absent; and one or more R 50 C optionally substituted with 1-4 alkylene; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52)2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; and C 1-20Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 2-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 and forming a heterocycle optionally substituted with, for a compound or salt of formula (II), W 3 When does not exist: W 1 is C1 alkylene, and W 2 is a single bond, and L 3 is not a single bond; W 1 is C 2-4 alkylene, W 2 is a single bond; or W 1 and W 2 are each C1 alkylene, and L 3 is not a single bond, and wherein each C alkylene is independently one or more R 50 is optionally substituted with

[0035] In one aspect, the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the FMS-like tyrosine kinase-3 (FLT3) gene, the isocitrate dehydrogenase 1 (IDH1) gene, the isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, the method comprising administering to the subject a compound of Formula (II).

[0036] In one aspect, the disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the FMS-like tyrosine kinase-3 (FLT3) gene, the isocitrate dehydrogenase 1 (IDH1) gene, the isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, the method comprising administering to a subject a compound of formula (III):

[0037] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject; H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0038] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 Each of -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the groups is -C(O)- or -C(R A1 )(R A2 )-C(O)-; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; C is a single bond, C3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50the groups together can optionally form a bridge or a ring; R B is R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R C is hydrogen and R 50 are independently selected for each occurrence, or two R C the groups together can optionally form a bridge or a ring; R A1 and R A2 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, p is an integer from 1 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52)2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0039] In one aspect, the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the FMS-like tyrosine kinase-3 (FLT3) gene, the isocitrate dehydrogenase 1 (IDH1) gene, the isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, the method comprising administering to a subject a compound of formula (IV):

[0040] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject;

[0041] [ka] is a fused thienyl or fused phenyl group; G a is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from -E 1 -R 4a and optionally one or more R 50 Further substituted with; R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl; R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; X a -Y a is -N(R 52 )-C(=O)-, -C(=O)-O-, -C(=O)-N(R 52 )-, -CHN(R 52 )-CH2-, -C(=O)N(R 52 )-CH2-, -CH2CH2-N(R 52 )-, -CHN(R 52 )—C(═O)—, and —CH2OCH2—; or X a and Y a does not form a chemical bond, where: X ais selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and Y a is cyano, hydroxy, and -CHR 50 Selected from; E 1 does not exist or -C(=O)-, -C(=O)N(R 52 )-, -[C(R 14a )2] 1-5 O-, -[C(R 14a )2] 1-5 NR 52 -, -[C(R 14a )2] 1-5 -, -CH2(=O)-, and -S(=O)2-; R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; R 14a is selected from hydrogen and alkyl; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52, -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0042] In one aspect, the present disclosure provides a method of treating a hematological malignancy in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the FMS-like tyrosine kinase-3 (FLT3) gene, the isocitrate dehydrogenase 1 (IDH1) gene, the isocitrate dehydrogenase 2 (IDH2) gene, or a combination thereof, the method comprising administering to a subject a compound of formula (VI):

[0043] [ka] Alternatively, the method comprises administering a pharmaceutically acceptable salt or prodrug thereof to a subject, wherein H2 is C 3-12 selected from carbocycles and 3-12 membered heterocycles; H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0044] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 each independently represents -C(RA1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2 )—C(O)—, and —N═C(NH2)—; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the following is -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2 )—C(O)— or —N═C(NH2)—; Z 5 and Z 6 is -C(R A3 )- and -N- independently selected; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 4 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; where L 1 , L 2 , or L 4 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is hydrogen and R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R H2 is R 50 are independently selected for each occurrence, or two R H2 the groups together can optionally form a bridge or a ring; R A1 , R A2 , and R A3 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, r is an integer from 1 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52)2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0045] In some embodiments, the hematological malignancy is selected from malignant lymphoma, leukemia, mature B-cell neoplasm, mature T-cell and natural killer (NK) cell neoplasm, precursor lymphoid neoplasm, Hodgkin's lymphoma (HL), plasma cell neoplasm, mast cell tumor, histiocytic and accessory lymphoid cell neoplasm, immunoproliferative disorder, myeloid leukemia, and myelodysplastic syndrome (MDS). In some embodiments, the hematological malignancy is selected from acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, mixed lineage leukemia, and myelodysplastic syndrome. In some embodiments, the hematological malignancy is acute myeloid leukemia. In some embodiments, relapse of the hematological malignancy is prevented.

[0046] In some embodiments, the mutation in the nucleophosmin (NPM1) gene is a mutation in exon 12 of the NPM1 gene. In some embodiments, the mutation in the nucleophosmin (NPM1) gene is a frameshift mutation. In some embodiments, the mutation in the nucleophosmin (NPM1) gene is an insertion of 2 to 9 bases, such as an insertion of 4 bases. In some embodiments, the insertion of 4 bases is selected from TCTG, CATG, CCTG, CGTG, CAGA, CTTG, and TATG. In some embodiments, the insertion is an insertion of 9 bases. In some embodiments, the insertion of 9 bases is selected from CTCTTGCCC and CCCTGGAGA. In some embodiments, the mutation in the nucleophosmin (NPM1) gene comprises a deletion of nucleotides 965-969 (GGAGG). In some embodiments, the subject further exhibits a mutation in the FLT3 gene. In some embodiments, the mutation in the FLT3 gene is an internal tandem duplication. In some embodiments, the subject further exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene.

[0047] In some embodiments, the mutation in the FLT3 gene is in the tyrosine kinase domain. In some embodiments, the mutation is in the nucleophosmin (NPM1) gene and the FMS-like tyrosine kinase-3 (FLT3) gene. In some embodiments, the mutation is in the nucleophosmin (NPM1) gene, the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, the isocitrate dehydrogenase 2 (IDH2) gene, and the FMS-like tyrosine kinase-3 (FLT3) gene. In some embodiments, the subject exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene.

[0048] In one aspect, the disclosure provides a method of treating Ewing's sarcoma, said method comprising administering to a patient a compound of formula (IA):

[0049] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject; H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; C is a 3-12 membered heterocycle; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51)-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 57 is selected from: Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52)2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, =N(R 52 ); and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is —NO, —CN, —SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, and, =N(R 52 ), each occurrence of which is substituted with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl; R 58 is hydrogen; and, C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12carbocycle and 3- to 12-membered heterocycle, each of which is selected from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IA), C is azetidinylene, piperidinylene, or piperazinylene; and R 57 But -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 When: p is an integer from 1 to 6; and / or L 3 is one or more R 50 where L 3 is not -CHCH(OH)-.

[0050] In one aspect, the disclosure provides a method of treating Ewing's sarcoma, said method comprising administering to a patient a compound of formula (IB):

[0051] [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof; H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A, B, and C are 3-12 independently selected from carbocycle and 3-12 membered heterocycle; L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51)C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 is replaced by; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 56 appears, -NO2, -OR 59 , -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54, -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from carbocycles, and 3- to 12-membered heterocycles; R 56 Each C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is independently selected from halogen, -NO2, -CN, -OR 59 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52, -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from Furthermore, where R 56 optionally forms a single bond to Ring C; and R 59 independently, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 Carbocycles and 3- to 12-membered heterocycles, each of which may be selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IB), R 56 When is -CH3, L 3is not further substituted with -OH, -NH2, or -CN.

[0052] In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is C 1-3 Crosslinks can be formed.

[0053] In one aspect, the disclosure provides a method of treating Ewing's sarcoma, said method comprising administering to a patient a compound of formula (II):

[0054] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject; H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51)C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; R A , R B , and R C are each independently, R 50 from each occurrence, or two R A group or two R B the groups together can optionally form a bridge or a ring; m and n are each independently an integer of 0 to 6; W 1 is one or more R 50 optionally substituted with C 1-4 is alkylene; W 2 is a single bond; and one or more R50 C optionally substituted with 1-4 alkylene; W 3 is absent; and one or more R 50 C optionally substituted with 1-4 alkylene; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ); C 1-10Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52)2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 2-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 and forming a heterocycle optionally substituted with, for a compound or salt of formula (II), W 3 When does not exist: W 1 is C1 alkylene, and W 2 is a single bond, and L 3 is not a single bond; W 1 is C 2-4 alkylene, W 2 is a single bond; or W 1 and W 2 are each C1 alkylene, and L 3 is not a single bond, and wherein each C alkylene is independently one or more R 50 is optionally substituted with

[0055] In one aspect, the disclosure provides a method of treating Ewing's sarcoma, the method comprising administering to a patient a compound of formula (III):

[0056] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject; H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0057] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 Each of -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the groups is -C(O)- or -C(R A1 )(R A2 )-C(O)-; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; C is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R C is hydrogen and R 50 are independently selected for each occurrence, or two R Cthe groups together can optionally form a bridge or a ring; R A1 and R A2 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, p is an integer from 1 to 6; and / or R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52)(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52)2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0058] In one aspect, the disclosure provides a method of treating Ewing's sarcoma, said method comprising administering to a patient a compound of formula (IV):

[0059] [ka] Alternatively, administering a pharmaceutically acceptable salt or prodrug thereof to a subject;

[0060] [ka] is a fused thienyl or fused phenyl group; G a is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from -E 1 -R 4a and optionally one or more R 50 Further substituted with; R 2ais selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl; R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; X a -Y a is -N(R 52 )-C(=O)-, -C(=O)-O-, -C(=O)-N(R 52 )-, -CHN(R 52 )-CH2-, -C(=O)N(R 52 )-CH2-, -CH2CH2-N(R 52 )-, -CHN(R 52 )—C(═O)—, and —CH2OCH2—; or X a and Y a does not form a chemical bond, where: X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and Y a is cyano, hydroxy, and -CHR 50 Selected from; E 1 does not exist or -C(=O)-, -C(=O)N(R 52 )-, -[C(R 14a )2] 1-5 O-, -[C(R 14a )2] 1-5 NR 52 -, -[C(R 14a )2] 1-5 -, -CH2(=O)-, and -S(=O)2-; R 4ais selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; R 14a is selected from hydrogen and alkyl; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0061] In one aspect, the disclosure provides a method of treating Ewing's sarcoma, said method comprising administering to a patient a compound of formula (VI):

[0062] [ka] Alternatively, the method comprises administering a pharmaceutically acceptable salt or prodrug thereof to a subject, wherein H2 is C 3-12 selected from carbocycles and 3-12 membered heterocycles; H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0063] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 each independently represents -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2 )—C(O)—, and —N═C(NH2)—; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the following is -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2)—C(O)— or —N═C(NH2)—; Z 5 and Z 6 is -C(R A3 )- and -N- independently selected; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 4 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50where L 1 , L 2 , or L 4 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is hydrogen and R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R H2 is R 50 are independently selected for each occurrence, or two R H2 the groups together can optionally form a bridge or a ring; R A1 , R A2 , and R A3 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, r is an integer from 1 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0064] In some embodiments, the subject exhibits an EWSR1-FLI1 gene fusion, an EWSR1-ERG gene fusion, or an EWSR1-FEV gene fusion. In some embodiments, the subject exhibits a FUS-NCATc2 gene fusion, a CIC-FOXO4 gene fusion, or an ETV6-NTRK3 gene fusion. In some embodiments, the subject exhibits a mutation in the STAG2 gene, a mutation in the TP53 gene, or a CDKN2A deletion.

[0065] In some embodiments, for compounds of Formula (IA) or Formula (IB), C is a 5- to 12-membered heterocycle, wherein the heterocycle contains at least one nitrogen atom. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is selected from piperidinyl and piperazinyl. In some embodiments, C is selected from:

[0066] [ka] In some embodiments, R 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, C is selected from:

[0067] [ka] where R 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 ; and -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R52 )2, -S(=O)2NR 53 R 54 , and -NR 52 S(=O)2R 52 C substituted with one or more substituents selected from 1-10 In some embodiments, for compounds of Formula (IA) or Formula (IB), R 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, for compounds of formula (IA) or formula (IB), R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, for compounds of Formula (IA) or Formula (IB), R C is C 1-3 Alkyl and C 1-3 haloalkyl.

[0068] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), or Formula (III), H is selected from one or more R 50 A is a 5- to 12-membered heterocycle optionally substituted with; A is a 3- to 12-membered heterocycle; and B is a 3- to 12-membered heterocycle.

[0069] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), or Formula (III), H is selected from one or more R 50 In some embodiments, H is a 5- to 12-membered bicyclic heterocycle optionally substituted with one or more R 50 and optionally substituted thienopyrimidinyl.

[0070] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), or Formula (III), H is

[0071] [ka] and; X 1 and X 2 are each independently CR 2 and N are selected from;X 3 and X 4 are each independently selected from C and N; Y 1 and Y 2 are each independently, CR 3 , N, NR 4 , O, and S; R 1 , R 2 , and R 3 are independently hydrogen and R 50 are selected each time they appear; and R 4 is R 51 In some embodiments, X 3 and X 4 are each C. In some embodiments, X 1 is CR 2 and R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, X is selected from alkynyl. 1 is CR 2 and R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, X is selected from alkynyl. 2 is N. In some embodiments, Y 2 is CR 3 and R 3 is hydrogen, halogen, -OH, -N(R 52 )2, -CN, -C(O)OR 52 , C 1-3 Alkyl, and C 1-3 In some embodiments, R is selected from haloalkyl. 1 is C 1-3 It is haloalkyl.

[0072] In some embodiments, for compounds of Formula (IA), Formula (IB), or Formula (II), A is a 5- to 8-membered heterocycle. In some embodiments, A is a 6-membered monocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, A is selected from piperidinylene and piperazinylene. In some embodiments, A is

[0073] [ka] is.

[0074] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (VI), A is a 7-12 membered spirocyclic heterocycle or a C spirocyclic carbocycle. In some embodiments, A is a 7-12 membered heterocyclic heterocycle, such as a 7-10 membered spirocyclic heterocycle. In some embodiments, A is

[0075] [ka] and Z 1 , Z2 , Z 3 , and Z 4 Each of -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the groups is -C(O)- or -C(R A1 )(R A2 )-C(O)-; R A1 and R A2 are independently hydrogen and R 50 In some embodiments, R A1 and R A2 are each independently hydrogen, halo, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Each occurrence is selected from haloalkoxy, -CN, -NO2, and OH. In some embodiments, A is selected from:

[0076] [ka]

[0077] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (VI), B is a 6- to 12-membered bicyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, B is indolylene. In some embodiments, B is selected from the group consisting of one or more R B optionally substituted with

[0078] [ka] is.

[0079] In some embodiments, for compounds of Formula (IA), Formula (IB), or Formula (II), H is selected from one or more R 50 A is selected from piperidinylene and piperazinylene; and B is indolylene.

[0080] In some embodiments, for compounds of Formula (IA), Formula (IB), or Formula (II), H is replaced with -CH2CF3.

[0081] In some embodiments, for compounds of Formula (IA), Formula (IB), or Formula (II), m is 0. In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (VI), n is an integer from 1 to 3.

[0082] In some embodiments, for Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (VI), L 1 In some embodiments, L 1 -N(R 51 )-.

[0083] In some embodiments, for Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (VI), L 2 contains less than 10 atoms. In some embodiments, L 2 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is alkylene. 2 is -CH2-, -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)2-.

[0084] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), or Formula (III), L 3 contains less than 20 atoms. In some embodiments, L 3 is one or more R 50 optionally substituted with C 1-6 In some embodiments, L is alkylene. 3 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is alkylene. 3 is -CH-. In some embodiments, L 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, optionally further substituted with one or more R 50 In some embodiments, L is a C alkylene substituted with 3 is =O,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkyl(cyclopropyl), C 1-3 Alkyl (NR 52 C(O)R 52 ) or -O(C 1-6 In some embodiments, L 3 is substituted with -CH3. In some embodiments, L 3 teeth,

[0085] [ka] In some embodiments, R 50 is methyl. In some embodiments, L 3 teeth,

[0086] [ka] In some embodiments, R 56 is methyl.

[0087] In some embodiments, for compounds of Formula (IA), Formula (IB), or Formula (II), H is selected from one or more R 50 A is a 3-12 membered heterocycle; B is a 6-12 membered bicyclic heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3.

[0088] In some embodiments, for compounds of formula (IA): H is one or more R 50 thienopyrimidinyl optionally substituted with A is selected from piperidinylene and piperazinylene; B is indolylene; L 1 and L 2 are each independently selected from -O-, -S-, -NH-, or -CH2-; L 3 represents a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51)-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 3 Two Rs bonded to the same and different atoms of 50 the groups together can optionally form a ring; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group or two R C the groups together can optionally form a ring; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R 57 is selected from: -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)NH(C 1-6alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2; and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is —S(═O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, and -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, which is selected each time it appears, C1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl; R 58 is hydrogen; and C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 It is optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring.

[0089] In some embodiments, for compounds of formula (IB): H is one or more R 50 thienopyrimidinyl optionally substituted with A is selected from piperidinylene and piperazinylene; B is indolylene; L 1 and L 2 are each independently selected from -O-, -S-, -NH-, or -CH2-; L 3 is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 is replaced by; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R 56 appears, -OR 59 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, R 56 Each C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is independently selected from halogen, -NO2, -CN, -OR 59 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from Furthermore, where R 56 optionally forms a single bond to Ring C; and R 59 independently, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 Carbocycles and 3- to 12-membered heterocycles are selected whenever they occur, and each of them is selected from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 It is optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring.

[0090] In some embodiments, for compounds of formula (IA), R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -S(=O)2NR 53 R 54 In some embodiments, R 57 is selected from —S(═O)2CH3 and —S(═O)2NHCH3.

[0091] In some embodiments, for compounds of formula (IA), C is -S(=O)R 58 , -S(=O)2N(R 52 )2, or -S(=O)2NR 53 R 54 is replaced by

[0092] In some embodiments, for a compound of Formula (IA), Formula (IB), Formula (II), or Formula (III), H is

[0093] [ka] and R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl-OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 is selected from -NH2, -CH3, and -NHCH3.

[0094] In some embodiments, for compounds of Formula (IA), Formula (IB), Formula (II), or Formula (III), L 3 teeth,

[0095] [ka] is selected from.

[0096] In some embodiments, for Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (VI), the compound is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 90% enantiomeric excess. In some embodiments, for Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (IV), or Formula (VI), the compound is isotopically enriched. In some embodiments, for a compound of Formula (IA) or Formula (IB), the compound is selected from Table 1. In some embodiments, for a compound of Formula (II), the compound is selected from Table 3, Table 5, or Table 7. In some embodiments, for a compound of Formula (IV), the compound is selected from Table 4. In some embodiments, for a compound of Formula (IV), the compound is selected from Table 4.

[0097] In some embodiments, for compounds of formula (II), W 1 , W 2 , and W 3 are each independently, C 1-4 alkylene, wherein C 1-4 Each alkylene may be one or more R 50 In some embodiments, W 1 , W 2 , and W 3 Each is a C alkylene. In some embodiments, W 1 and W 2 are each C1 alkylene, and W 3 does not exist.

[0098] In some embodiments, for compounds of formula (II), R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 is selected from.

[0099] In some embodiments, the methods described herein further comprise reducing expression of a target gene. In some embodiments, the target gene is selected from Hoxa5, Hoxa7, Hoxa9, Hoxa10, Hoxb2, Hoxb3, Hoxb4, Hoxb5, Hoxb8, Hoxd10, Hoxd11, Hoxd13, DLX2, PBX3, Meis1, Mir196b, Flt3, and Bahcc1. In some embodiments, the target gene is Hoxa9, DLX2, PBX3, or Meis1. In some embodiments, the methods described herein comprise administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a DOT1L inhibitor. In some embodiments, the second therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is romidepsin. In some embodiments, the FLT3 inhibitor is midostaurin. In some embodiments, the subject is a human. In some embodiments, the methods described herein further comprise obtaining a nucleic acid sample from the subject. In some embodiments, the nucleic acid sample comprises a nucleic acid selected from genomic DNA, cDNA, circulating tumor DNA, cell-free DNA, RNA, and mRNA. In some embodiments, the methods described herein further comprise obtaining a biological sample from the subject. In some embodiments, the biological sample is a tissue sample. In some embodiments, the tissue sample is fixed, paraffin-embedded, fresh, or frozen. In some embodiments, the tissue sample is derived from a fine needle, core, or other type of biopsy. In some embodiments, the biological sample is whole blood or plasma. In some embodiments, the methods described herein further comprise performing nucleic acid analysis on the nucleic acid sample. In some embodiments, the nucleic acid analysis comprises PCR, sequencing, hybridization, microarray, SNP, cell-free nucleic acid analysis, or whole genome sequencing.In some embodiments, the subject has been tested for the presence of a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, or a mixed lineage leukemia (MLL) gene amplification. In some embodiments, the methods described herein further comprise testing the subject for the presence of a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, or a mixed lineage leukemia (MLL) gene amplification.

[0100] In some embodiments, the subject has been tested for the presence of a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, a mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or a mixed lineage leukemia (MLL) gene amplification. In some embodiments, the methods described herein further comprise testing the subject for the presence of a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, a mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or a mixed lineage leukemia (MLL) gene amplification. In some embodiments, the subject has been tested for the presence of an MLL rearrangement, a partial tandem duplication of MLL, or an elevated MEIS1 expression level. In some embodiments, the methods described herein further comprise testing the subject for the presence of an MLL rearrangement, a partial tandem duplication of MLL, or an elevated MEIS1 expression level. INCORPORATION BY REFERENCE

[0101] All publications, patents, or patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0102] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth embodiments in which the principles of the invention are utilized, and the accompanying drawings in which: [Figure 1]Amino acid sequence of human menin, isoform 1 (SEQ ID NO:1). [Figure 2] Amino acid sequence of human menin, isoform 2 (SEQ ID NO:2). [Figure 3] Amino acid sequence of human menin, isoform 3 (SEQ ID NO:3). [Figure 4] 1 depicts cd11b cell surface expression in compound-treated OCI-AML3 cells. [Figure 5] 1 depicts the change in OCI-AML3 tumor volume in vehicle- and compound-treated mice. [Figure 6A] Depicts percentages of CD45+ / CD38+ blasts, CD45+ / CD11b+ monocytes, and CD45+ / CD14+ monocytes in vehicle and compound treated AM7577 models. [Figure 6B] Depicts percentages of CD45+ / CD38+ blasts, CD45+ / CD11b+ monocytes, and CD45+ / CD14+ monocytes in vehicle and compound treated AM7577 models. [Figure 6C] Depicts percentages of CD45+ / CD38+ blasts, CD45+ / CD11b+ monocytes, and CD45+ / CD14+ monocytes in vehicle and compound treated AM7577 models. [Figure 7A] 1 depicts overall survival, bone marrow phenotype at sacrifice, and spleen weight at sacrifice in vehicle and compound treated AM7577 models. [Figure 7B] 1 depicts overall survival, bone marrow phenotype at sacrifice, and spleen weight at sacrifice in vehicle and compound treated AM7577 models. [Figure 7C] 1 depicts overall survival, bone marrow phenotype at sacrifice, and spleen weight at sacrifice in vehicle and compound treated AM7577 models. [Figure 8A] 1 depicts the percentage of CD45+ / CD38+ blasts and CD45+ / CD11b+ monocytes in vehicle, compound, and quizartinib-treated AM7577 models. [Figure 8B]1 depicts the percentage of CD45+ / CD38+ blasts and CD45+ / CD11b+ monocytes in vehicle, compound, and quizartinib-treated AM7577 models. [Figure 9A] 1 depicts overall survival, bone marrow phenotype at 7 and 21 days, bone marrow AML blasts at sacrifice, and spleen weight at sacrifice in vehicle, compound, and quizartinib treated AM7577 models. [Figure 9B] 1 depicts overall survival, bone marrow phenotype at 7 and 21 days, bone marrow AML blasts at sacrifice, and spleen weight at sacrifice in vehicle, compound, and quizartinib treated AM7577 models. [Figure 9C] 1 depicts overall survival, bone marrow phenotype at 7 and 21 days, bone marrow AML blasts at sacrifice, and spleen weight at sacrifice in vehicle, compound, and quizartinib treated AM7577 models. [Figure 9D] 1 depicts overall survival, bone marrow phenotype at 7 and 21 days, bone marrow AML blasts at sacrifice, and spleen weight at sacrifice in vehicle, compound, and quizartinib treated AM7577 models. [Figure 9E] 1 depicts overall survival, bone marrow phenotype at 7 and 21 days, bone marrow AML blasts at sacrifice, and spleen weight at sacrifice in vehicle, compound, and quizartinib treated AM7577 models. [Figure 10] 1 depicts the percentage of CD45+ / CD33+ blasts in vehicle, compound, and quizartinib-treated LXFE 2734 models. [Figure 11] 1 depicts overall survival in the LXFE 2734 model treated with vehicle, compound, and quizartinib. [Figure 12] 1 depicts a dose-response curve for acute myeloid leukemia cells treated with Compound A. [Figure 13] 1 depicts a dose-response curve for B-cell acute lymphoblastic leukemia cells treated with Compound A. DETAILED DESCRIPTION OF THE INVENTION

[0103] The present invention provides compositions and methods useful for treating hematological malignancies and Ewing's sarcoma. In one aspect, the present invention provides a method for treating hematological malignancies, such as acute myeloid leukemia, in subjects exhibiting a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, a mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) gene amplification. In one aspect, the present invention provides a method for treating hematological malignancies, such as acute myeloid leukemia or acute lymphoblastic leukemia, in subjects exhibiting an MLL rearrangement, optionally with an elevated MEIS1 expression level. In some embodiments, the subject exhibits a partial tandem duplication of MLL (MLL-PTD). The subject methods generally include administering a menin inhibitor to a subject in need thereof. In some embodiments, the menin inhibitor administered to treat a hematological malignancy is a compound of formula (IA) or a compound of formula (IB). In some embodiments, the menin inhibitor administered to treat a hematological malignancy is a compound of formula (II). In some embodiments, the menin inhibitor administered to treat a hematological malignancy is a compound of formula (III). In some embodiments, the menin inhibitor administered to treat a hematological malignancy is a compound of formula (IV). In some embodiments, the menin inhibitor administered to treat a hematological malignancy is a compound of formula (VI).

[0104] In another aspect, the present invention provides a method of treating Ewing's sarcoma by administering a menin inhibitor to a subject in need thereof. In some embodiments, the menin inhibitor administered to treat Ewing's sarcoma is a compound of Formula (IA) or a compound of Formula (IB). In some embodiments, the menin inhibitor administered to treat Ewing's sarcoma is a compound of Formula (II). In some embodiments, the menin inhibitor administered to treat Ewing's sarcoma is a compound of Formula (III). In some embodiments, the menin inhibitor administered to treat Ewing's sarcoma is a compound of Formula (IV). In some embodiments, the menin inhibitor administered to treat Ewing's sarcoma is a compound of Formula (VI).

[0105] In some embodiments, the subject being treated has been tested for the presence of genetic abnormalities or mutations. In some cases, the subject has been tested for the presence of nucleoporin 98 (NUP98) gene fusions, mutations in the nucleophosmin (NPM1) gene, mutations in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, mutations in the FMS-like tyrosine kinase-3 (FLT3) gene, mutations in the isocitrate dehydrogenase 1 (IDH1) gene, mutations in the isocitrate dehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) gene amplification. In some cases, the subject has been tested for elevated MEIS1 expression of MLL, MLL rearrangements, or partial tandem duplications. A wide variety of nucleic acid samples and analyses are available for such testing. A nucleic acid sample may be obtained from the subject. In some cases, the nucleic acid sample comprises a nucleic acid selected from genomic DNA, cDNA, circulating tumor DNA, cell-free DNA, RNA, and mRNA. A biological sample may be obtained from a subject. In some cases, the biological sample is a tissue sample (e.g., a fixed, paraffin-embedded, fresh, or frozen tissue sample). The tissue sample may be derived from a fine needle, core, or other type of biopsy. In some cases, the biological sample is whole blood or plasma.

[0106] In some embodiments, nucleic acid analysis may be performed on a biological sample containing nucleic acids. Non-limiting examples of nucleic acid analysis include PCR, sequencing, hybridization, microarray, SNP, cell-free nucleic acid analysis, and whole genome sequencing.

[0107] The subject may exhibit a nucleoporin 98 (NUP98) gene fusion. In some cases, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 with a homeodomain partner gene. In some cases, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 with a non-homeodomain partner gene. In some cases, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98 with a partner gene selected from HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23, JARID1A, NSD1, NSD3, MLL, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAP1GDS1, ADD3, DDX10, TOP1, TOP2B, LNP1, RARG, ANKRD28, and POU1F1.

[0108] The subject may have a mutation in the nucleophosmin (NPM1) gene. In some cases, the mutation in the nucleophosmin (NPM1) gene is a mutation in exon 12 of the NPM1 gene. In some cases, the mutation in the nucleophosmin (NPM1) gene is a frameshift mutation. In some cases, the mutation in the nucleophosmin (NPM1) gene includes an insertion of 2-9 bases, such as an insertion of 4 bases (e.g., TCTG, CATG, CCTG, CGTG, CAGA, CTTG, and TATG). In some cases, the insertion is an insertion of 9 bases (e.g., CTCTTGCCC and CCCTGGAGA). In some cases, the mutation in the nucleophosmin (NPM1) gene includes a deletion of nucleotides 965-969 (GGAGG).

[0109] The subject may have a mutation in the FLT3 gene. In some embodiments, the mutation in the FLT3 gene is an internal tandem duplication (FLT3-ITD). In some cases, the mutation in the FLT3 gene is an in-frame internal tandem duplication mutation of a nucleotide sequence within exon 14. The size of the FLT3-ITD mutation may vary from 3 to 400 bp or more. In some cases, the FLT3-ITD mutation is near residues 590-600 of the FLT3 amino acid sequence. The FLT3-ITD mutation may be located in exon 14, exon 15, and / or an intron between exons 14 and 15. The subject may have both a partial tandem duplication of the MLL gene and a FLT3-ITD mutation. The subject may have an activating FLT3 mutation. In some cases, the mutation in the FLT3 gene is a point mutation involving the tyrosine kinase domain. In some cases, the mutation in the FLT3 gene is a point mutation at aspartate 835 or isoleucine 836.

[0110] The subject may have a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene. In some cases, the mutation in the DNMT3A gene is an R882 mutation. In some cases, the mutation in the DNMT3A gene is not an R882 mutation. In some cases, the mutation in the DNMT3A gene is a frameshift deletion, a missense mutation, a nonsense mutation, a splice site substitution, a splice site deletion, or a whole-gene deletion.

[0111] The subject may have a mutation in the isocitrate dehydrogenase 1 (IDH1) gene or the isocitrate dehydrogenase 2 (IDH2) gene. Optionally, the mutation in the isocitrate dehydrogenase 1 (IDH1) gene is a heterozygous point mutation in codon 132. Optionally, the mutation in the isocitrate dehydrogenase 2 (IDH2) gene is a heterozygous point mutation in codon 172 or 140. In some embodiments, the mutation in the isocitrate dehydrogenase 2 (IDH2) gene is R140Q.

[0112] The subject may have one or more of an NPM1 mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, and a DNMT3A mutation. In some cases, the subject has an NPM1 mutation, an FLT3 mutation, an IDH2 mutation, and a DNMT3A mutation. In some cases, the subject has an NPM1 mutation, an IDH1 mutation, an FLT3 mutation, and a DNMT3A mutation. In some cases, the subject has an NPM1 mutation, an FLT3 mutation, and a DNMT3A mutation. In some cases, the subject has an NPM1 mutation, an FLT3 mutation, and an IDH1 mutation. In some cases, the subject has an NPM1 mutation, an FLT3 mutation, and an IDH2 mutation. In some cases, the subject has an NPM1 mutation, an DNMT3A mutation, and an IDH1 mutation. In some cases, the subject has an NPM1 mutation, an DNMT3A mutation, and an IDH2 mutation. In some cases, subjects present with an NPM1 mutation and an FLT3 mutation.

[0113] The subject may present with a mixed lineage leukemia (MLL) gene amplification. The subject may present with a mixed lineage leukemia (MLL) gene rearrangement. The subject may present with an 11q23 rearrangement. The subject may present with a partial tandem duplication of MLL.

[0114] The subject may have an EWSR1-FLI1 gene fusion, an EWSR1-ERG gene fusion, or an EWSR1-FEV gene fusion. In some embodiments, the subject may have a FUS-NCATc2 gene fusion, a CIC-FOXO4 gene fusion, or an ETV6-NTRK3 gene fusion. In some embodiments, the subject may have a mutation in the STAG2 gene, a mutation in the TP53 gene, or a CDKN2A deletion.

[0115] Subjects were randomly assigned to the Myeloid Ectopic Viral Insertion Site 1 Homolog (MEIS1) expression level (MEIS1 high) may exhibit elevated expression levels. As used herein, "expression" refers to the process by which a polynucleotide is transcribed into mRNA and / or the process by which the transcribed mRNA (also called a "transcript") is subsequently translated into a peptide, polypeptide, or protein. The transcript and encoded polypeptide are collectively referred to as a "gene product." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. The level of expression (or, alternatively, "expression level") of the MEIS1 gene can be determined, for example, by determining the level of MEIS1 polynucleotides, polypeptides, and / or gene products. "Differentially expressed" or "differential expression," as applied to a subject nucleotide sequence (e.g., gene) or polypeptide sequence, refers to the differential production of mRNA transcribed and / or translated from the nucleotide sequence or protein product encoded by the nucleotide sequence. Compared to the expression level in a reference sample (i.e., the reference level), a differentially expressed sequence may be overexpressed or underexpressed. As used herein, elevated expression levels refer to increased expression, typically at least 1.25-fold, alternatively at least 1.5-fold, alternatively at least 2-fold, alternatively at least 3-fold, alternatively at least 4-fold, or alternatively at least 10-fold, of that detected in a reference sample. As used herein, low expression refers to decreased expression, typically at least 1.25-fold, alternatively at least 1.5-fold, alternatively at least 2-fold, alternatively at least 3-fold, alternatively at least 4-fold, or alternatively at least 10-fold, of that detected in a reference sample. Low expression encompasses the absence of expression of a particular sequence as evidenced by the absence of detectable expression in a test subject compared to a reference sample.

[0116] The present disclosure provides compounds for modulating the interaction of menin with proteins such as MLL1, MLL2, and MLL-fusion oncoproteins. In certain embodiments, the present disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules, including, but not limited to, MLL1, MLL2, and MLL-fusion oncoproteins. The compounds of the present disclosure may be used in methods for the treatment of a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL-fusion proteins, and menin, such as hematological malignancies and Ewing's sarcoma. In some cases, the hematological malignancy comprises a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, a mutation in the isocitrate dehydrogenase 2 (IDH2) gene, and / or a mixed lineage leukemia (MLL) gene amplification. In certain embodiments, the compounds of the present disclosure interact non-covalently with menin and inhibit the interaction between menin and MLL. In certain embodiments, the compounds of the present disclosure covalently bind to menin and inhibit the interaction between menin and MLL.

[0117] In some embodiments, the present disclosure provides compounds or salts thereof that selectively bind to menin protein and / or modulate the interaction of menin with MLL proteins (e.g., MLL1, MLL2, or MLL fusion proteins). In certain embodiments, the compounds modulate menin protein by binding to or interacting with one or more amino acids and / or one or more metal ions. Certain compounds may occupy the F9 and / or P13 pockets of menin. Binding of the compounds disclosed herein may interfere with downstream signaling of menin or MLL (e.g., MLL1, MLL2, or MLL fusion proteins).

[0118] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0119] "Nucleoporin 98 (NUP98) gene fusion" refers to a gene encoding a protein with an N-terminal fragment of NUP98 fused to a partner protein. "Nucleoporin 98 (NUP98) fusion protein" refers to a protein having an N-terminal fragment of NUP98 fused to a partner protein. Non-limiting examples of partner proteins include HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23, JARID1A, NSD1, NSD3, MLL, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAP1GDS1, ADD3, DDX10, TOP1, TOP2B, LNP1, RARG, ANKRD28, and POU1F1. NUP98 fusion proteins may be generated through the joining of a gene encoding NUP98 with a gene encoding a partner protein to create a fusion gene, the translation of which may result in one or more polypeptides possessing functional properties from each of the original proteins.

[0120] "MLL fusion protein" refers to a protein having an N-terminal fragment of MLL fused to a partner protein. Non-limiting examples of partner proteins include 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22, 9p13.3, and 9p22. (MLLT3 / AF9), ABI1, ABI2, ACACA, ACTN4, AFF1 / AF4, AFF3 / LAF4, AFF4 / AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13, C2CD3, CASC5, CASP8AP2, CBL, CEP164, CEP170B, CREBBP, DCP1A, DCPS, EEFSEC / SELB, ELL, EPS15, FLNA, FNBP1, FOXO3, GAS7, GMPS, KIAA15 MLL fusion proteins may also be generated by combining a gene encoding an MLL protein with a gene encoding a partner protein to create a fusion gene. Translation of this fusion gene may result in one or more polypeptides with functional properties derived from each of the original proteins.

[0121] The term “C x-y " or "C x -C y " when used in conjunction with a chemical moiety such as alkyl, alkynyl, or alkenyl, is meant to include groups containing x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups, containing x to y carbon atoms in the chain. x-yalkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted, straight or branched chain unsaturated hydrocarbon group containing at least one double or triple bond, respectively. Unless otherwise specifically stated in the specification, x-y Alkyl, C x-y Alkenyl, or C x-y The alkynyl is optionally substituted with one or more substituents such as those described herein.

[0122] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. Carbocycles can include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, a carbocycle is aryl. In some embodiments, a carbocycle is cycloalkyl. In some embodiments, a carbocycle is cycloalkenyl. In typical embodiments, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit, is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, carbocycles are optionally substituted with one or more substituents, such as those described herein.

[0123] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Typical heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles can include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. A heterocycle can be attached to the remainder of the molecule through any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle, as valence allows. In some embodiments, a heterocycle is heteroaryl. In some embodiments, a heterocycle is heterocycloalkyl. In typical embodiments, a heterocycle (e.g., pyridyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene.

[0124] "Heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, each of which may be independently selected from N, O, and S. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic, and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]iminophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]iminophenyl, benzothieno[3,2-d]pyrimidinyl, benzothiazolyl, benzo[4,6]iminophenyl ... dazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridaz ...10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2 -Oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d] Pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H -cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3c]pridinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in this specification, the term "heteroaryl" is meant to include heteroaryl as defined above, optionally substituted with one or more substituents, such as those described herein.

[0125] The compounds of the present disclosure include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts of such compounds having the same type of activity, and active metabolites, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), stereopolymorphs, and amorphous forms of the compounds, as well as combinations thereof.

[0126] The compounds disclosed herein may exhibit their natural isotopic abundance or may be artificially enriched in one or more of the atoms with a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of this disclosure. For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3 It has three naturally occurring isotopes, designated H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating in vivo pathways of drug excretion and metabolism. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0127] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. Enantiomers are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers with at least two asymmetric atoms but that are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which asymmetric centers can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The subject chemical entities, pharmaceutical compositions, and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via appropriate methods, including, but not limited to, chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over another can be determined.

[0128] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the Z- or E-form (or cis- or trans-form). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E-, and tautomeric forms as well.

[0129] The term "substituted" refers to moieties having substituents replacing hydrogen on one or more carbon or heteroatoms of the structure. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is considered to include all permissible substituents of organic compounds. In broad aspects, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyanonitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocycle, heterocycle, cycloalkyl, heterocycloalkyl, aromatic moiety, and heteroaromatic moiety. In some embodiments, substituents can include any of the substituents described herein, such as halogen, hydroxyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -Rb -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a)2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2); where R a are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl; R a are each, as valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a)2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2); and wherein R B are each independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; R C are each straight or branched alkylene, alkenylene, or alkynylene chains.

[0130] It is understood by those skilled in the art that substituents, where appropriate, can themselves be substituted. Unless specifically designated "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0131] Where substituents are specified by their conventional chemical formula and written from left to right, they equally encompass the chemically identical substituents that result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0132] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0133] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect its intended use, including, but not limited to, the treatment of diseases as defined below. A therapeutically effective amount will vary depending on the intended therapeutic use (in vivo), or the subject and disease state being treated, e.g., the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that elicits a specific response in target cells, e.g., a decrease in platelet adhesion and / or cell migration. Specific dosage amounts will vary depending on the particular compound selected, the subsequent dosing regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0134] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit, it is meant the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic benefit may be achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that the subject experiences improvement, even though the subject may still be affected by the underlying disorder. In certain embodiments, with respect to a prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease or who reports one or more physiological symptoms of a disease, even if no diagnosis of the disease has been made.

[0135] A "therapeutic benefit," as that term is used herein, encompasses therapeutic benefits and / or prophylactic benefits, as described above. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0136] The terms "co-administration," "administered in combination with," and their grammatical equivalents encompass the administration of two or more agents to an animal, including a human, whereby the agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0137] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and / or MLL fusion protein). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target; however, specifically included within this definition are compounds that inhibit the biological activity of a target protein by interacting with other members of a signaling pathway in which the target protein is a member. A preferred biological activity inhibited by an antagonist is associated with tumor progression, growth, or spread.

[0138] The term "agonist," as used herein, refers to a compound capable of initiating or enhancing the biological function of a target protein, whether by inhibiting the activity or expression of the target protein or not. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. Preferred agonists herein specifically interact (e.g., bind) with the target, although specifically included within this definition are compounds that initiate or enhance the biological activity of a target polypeptide by interacting with other members of a signaling pathway in which the target polypeptide is a member.

[0139] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted to and within cells to induce intracellular responses. A modulator of a signal transduction pathway refers to a compound that regulates the activity of one or more cellular proteins that map to the same specific signal transduction pathway. A modulator can increase (agonist) or inhibit (antagonist) the activity of a signal transduction molecule.

[0140] "Anticancer agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in the treatment of neoplastic disease. One type of anti-cancer agent includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic and / or other agents to a subject by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of a suppository.

[0141] "Subject" refers to an animal, such as a mammal (e.g., a human). The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human. "Mammal" includes both humans and domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife.

[0142] The term "prodrug" is intended to refer to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (IV), or Formula (VI)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject but is converted in vitro, e.g., by hydrolysis, to an active compound. Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," (1987) ACS Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press). Each of these is fully incorporated herein by reference. The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of active compounds are typically prepared by modifying functional groups present in the active compound in such a way that the modifier is cleaved to the parent active compound, either by routine manipulation or in vivo, as described herein. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxy functional groups or acetamide, formamide and benzamide derivatives of amine functional groups in active compounds.

[0143] The term "in vivo" refers to events that take place in a subject's body.

[0144] The term "in vitro" refers to an event that occurs outside of a subject's body. For example, an in vitro assay includes any assay that is performed outside of a subject. An in vitro assay includes cell-based assays in which living or dead cells are utilized. An in vitro assay also includes cell-free assays in which intact cells are not utilized.

[0145] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples of when the event or circumstance occurs and examples of when it does not occur. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the description includes both substituted aryl groups and aryl groups with no substitution.

[0146] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye, coloring agent, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0147] The present disclosure provides compounds for modulating the interaction of menin with proteins such as MLL1, MLL2, and MLL-fusion oncoproteins. In certain embodiments, the present disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules, including, but not limited to, MLL1, MLL2, and MLL-fusion oncoproteins. The compounds of the present disclosure may be used in methods for treating a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL-fusion proteins, and menin, such as hematological malignancies and Ewing's sarcoma. In certain embodiments, the compounds of the present disclosure covalently bind to menin and inhibit the interaction of menin with MLL. In certain embodiments, the compounds of the present disclosure non-covalently interact with menin and inhibit the interaction of menin with MLL.

[0148] In some embodiments, the present disclosure provides compounds or salts that selectively bind to menin protein and / or modulate the interaction of menin with MLL proteins (e.g., MLL1, MLL2, or MLL fusion proteins). In certain embodiments, the compounds modulate menin protein by binding to or interacting with one or more amino acids and / or one or more metal ions. Certain compounds may occupy the F9 and / or P13 pockets of menin. Binding of the compounds disclosed herein may disrupt downstream signaling of menin or MLL (e.g., MLL1, MLL2, or MLL fusion proteins).

[0149] In certain embodiments, the present disclosure provides a compound of formula (IA):

[0150] [ka] Alternatively, a pharmaceutically acceptable salt or prodrug thereof is provided, H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; C is a 3-12 membered heterocycle; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1, L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52)2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52, -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 57 is selected from: Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R54 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, =N(R 52 ); and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is —NO, —CN, —SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52, -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, and, =N(R 52 ), each occurrence of which is substituted with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl; R 58 is hydrogen; and, C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IA), C is azetidinylene, piperidinylene, or piperazinylene; and R 57 But -S(=O)2R 58 , -S(=O)2N(R52 )2, or -NR 52 S(=O)2R 52 When: p is an integer from 1 to 6; and / or L 3 is one or more R 50 where L 3 is not -CHCH(OH)-.

[0151] In some embodiments, the compound of formula (IA) may be represented by:

[0152] [ka] etc.

[0153] [ka] where R 1 , R 2 , and R 3 are independently hydrogen and R 50 In some embodiments, R 1 is R 50 In some embodiments, R 1 is -CH2CF3, etc., C 1-3 In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52, -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R 3 is hydrogen, halogen, -OH, -N(R 52 )2, -CN, -C(O)OR 52 , C 1-3 Alkyl, and C 1-3 In some embodiments, R is selected from haloalkyl. 51 is hydrogen, etc., R 51 is selected from hydrogen and alkyl. In some embodiments, R a is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, -C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10In some embodiments, m is 0. In some embodiments, L 2 is -O-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, C 1-4 Alkylene, and C 1-4 In some embodiments, L is selected from heteroalkylene. 2 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is alkylene. 2 is one or more R 50 optionally substituted with C 1-2 In some embodiments, L is alkylene. 2 is -CH2-, -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)-. In some embodiments, L 2 is -CH-. In some embodiments, R B is present at one or more positions of the indole, such as at positions 2, 3, 4, or 6 of the indole. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , and C 1-2 alkyl, and the like. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , C 1-3 Alkyl, and optionally substituted C 1-3 In some embodiments, n is an integer from 1 to 4, such as an integer from 2 to 3. In some embodiments, n is 2. In some embodiments, L 3 is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is selected from one or more R 50 In some embodiments, L 3 is one or more R 50 optionally substituted with C 1-6 In some embodiments, L is alkylene. 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, optionally further substituted with one or more R 50 In some embodiments, L is a C alkylene substituted with 3 is =O,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkyl(cyclopropyl), C 1-3 Alkyl (NR 52 C(O)R 52 ) or -O(C 1-6 In some embodiments, L 3 is substituted with -CH3. In some embodiments, L3 teeth,

[0154] [ka] Selected from R 50 is optionally methyl. In some embodiments, C is a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is

[0155] [ka] In some embodiments, C is selected from

[0156] [ka] In some embodiments, C is selected from:

[0157] [ka] In some embodiments, C is selected from one or more R C optionally substituted with

[0158] [ka] In some embodiments, C is selected from:

[0159] [ka] where R 57 is -S(=O)R52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 ; and -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , and -NR 52 S(=O)2R 52 C substituted with one or more substituents selected from 1-10 In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, C is selected from:

[0160] [ka] In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54, -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , C 1-6 Alkyl, and -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, or -C(O)NR 53 R 54 C replaced with 1-6 In some embodiments, C is selected from:

[0161] [ka] In some embodiments, R Cis -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is united, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 In some embodiments, p is selected from an integer from 0 to 4, such as from 0 to 2. In some embodiments, p is 0. In some embodiments, R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 ; and C 1-6 Alkyl and C 2-6 alkenyl, each of which is selected from -S(=O)R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 Each occurrence of R is independently substituted with one or more substituents selected from 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , and -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, and -NR 52 S(=O)NR 53 R 54 C substituted with one or more substituents selected from 1-6 In some embodiments, R 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, R 57 is selected from —S(═O)CH 3 , —S(═O) 2CH 3 , —S(═O) 2NH 2 , —NHS(═O) 2CH 3 , and —S(═O) 2NHCH 3 .

[0162] In some embodiments, the compound of formula (IA) may be represented by:

[0163] [ka] etc.

[0164] [ka] In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52, -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , and C 1-2 alkyl, and the like. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , C 1-3 Alkyl, and optionally substituted C 1-3 In some embodiments, L is selected from alkyl. 3 is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is selected from one or more R 50 In some embodiments, L 3 is one or more R 50 optionally substituted with C 1-6 In some embodiments, L is alkylene. 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, optionally further substituted with one or more R 50 In some embodiments, L is a C alkylene substituted with 3 is =O,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkyl(cyclopropyl), C1-3 Alkyl (NR 52 C(O)R 52 ) or -O(C 1-6 In some embodiments, L 3 is substituted with -CH3. In some embodiments, L 3 teeth,

[0165] [ka] Selected from R 50 is optionally methyl. In some embodiments, C is a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is

[0166] [ka] In some embodiments, C is selected from

[0167] [ka] In some embodiments, C is selected from:

[0168] [ka] In some embodiments, C is selected from one or more R C optionally substituted with

[0169] [ka] In some embodiments, C is selected from:

[0170] [ka] where R 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 ; and -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , and -NR 52 S(=O)2R 52 C substituted with one or more substituents selected from 1-10 In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, C is selected from:

[0171] [ka] In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52, -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , C 1-6 Alkyl, and -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, or -C(O)NR 53 R 54 C replaced with 1-6 In some embodiments, C is selected from:

[0172] [ka] In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is united, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 In some embodiments, p is selected from an integer from 0 to 4, such as from 0 to 2. In some embodiments, p is 0. In some embodiments, R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 ; and C 1-6 Alkyl and C 2-6 alkenyl, each of which is selected from -S(=O)R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 Each occurrence of R is independently substituted with one or more substituents selected from 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , and -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, and -NR 52 S(=O)NR 53 R 54 C substituted with one or more substituents selected from 1-6 In some embodiments, R 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, R 57 is selected from —S(═O)CH 3 , —S(═O) 2CH 3 , —S(═O) 2NH 2 , —NHS(═O) 2CH 3 , and —S(═O) 2NHCH 3 .

[0173] In some embodiments, the compound of formula (IA) may be represented by:

[0174] [ka] etc.

[0175] [ka] In some embodiments, C is selected from 5-7 membered monocyclic heterocycles, such as piperidinyl and piperazinyl. 50 is methyl, etc., R 50 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 52 In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, R 57 is —S(═O)2CH3. In some embodiments, R 50 is methyl and R 57 is —S(═O)2CH3. In some embodiments, R 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52, -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 is methyl or -NHCH. In some embodiments, R 2 is H.

[0176] In some embodiments, the compound of formula (IA) may be represented by:

[0177] [ka] etc.

[0178] [ka] In some embodiments, C is selected from 5-7 membered monocyclic heterocycles, such as piperidinyl and piperazinyl. 50 is methyl, etc., R 50 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 52 In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, R 57 is —S(═O)2CH3. In some embodiments, R 50 is methyl and R 57is —S(═O)2CH3. In some embodiments, R 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 is methyl or -NHCH. In some embodiments, R 2 is H.

[0179] In certain embodiments, the present disclosure provides a compound of formula (IB):

[0180] [ka] or a pharmaceutically acceptable salt thereof, H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A, B, and C are 3-12 independently selected from carbocycle and 3-12 membered heterocycle; L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 is replaced by; R A , R B , and R C are R 50 or two R attached to the same or different atoms. A group, two R B group, or two R C the groups together can optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54, -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52, -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52)2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 forming a heterocycle optionally substituted with R 56 appears, -NO2, -OR 59 , -SR 52 , -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from carbocycles, and 3- to 12-membered heterocycles; R 56 Each C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is independently selected from halogen, -NO2, -CN, -OR 59 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from Furthermore, where R 56 optionally forms a single bond to Ring C; and R 59 independently, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 Carbocycles and 3- to 12-membered heterocycles, each of which may be selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; wherein for a compound or salt of formula (IB), R 56 When is -CH3, L 3is not further substituted with -OH, -NH2, or -CN.

[0181] In some embodiments, the compound of formula (IB) may be represented by:

[0182] [ka] etc.

[0183] [ka] where R 1 , R 2 , and R 3 are independently hydrogen and R 50 In some embodiments, R 1 is R 50 In some embodiments, R 1 is -CH2CF3, etc., C 1-3 In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R 3 is hydrogen, halogen, -OH, -N(R 52 )2, -CN, -C(O)OR 52 , C 1-3 Alkyl, and C 1-3 In some embodiments, R is selected from haloalkyl. 51 is hydrogen, etc., R 51 is selected from hydrogen and alkyl. In some embodiments, R a is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, -C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, m is 0. In some embodiments, L 2 is -O-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R51 )S(O)2-, -S(O)2N(R 51 )-, C 1-4 Alkylene, and C 1-4 In some embodiments, L is selected from heteroalkylene. 2 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is alkylene. 2 is one or more R 50 optionally substituted with C 1-2 In some embodiments, L is alkylene. 2 is -CH2-, -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)-. In some embodiments, L 2 is -CH-. In some embodiments, R B is present at one or more positions of the indole, such as at positions 2, 3, 4, or 6 of the indole. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR53 R 54 , and C 1-2 alkyl, and the like. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , C 1-3 Alkyl, and optionally substituted C 1-3 In some embodiments, n is an integer from 1 to 4, such as an integer from 2 to 3. In some embodiments, n is 2. In some embodiments, L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 In some embodiments, L 3 is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 In some embodiments, L 3 is C 1-6 alkylene, which is selected from one or more R 56 and optionally further substituted with one or more R 50 In some embodiments, L 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, optionally further substituted with one or more R 50 In some embodiments, L is a C alkylene substituted with 3 is =O,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkyl(cyclopropyl), C 1-3 Alkyl (NR 52 C(O)R 52 ) or -O(C 1-6 In some embodiments, L 3is substituted with -CH3. In some embodiments, L 3 teeth,

[0184] [ka] Selected from R 56 is optionally methyl. In some embodiments, C is C 3-12 In some embodiments, C is selected from a carbocycle and a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is

[0185] [ka] are selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0186] [ka] Selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0187] [ka] Selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from one or more R C optionally substituted with

[0188] [ka] Selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0189] [ka] where R 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 ; and -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , and -NR 52 S(=O)2R 52 C substituted with one or more substituents selected from 1-10 In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, C is selected from:

[0190] [ka] In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52)2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is united, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 In some embodiments, p is selected from an integer from 0 to 4, such as from 0 to 2. In some embodiments, p is 0. In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52)2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , C 1-6 Alkyl, and -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, or -C(O)NR 53 R 54 C replaced with 1-6 In some embodiments, C is selected from:

[0191] [ka] is selected from.

[0192] In some embodiments, the compound of formula (IB) may be represented by:

[0193] [ka] etc.

[0194] [ka] In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52, -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , and C 1-2 alkyl, and the like. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , C 1-3 Alkyl, and optionally substituted C 1-3 In some embodiments, L is selected from alkyl. 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 In some embodiments, L 3 is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is selected from one or more R 56 and optionally further substituted with one or more R 50 In some embodiments, L 3 is C 1-6 alkylene, which is selected from one or more R 56 and optionally further substituted with one or more R 50 In some embodiments, L 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, optionally further substituted with one or more R 50 In some embodiments, L is a C alkylene substituted with 3 is =O,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkyl(cyclopropyl), C 1-3 Alkyl (NR 52 C(O)R52 ) or -O(C 1-6 In some embodiments, L 3 is substituted with -CH3. In some embodiments, L 3 teeth,

[0195] [ka] Selected from R 56 is optionally methyl. In some embodiments, C is C 3-12 In some embodiments, C is selected from a carbocycle and a 3-12 membered heterocycle, such as a 5-12 membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from a 5-7 membered monocyclic heterocycle, an 8-10 membered fused bicyclic heterocycle, and a 7-12 membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is

[0196] [ka] are selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0197] [ka] Selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0198] [ka] Selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from one or more R C optionally substituted with

[0199] [ka] Selected from R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0200] [ka] where R 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 ; and -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , and -NR 52 S(=O)2R 52 C substituted with one or more substituents selected from 1-10 In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, 57 is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, C is selected from:

[0201] [ka] In some embodiments, R C is -C(O)R 52, -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 Alkyl, and C 1-3 haloalkyl, or two R attached to different atoms C The base is united, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 In some embodiments, p is selected from an integer from 0 to 4, such as from 0 to 2. In some embodiments, p is 0. In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , C 1-6 Alkyl, and -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, or -C(O)NR 53 R 54 C replaced with 1-6 In some embodiments, C is selected from:

[0202] [ka] is selected from.

[0203] In some embodiments, the compound of formula (IB) may be represented by:

[0204] [ka] etc.

[0205] [ka] In some embodiments, C is selected from 5-7 membered monocyclic heterocycles, such as piperidinyl and piperazinyl. 56 is methyl, etc., R 56 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 52 In some embodiments, R C is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, C is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, p is an integer from 1 to 3, such as p is 1. In some embodiments, R C is —S(═O)2CH3. In some embodiments, R 56 is methyl and R C is —S(═O)2CH3. In some embodiments, R 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 is methyl or -NHCH. In some embodiments, R 2 is H.

[0206] In some embodiments, the compound of formula (IB) may be represented by:

[0207] [ka] etc.

[0208] [ka] In some embodiments, C is selected from 5-7 membered monocyclic heterocycles, such as piperidinyl and piperazinyl. 56 is methyl, etc., R 56 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 52 In some embodiments, R C is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3, C is -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 In some embodiments, p is an integer from 1 to 3, such as p is 1. In some embodiments, R C is —S(═O)2CH3. In some embodiments, R 56 is methyl and R C is —S(═O)2CH3. In some embodiments, R 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 is methyl or -NHCH. In some embodiments, R 2 is H.

[0209] In certain embodiments, the present disclosure provides a compound of formula (II):

[0210] [ka] Alternatively, a pharmaceutically acceptable salt or prodrug thereof is provided, H is C 5-12 carbocycle and 5-12 membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; B is C 3-12 selected from carbocycles and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51)-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 optionally substituted with; R A , R B , and R C are each independently, R 50 from each occurrence, or two R A group or two R B the groups together can optionally form a bridge or a ring; m and n are each independently an integer of 0 to 6; W 1 is one or more R 50 optionally substituted with C 1-4 is alkylene; W 2 is a single bond; and one or more R 50 C optionally substituted with 1-4 alkylene; W 3 is absent; and one or more R 50 C optionally substituted with 1-4 alkylene; R 50Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54, -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 2-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 and forming a heterocycle optionally substituted with, for a compound or salt of formula (II), W 3 When does not exist: W 1 is C1 alkylene, and W 2 is a single bond, and L 3 is not a single bond; W 1 is C 2-4 alkylene, W 2 is a single bond; or W 1 and W 2 are each C1 alkylene, and L 3 is not a single bond, and wherein each C alkylene is independently one or more R 50 is optionally substituted with

[0211] In certain embodiments, the compound of formula (II) may be represented by:

[0212] [ka] etc.

[0213] [ka] where R 1 , R 2, and R 3 are independently hydrogen and R 50 In some embodiments, R 1 is R 50 In some embodiments, R 1 is -CH2CF3, etc., C 1-3 In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R 3 is hydrogen, halogen, -OH, -N(R 52 )2, -CN, -C(O)OR 52 , C 1-3Alkyl, and C 1-3 In some embodiments, R is selected from haloalkyl. 51 is hydrogen, etc., R 51 is selected from hydrogen and alkyl. In some embodiments, R a is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, -C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, m is an integer from 0 to 3. In some embodiments, m is 0. In some embodiments, L 2 -O-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, C 1-4 Alkylene, and C 1-4 In some embodiments, L is selected from heteroalkylene. 2 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is alkylene. 2 is one or more R 50 optionally substituted with C 1-2 In some embodiments, L is alkylene. 2 is -CH2-, -N(R 51)-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)-. In some embodiments, L 2 is -CH-. In some embodiments, R B is present at one or more positions of the indole, such as at positions 2, 3, 4, or 6 of the indole. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , and C 1-2 alkyl, and the like. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , C 1-3 Alkyl, and optionally substituted C 1-3 In some embodiments, n is an integer from 1 to 4, such as an integer from 2 to 3. In some embodiments, n is 2. In some embodiments, L 3 is one or more R 50optionally substituted with C 1-4 In some embodiments, L is alkylene. 3 is one or more R 50 optionally substituted with C 1-2 In some embodiments, L is alkylene. 3 is -CH2-. In some embodiments, W 1 is one or more R 50 optionally substituted with C 1-4 In some embodiments, W is alkylene. 1 is one or more R 50 optionally substituted with C 1-2 In some embodiments, W is alkylene. 1 is a C alkylene or -CH-, 1-2 In some embodiments, W is alkylene. 2 is one or more R 50 optionally substituted with C 1-4 In some embodiments, W is alkylene. 2 is one or more R 50 optionally substituted with C 1-2 In some embodiments, W is alkylene. 2 is a C alkylene or -CH-, 1-2 In some embodiments, W is alkylene. 3 In some embodiments, W 3 is one or more R 50 optionally substituted with C 1-4 In some embodiments, W is alkylene. 3 is one or more R 50 optionally substituted with C 1-2 In some embodiments, W is alkylene. 3 is a C alkylene or -CH-, 1-2 In some embodiments, R is alkylene. C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C teeth,

[0214] [ka] is selected from.

[0215] In certain embodiments, the compound of formula (II) may be represented by:

[0216] [ka] etc.

[0217] [ka] In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52, -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , and C 1-2 alkyl, and the like. B is halogen, -CN, -OR 52 , -N(R 52 )2, -NR53 R 54 , C 1-3 Alkyl, and optionally substituted C 1-3 In some embodiments, L is selected from alkyl. 3 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is alkylene. 3 is one or more R 50 optionally substituted with C 1-2 In some embodiments, L is alkylene. 3 is -CH2-. In some embodiments, W 1 is one or more R 50 optionally substituted with C 1-4 In some embodiments, W is alkylene. 1 is one or more R 50 optionally substituted with C 1-2 In some embodiments, W is alkylene. 1 is a C alkylene or -CH-, 1-2 In some embodiments, W is alkylene. 2 is one or more R 50 optionally substituted with C 1-4 In some embodiments, W is alkylene. 2 is one or more R 50 optionally substituted with C 1-2 In some embodiments, W is alkylene. 2 is a C alkylene or -CH-, 1-2 In some embodiments, W is alkylene. 3 In some embodiments, W 3 is one or more R 50 optionally substituted with C 1-4 In some embodiments, W is alkylene. 3 is one or more R 50 optionally substituted with C 1-2 In some embodiments, W is alkylene. 3 is a C alkylene or -CH-, 1-2In some embodiments, R is alkylene. C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C teeth,

[0218] [ka] is selected from.

[0219] In certain embodiments, the compound of formula (II) may be represented by:

[0220] [ka] In some embodiments, R 2 is R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 In some embodiments, R C teeth,

[0221] [ka] is selected from.

[0222] In certain embodiments, the present disclosure provides a compound of formula (III):

[0223] [ka] Alternatively, a pharmaceutically acceptable salt or prodrug thereof is provided, H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0224] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 Each of -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -C(O)-, and -C(R A1 )(R A2 )-C(O)-; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the groups is -C(O)- or -C(R A1 )(R A2 )-C(O)-; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; C is a single bond, C 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 3 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 3 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; RC is hydrogen and R 50 are independently selected for each occurrence, or two R C the groups together can optionally form a bridge or a ring; R A1 and R A2 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, p is an integer from 1 to 6; and / or R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52)2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54, -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atom to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0225] In certain embodiments, the compound of formula (III) may be represented by:

[0226] [ka] etc.

[0227] [ka] where R 1 , R 2 , and R 3 are independently hydrogen and R 50 In some embodiments, R 1 is R 50 In some embodiments, R 1 is -CH2CF3, etc., C 1-3In some embodiments, R 2 is hydrogen and R 50 In some embodiments, R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, C 1-3 Alkyl OR 52 , C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, R is selected from alkynyl. 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2 alkyl, and the like. 2 is halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R 52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl. Optionally, R 2 is selected from -NH, -CH, -OCH, -CHOH, and -NHCH. In some embodiments, R 3 is hydrogen, halogen, -OH, -N(R 52 )2, -CN, -C(O)OR 52 , C 1-3 Alkyl, and C 1-3 In some embodiments, R is selected from haloalkyl. 52 is hydrogen, etc., R 52 is selected from hydrogen and alkyl.

[0228] In some embodiments, with respect to compounds of formula (III), A is

[0229] [ka] is selected from.

[0230] In certain embodiments, the present disclosure provides a compound of formula (IV):

[0231] [ka] Alternatively, a pharmaceutically acceptable salt or prodrug thereof is provided,

[0232] [ka] is a fused thienyl or fused phenyl group; G a is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from -E 1 -R 4a and optionally one or more R 50 Further substituted with; R 2a is selected from hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, and aralkyl; R 3a and R 3b are each independently selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; X a -Y a is -N(R 52 )-C(=O)-, -C(=O)-O-, -C(=O)-N(R 52 )-, -CHN(R 52 )-CH2-, -C(=O)N(R 52 )-CH2-, -CH2CH2-N(R52 )-, -CHN(R 52 )—C(═O)—, and —CH2OCH2—; or X a and Y a does not form a chemical bond, where: X a is selected from hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, and haloalkoxy; and Y a is cyano, hydroxy, and -CHR 50 Selected from; E 1 does not exist or -C(=O)-, -C(=O)N(R 52 )-, -[C(R 14a )2] 1-5 O-, -[C(R 14a )2] 1-5 NR 52 -, -[C(R 14a )2] 1-5 -, -CH2(=O)-, and -S(=O)2-; R 4a is selected from hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; R 14a is selected from hydrogen and alkyl; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52)2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53 and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0233] In some embodiments, for compounds of formula (IV), G a is piperidinyl. In some embodiments, the compound of formula (IV) is represented by:

[0234] [ka] R 17a and R 18a are independently hydrogen and R 50 Selected from; R 24a is selected from hydrogen and fluoro.

[0235] In some embodiments, for compounds of formula (IV), R 3a and R 3b is independently selected from hydrogen and halo. a and Y a does not form a chemical bond, and X a is hydrogen. In some embodiments, R4a is selected from hydrogen; and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, aralkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl, each of which is selected from R 50 In some embodiments, R 4a is R 50 is a heterocyclo substituted with

[0236] In certain embodiments, the present disclosure provides a compound of formula (VI):

[0237] [ka] Alternatively, a pharmaceutically acceptable salt or prodrug thereof is provided, H2 is C 3-12 selected from carbocycles and 3-12 membered heterocycles; H is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 50 optionally substituted with; A is,

[0238] [ka] and; Z 1 , Z 2 , Z 3 , and Z 4 each independently represents -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2)—C(O)—, and —N═C(NH2)—; Z 1 , Z 2 , Z 3 , and Z 4 Only one of the following is -O-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-N(R 51 )-, -C(O)-, -C(R A1 )(R A2 )—C(O)— or —N═C(NH2)—; Z 5 and Z 6 is -C(R A3 )- and -N- independently selected; B is a single bond, C is 3-12 selected from carbocycles, and 3-12 membered heterocycles; L 1 , L 2 , and L 4 are each independently a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -N(R 51 )C(O)O-, -OC(O)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, -C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51)S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)-, -S(O)N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 )-; independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 , L 2 , or L 4 Either one of two R attached to the same atom or different atoms 50 the groups together can optionally form a bridge or a ring; R B is hydrogen and R 50 are independently selected for each occurrence, or two R B the groups together can optionally form a bridge or a ring; R H2 is R 50 are independently selected for each occurrence, or two R H2 the groups together can optionally form a bridge or a ring; R A1 , R A2 , and R A3 are independently hydrogen and R 50 From, selected every time it appears; n is an integer from 0 to 6, r is an integer from 1 to 6; R 50 Each time it appears, it is chosen from the following: Halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 51 Each time it appears, it is chosen from the following: Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, each of which independently is halogen, —NO, —CN, —OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 3-12 each occurrence of which is optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 Carbocycles and 3- to 12-membered heterocycles, R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring may independently be halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)NR 53 R 54 , -C(O)R 52 , -C(O)OR 52, -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C 3-12 Carbocycles and 3- to 12-membered heterocycles; R 52 appears every time hydrogen; 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted with a carbocyclic or 3- to 6-membered heterocyclic ring; and R 53and R 54 together with the nitrogen atoms to which they are attached, form one or more R 50 Forms a heterocycle optionally substituted with

[0239] In certain embodiments, the compound of formula (VI) may be represented by:

[0240] [ka] etc.

[0241] [ka] In some embodiments, L 4 is selected from -O- and -NH-. In some embodiments, Z 5 and Z 6 Each is N. In some embodiments, B is C, such as cyclohexane. 3-12 In some embodiments, B is a carbocyclic ring.

[0242] [ka] etc.

[0243] [ka] In some embodiments, H2 is one or more R H2 optionally further substituted with

[0244] [ka] In some embodiments, H2 is

[0245] [ka] In some embodiments, L 4is selected from -O- and -NH-; Z 5 and Z 6 are N, and B is

[0246] [ka] etc.

[0247] [ka] and H2 is

[0248] [ka] One or more R such as H2 optionally further substituted with

[0249] [ka] is.

[0250] In some embodiments, with respect to compounds of formula (VI), A is

[0251] [ka] is selected from.

[0252] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and their substituents may be chosen to provide stable moieties and compounds.

[0253] The chemicals described herein used in the subject methods can be synthesized according to one or more of the exemplary schemes herein and / or techniques known in the art. The materials used herein are commercially available or generally prepared by synthetic methods known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are used for illustrative purposes. Various steps are described and depicted in Scheme 1 and Examples 1-11, although in some cases the steps may be performed in an order different from that shown in Scheme 1 and Examples 1-11. Various modifications to these synthetic reaction schemes may be made and will be suggested to those of skill in the art with reference to this disclosure, which may be incorporated herein. Reference symbols or R groups in each scheme do not necessarily correspond to reference symbols or R groups in the claims or other schemes or tables herein.

[0254] Unless specified to the contrary, reactions described herein generally occur at atmospheric pressure within a temperature range of −10° C. to 200° C. Furthermore, unless otherwise specified, reaction times and conditions are intended to be approximate reaction times and conditions, e.g., reactions occur at about atmospheric pressure within a temperature range of about −10° C. to about 110° C. for about 1 hour to about 24 hours; The remaining reaction is run overnight for an average of about 16 hours.

[0255] Generally, compounds of the present disclosure used in the subject methods, including compounds of formula (IA), (IB), (II), (III), and (VI), may be prepared by the following reaction schemes:

[0256] [ka]

[0257] In some embodiments, compounds of formula 1-7 can be prepared according to Scheme 1. For example, methanesulfonyl chloride can be added to a solution of alcohol 1-1 and triethylamine to give mesylate 1-2. Addition of mesylate 1-2 to a solution of CsCO and amine 1-3 can provide compounds of formula 1-4. Coupling of 1-4 to amine 1-5 can proceed according to methods known in the art to give compounds of formula 1-6. Addition of TFA can result in the formation of R 57 A free amine can be revealed which can be optionally reacted with -LG (LG is a suitable leaving group) to produce compounds of formula 1-7.

[0258] In some embodiments, compounds of the present disclosure used in the subject methods, e.g., compounds of a formula given in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, are synthesized according to one of the general routes outlined in Scheme 1, Examples 1-11, or by methods known in the art. In some embodiments, exemplary compounds used in the subject methods can include, but are not limited to, a compound selected from Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a salt thereof.

[0259] [Table 1-1]

[0260] [Table 1-2]

[0261] [Table 1-3]

[0262] [Table 1-4]

[0263]

Table 1-5

[0264]

Table 1-6

[0265]

Table 1-7

[0266]

Table 1-8

[0267]

Table 1-9

[0268]

Table 1-10

[0269]

Table 1-11

[0270]

Table 1-12

[0271]

Table 1-13

[0272]

Table 1-14

[0273]

Table 1-15

[0274]

Table 1-16

[0275]

Table 1-17

[0276]

Table 1-18

[0277]

Table 2-1

[0278]

Table 2-2

[0279]

Table 2-3

[0280]

Table 3-1

[0281]

Table 3-2

[0282]

Table 3-3

[0283]

Table 3-4

[0284]

Table 3-5

[0285]

Table 3-6

[0286]

Table 3-7

[0287]

Table 3-8

[0288]

Table 3-9

[0289]

Table 3-10

[0290]

Table 4-1

[0291]

Table 4-2

[0292]

Table 4-3

[0293]

Table 4-4

[0294]

Table 4-5

[0295]

Table 4-6

[0296]

Table 4-7

[0297]

Table 4-8

[0298]

Table 4-9

[0299]

Table 4-10

[0300]

Table 4-11

[0301]

Table 4-12

[0302]

Table 4-13

[0303]

Table 4-14

[0304]

Table 4-15

[0305]

Table 4-16

[0306]

Table 4-17

[0307]

Table 4-18

[0308]

Table 4-19

[0309]

Table 4-20

[0310]

Table 4-21

[0311]

Table 4-22

[0312]

Table 4-23

[0313]

Table 4-24

[0314]

Table 4-25

[0315]

Table 4-26

[0316]

Table 4-27

[0317]

Table 4-28

[0318]

Table 5-1

[0319]

Table 5-2

[0320]

Table 5-3

[0321]

Table 5-4

[0322]

Table 5-5

[0323]

Table 5-6

[0324]

Table 5-7

[0325]

Table 5-8

[0326]

Table 5-9

[0327]

Table 5-10

[0328]

Table 5-11

[0329]

Table 5-12

[0330]

Table 5-13

[0331]

Table 6-1

[0332]

Table 6-2

[0333]

Table 6-3

[0334]

Table 6-4

[0335]

Table 6-5

[0336]

Table 6-6

[0337]

Table 6-7

[0338]

Table 6-8

[0339]

Table 6-9

[0340]

Table 6-10

[0341]

Table 6-11

[0342]

Table 6-12

[0343]

Table 6-13

[0344]

Table 6-14

[0345]

Table 6-15

[0346]

Table 6-16

[0347]

Table 6-17

[0348]

Table 6-18

[0349]

Table 6-19

[0350]

Table 6-20

[0351]

Table 7-1

[0352]

Table 7-2

[0353]

Table 7-3

[0354]

Table 7-4

[0355] [Table 7-5]

[0356] [Table 7-6]

[0357] [Table 7-7]

[0358] [Table 7-8]

[0359] [Table 7-9]

[0360] [Table 7-10]

[0361] Pharmaceutical Composition

[0362] The compositions and methods of the present disclosure may be used to treat individuals. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound or salt of formula (IA), formula (IB), formula (II), formula (III), formula (IV), or formula (VI) and a pharmaceutically acceptable carrier.

[0363] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In further embodiments, the pharmaceutical composition comprises a compound as disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below.

[0364] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, intravaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection, as well as intramuscular, subcutaneous, intravenous, and intramedullary injection.

[0365] In certain embodiments, compositions of compounds or salts of Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (IV), or Formula (VI) are administered locally rather than systemically, e.g., by injecting the compound directly into an organ, often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. In yet other embodiments, compounds or salts of Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (IV), or Formula (VI) are delivered in targeted drug delivery systems, e...

Claims

1. 1. A pharmaceutical composition comprising a menin inhibitor for use in a method of treating a hematological malignancy in a subject exhibiting a nucleoporin 98 (NUP98) gene fusion, said treatment comprising administering said menin inhibitor to said subject, said menin inhibitor being selected from the group consisting of compound I-151, 【Chemical 1】 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the NUP98 gene fusion is a gene fusion of NUP98 with a homeodomain partner gene.

3. 2. The pharmaceutical composition of claim 1, wherein the NUP98 gene fusion is a gene fusion of NUP98 with a non-homeodomain partner gene.

4. 2. The pharmaceutical composition of claim 1, wherein the NUP98 gene fusion is a gene fusion of NUP98 with a partner gene selected from HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23, JARID1A, NSD1, NSD3, MLL, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAP1GDS1, ADD3, DDX10, TOP1, TOP2B, LNP1, RARG, ANKRD28, and POU1F1.

5. 2. The pharmaceutical composition of claim 1, wherein the NUP98 gene fusion is a gene fusion of NUP98 with a partner gene selected from HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23, JARID1A, NSD1, NSD3, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAP1GDS1, ADD3, DDX10, TOP1, TOP2B, LNP1, RARG, ANKRD28, and POU1F1.

6. 2. The pharmaceutical composition of claim 1, wherein the subject further exhibits a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene.

7. The pharmaceutical composition according to claim 6, wherein the mutation in the DNMT3A gene is an R882 mutation.

8. 7. The pharmaceutical composition of claim 6, wherein the mutation in the DNMT3A gene is not an R882 mutation.

9. 7. The pharmaceutical composition of claim 6, wherein the mutation in the DNMT3A gene is a frameshift deletion, a missense mutation, a nonsense mutation, a splice site substitution, a splice site deletion, or a whole gene deletion.

10. 10. The pharmaceutical composition of claim 1, wherein the subject further exhibits mixed lineage leukemia (MLL) gene amplification.

11. 2. The pharmaceutical composition of claim 1, wherein the hematological malignancy is acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, mixed lineage leukemia, or myelodysplastic syndrome.

12. 2. The pharmaceutical composition of claim 1, wherein the hematological malignancy is acute myeloid leukemia.

13. 2. The pharmaceutical composition of claim 1, wherein the hematological malignancy is acute lymphocytic leukemia.

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