Substituted inhibitors of menin-MLL and methods of use thereof

Abstract

Compounds and methods for inhibiting menin interactions with MLL1, MLL2, and MLL fusion oncoproteins are provided.SOLUTION: Compounds of a specific structure having a thieno [2, 3-d] pyrimidine skeleton are provided.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] <Cross reference> This application claims the benefit of U.S. Provisional Patent Application No. 62 / 309,372, filed March 16, 2016; U.S. Provisional Patent Application No. 62 / 334,369, filed May 10, 2016; U.S. Provisional Patent Application No. 62 / 431,389, filed December 7, 2016; and U.S. Provisional Patent Application No. 62 / 446,640, filed January 16, 2017, which applications are incorporated herein by reference. [Background technology]

[0002] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase important in the epigenetic regulation of gene transcription. Many acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed-lineage leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins, which result from chromosomal translocations of the MLL gene located on chromosome 11, band q23 (11q23). Chimeric MLL fusion proteins retain the approximately 1,400 amino acids from the N-terminus of MLL but are fused to one of approximately 80 partner proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, and GAS7). MLL fusion proteins lack the native histone methyltransferase activity of the MLL C-terminus and acquire the ability to regulate the transcription of numerous oncogenes, including HOX and MEIS1, resulting in increased cell proliferation and decreased cell differentiation, ultimately leading to leukemogenesis.

[0003] Menin, encoded by the multiple endocrine neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein involved in DNA processing and interaction with repair proteins, chromatin modifying proteins, and numerous transcription factors (Agarwal, et al.; Horm Metab Res, 2005, 37(6): 369-374). Association of menin with the N-terminus of MLL fusion proteins is required for the observed oncogenic activity of MLL fusion proteins. This association has been shown to constitutively upregulate the expression of HOX and MEIS1 oncogenes, reducing hematopoietic cell proliferation and differentiation leading to leukemic progression. Because menin has been shown to function as a common co-oncogenic factor in MLL-associated leukemias, the interaction between menin, MLL fusion proteins, and MLL represents a potential chemotherapeutic target.

[0004] The prognosis for patients (especially young children) with leukemias harboring chromosomal translocations of the MLL gene is dismal, with a 5-year survival rate of less than 40% (Slany; Haematologica, 2009, 94(7): 984-993). New therapeutic strategies are urgently needed to treat these leukemias. Small molecule inhibitors that block the menin-MLL interaction are therefore valuable targets for the treatment of diseases associated with MLL fusion proteins. Summary of the Invention

[0005] The present disclosure addresses a need in the art by providing compositions and methods for inhibiting protein-protein interactions between menin and MLL1, MLL2, and MLL-fusion oncoproteins. The compositions and methods herein may be useful for treating diseases dependent on the activity of MLL1, MLL2, MLL-fusion proteins, and / or menin, such as leukemia, solid cancers, and diabetes. In some embodiments, compounds of the present disclosure interact non-covalently with menin and inhibit the interaction between menin and MLL. In some embodiments, compounds of the present disclosure bind covalently to menin and inhibit the interaction between menin and MLL.

[0006] In some embodiments of the compounds provided herein, the compounds bind non-covalently or covalently to any one or more isoforms of menin, e.g., isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO:2), or isoform 3 (SEQ ID NO:3). In certain embodiments, the menin protein shares 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO:2), or isoform 3 (SEQ ID NO:3).

[0007] In one aspect, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof:

[0008] [ka] During the ceremony, H is C 5-12 selected from carbocycles and 5- to 12-membered heterocycles, 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- to 12-membered heterocycles; B is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles; C is a 3- to 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 )-; 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 bonded 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 each independently, 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 each independently represent an integer of 0 to 6; R 50 is independent, 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)2NR 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 ); Each is independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R[[ID=X]] 54 , -S(=O)R​​​​​​​​​​​​​, -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 C optionally substituted at each occurrence 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 selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle, where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 52S(=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 optionally substituted with one or more substituents selected from alkynyl; R 51 is independent, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently represents a halogen, -NO2, -CN, or -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 C optionally substituted at each occurrence 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 selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle, where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 optionally substituted with one or more substituents selected from alkynyl; R 52 are independently 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 at each occurrence, 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 teeth, Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -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, =S, =N(R 52 ); and Each independently: -NO2, -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, =S, and =N(R 52 substituted independently at each occurrence with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl selected from; and R 58 is hydrogen; and C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 a carbocycle, and a 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 (I), 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)-.

[0009] In one aspect, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0010] [ka] During the ceremony: H is C 5-12 selected from carbocycles and 5- to 12-membered heterocycles, each of which is selected from one or more R 50 optionally substituted with; A, B, and C are each independently 3-12 selected from carbocycles and 3- to 12-membered heterocycles; 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 )-; selected from 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 one or more R 50 optionally substituted with; R A , R B , and R C are each independently, 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 each independently represent an integer of 0 to 6; R 50 is independent, 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)2NR 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 ); Each is independently 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)2NR 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 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 optionally substituted with one or more substituents selected from alkynyl; R 51 is independent, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently represents a halogen, -NO2, -CN, or -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 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one or more substituents selected from alkynyl; R 52 are independently 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 at each occurrence, 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 is independent, -NO2, -OR 59 , -SR 52 , -NR 53 R 54 , -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 , -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, C 2-10 Alkynyl, C 3-12 selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Each alkynyl is independently selected from halogen, -NO2, -CN, and -OR. 59 , -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, =O, =S, =N(R 52 ), C 3-12 optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle at each occurrence; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one or more substituents selected from alkynyl; and Furthermore, here, 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 Carbocycle and 3- to 12-membered heterocycle at each occurrence, 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 (II), R 56When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0011] In some embodiments, for compounds of Formula (II), 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 bonded to different atoms C The base is C 1-3 Crosslinks can be formed.

[0012] For compounds of Formula (I) or (II), C can be a 5-12 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.

[0013] In some embodiments, for compounds of Formula (I), C is

[0014] [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 is selected from.

[0015] In some embodiments, for compounds of Formula (II), C is

[0016] [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 -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 is selected from. 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 .

[0017] For compounds of formula (I) or (II), R C is C 1-3 Alkyl and C 1-3 It may be selected from haloalkyl.

[0018] In some embodiments, for compounds of Formula (I) or (II), 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.

[0019] For compounds of formula (I) or (II), H may be present in one or more R 50 In some embodiments, H can be a 6-12 membered bicyclic heterocycle optionally substituted with one or more R 50 In some embodiments, H is optionally substituted thienopyrimidinyl.

[0020] [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 is selected at each occurrence from; 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, 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 1-3Alkyl, -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, 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.

[0021] For compounds of formula (I) or (II), A can be a 5- to 8-membered heterocycle, such as a 6-membered monocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, A is

[0022] [ka] and the like.

[0023] For compounds of formula (I) or (II), B can be a 6- to 12-membered bicyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, B is selected from one or more R B optionally substituted with

[0024] [ka] and the like.

[0025] In some embodiments, for compounds of Formula (I) or (II), H is selected from one or more R 50 A is selected from piperidinylene and piperazinylene; and B is indolylene.

[0026] For compounds of formula (I) or (II), H may be replaced with -CH2CF3. In some embodiments, m is 0. In some embodiments, n is an integer from 1 to 3. In some embodiments, L 1 In some embodiments, L contains less than 10 atoms. 1 -N(R 51 In some embodiments, L 2 In some embodiments, L contains less than 10 atoms. 2 is one or more R 50 C optionally substituted with 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-. In some embodiments, L 3 In some embodiments, L contains less than 20 atoms. 3 is one or more R 50 C optionally substituted with 1-6 In some embodiments, L is alkylene. 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, and optionally one or more R 50 In some embodiments, L is a C alkylene further 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 1-6In some embodiments, L is substituted with 3 is substituted with -CH3. In some embodiments, the compound of formula (I) or (II) is selected from Table 1.

[0027] For compounds of formula (I), L 3 teeth,

[0028] [ka] Optionally, R 50 is methyl. In some embodiments, for compounds of formula (II), L 3 teeth,

[0029] [ka] Optionally, R 56 is methyl. In certain embodiments, the present disclosure provides a substantially pure stereoisomer of a compound of Formula (I) or (II). Optionally, the stereoisomer is provided in at least 90% enantiomeric excess.

[0030] In some embodiments, for compounds of Formula (I) or (II), H is selected from one or more R 50 A is a 3- to 12-membered heterocycle; B is a 6- to 12-membered bicyclic heterocycle; m is an integer of 0 to 3; and n is an integer of 1 to 3.

[0031] In some embodiments, for compounds of Formula (I): 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—, and —CH—; L3 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 )-; selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 3 Two R's bonded to the same or different atoms of 50 the groups together can optionally form a ring; R A , R B , and R C are each independently, R 50 or two R attached to the same or different atoms, A group, two RB group, or two R C the groups can optionally be taken together to 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 teeth, -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, -P(O)(R 52 )2; and Each independently, -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)NR53 R 54 , -P(O)(OR 52 )2, and -P(O)(R 52 )2, C is substituted at each occurrence with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl selected from; and R 58 is hydrogen; and C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 a carbocycle, and a 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 ring or a 3- to 6-membered heterocyclic ring.

[0032] In some embodiments, for compounds of Formula (II): 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—, and —CH—; 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 one or more R 50 optionally substituted with; R A , R B , and R C are each independently, R 50 or two R attached to the same or different atoms, A group, two RB group, or two R C the groups may together 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 is independent, -OR 59 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 selected at each occurrence from alkynyl, where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Each alkynyl is independently selected from halogen, -NO2, -CN, and -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 53R 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 optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle at each occurrence; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 optionally substituted with one or more substituents selected from alkynyl; and Furthermore, here, 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 Carbocycle and 3- to 12-membered heterocycle at each occurrence, 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 ring or a 3- to 6-membered heterocyclic ring.

[0033] For compounds of formula (I), R 57 is -S(=O)2R, such as -S(=O)2CH3 and -S(=O)2NHCH3 58 , -S(=O)2N(R 52 )2, and -S(=O)2NR 53 R 54 For compounds of formula (II), C may be selected from -S(=O)R 58 , -S(=O)2N(R 52 )2, or -S(=O)2NR 53 R 54 may be substituted with

[0034] In some embodiments, in compounds of Formula (I) or (II), H is

[0035] [ka] and R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52)2, -CN, C 1-3 Alkyl, 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 -NH2, -CH3, and -NHCH3. In some embodiments, for compounds of formula (I) or (II), H is

[0036] [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 alkynyl. Optionally, R 2 is selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. For compounds of formula (I) or (II), L 3 teeth,

[0037] [ka] may be selected from:

[0038] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound or salt of Formula (I) or (II) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for injection.

[0039] In certain embodiments, the present disclosure provides a method for inhibiting the interaction of menin with one or more of MLL1, MLL2, MLL fusion proteins, and MLL-partial tandem duplications, the method comprising contacting menin with an effective amount of a compound or salt of formula (I) or (II). In certain embodiments, the present disclosure provides a method for inhibiting menin-MLL interaction, the method comprising contacting menin with an effective amount of a compound or salt of formula (I) or (II), wherein inhibition of the interaction is evidenced by a decrease in expression of an MLL fusion protein target gene. In certain embodiments, the present disclosure provides a method for stabilizing menin, the method comprising contacting menin with a compound or salt of formula (I) or (II).

[0040] In practicing any of the subject methods, the MLL fusion protein target gene can be HOXA9, DLX2, or MEIS1. The contacting step can include contacting a cell that expresses menin. In some embodiments, the method includes administering a second therapeutic agent. In some embodiments, the contacting step occurs in vivo. In some embodiments, the contacting step occurs in vitro.

[0041] In certain aspects, the disclosure provides methods of treating a disease or condition associated with an MLL fusion protein, the method comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I) or (II). In certain aspects, the disclosure provides methods of treating a disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound or salt of Formula (I) or (II). In some embodiments, the disease or condition comprises leukemia, hematological malignancy, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain cancer, or diabetes. In some embodiments, the leukemia comprises AML, ALL, mixed lineage leukemia, or leukemia with partial tandem duplication.

[0042] In certain aspects, the present disclosure provides a method of treating a disorder mediated by a chromosomal rearrangement on chromosome 11q23 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or salt of Formula (I) or (II). In certain aspects, the present disclosure provides a method of treating a disorder mediated by the interaction of menin with other proteins, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of Formula (I) or (II). In some embodiments, the subject is a human.

[0043] In certain aspects, the present disclosure provides kits comprising a pharmaceutical composition described herein and instructions for using the composition to treat a subject suffering from a disease or disorder mediated by the interaction of menin with other proteins.

[0044] <incorporation by reference> All publications, patents, and 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]

[0045] 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 illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [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] Figure 1 shows the change in MV4;11 tumor volume in vehicle and compound treated mice. [Figure 5] Figure 1 shows the luminescence of MV4;11-luc tumors in a xenograft mouse model of MLL leukemia treated with vehicle and compound after 6 days of treatment. [Figure 6] FIG. 6 depicts gene expression changes for DLX2, HOXA9, MEIS1, and CD11B in bone marrow samples obtained from mice treated with vehicle and compounds as indicated in FIG. [Figure 7] 1 depicts survival curves for vehicle and compound treated mice bearing MV4;11-luc tumors. [Figure 8] 1 shows the change in MV4;11 tumor volume in vehicle- and compound V-treated mice. [Figure 9] Gene expression changes of DLX2, HOXA9, MEIS1, and CD11B in bone marrow samples obtained from vehicle and compound treated mice are shown. [Figure 10] 1 depicts survival curves for vehicle- and compound-treated mice bearing MOLM13 tumors. [Figure 11] Figure 1 shows luminescence of MV4;11-luc tumors in vehicle and compound treated xenograft mouse models of MLL leukemia after 6 days of treatment. [Figure 12] FIG. 12 depicts gene expression changes for DLX2, HOXA9, MEIS1, and CD11B in bone marrow samples obtained from mice treated with vehicle and compounds as indicated in FIG. [Figure 13] 1 depicts survival curves for vehicle- and compound-treated mice bearing MOLM13 tumors. DETAILED DESCRIPTION OF THE INVENTION

[0046] 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.

[0047] "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, 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, These include FLNA, FNBP1, FOXO3, GAS7, GMPS, KIAA1524, LAMC3, LOC100131626, MAML2, ME2, MLLT1 / ENL, MLLT10 / AF10, MLLT11 / AF1Q, MLLT3 / AF9, MLLT4 / AF6, MLLT6 / AF17, MYH11, MYO1F, NA, NEBL, NRIP3, PDS5A, PICALM, PRPF19, PTD, RUNDC3B, SEPT11, SEPT2, SEPT5, SEPT6, SEPT9, SMAP1, TET1, TNRC18, TOP3A, VAV1, and Xq26.3 (CT45A2). MLL fusion proteins can also be generated by the joining of 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.

[0048] 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-y alkenyl" and "Cx-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.

[0049] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each ring atom 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 an exemplary embodiment, 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 is included in the definition of carbocycle, as valences permit. 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.

[0050] "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.

[0051] "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]imidazolyl ... zo[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-c]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]pyridazinyl, 5,6,7,8,9,10-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-5 H-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[2,3-c]pyridinyl, 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.

[0052] The compounds of the present disclosure also include crystalline and amorphous forms of the compounds, pharmaceutically acceptable salts of said 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 said compounds, as well as combinations thereof.

[0053] The compounds described herein exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in 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 includes: 1 H (protium), 2 H (deuterium), and 3 There are three naturally occurring isotopes, represented by H (tritium). Deuterium 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 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.

[0054] "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 of unknown absolute configuration can be designated (+) 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 may 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.

[0055] Chemical entities with carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis- or trans-forms). 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.

[0056] The term "substituted" refers to moieties having substituents replacing a 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 modification, 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 a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The 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, for example, halogen, hydroxyl, carbonyl (carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, 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, for example, 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, -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 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 , -Rb -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 ), -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); 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.

[0057] It will be understood by those skilled in the art that, where appropriate, substituents can themselves be substituted. Unless specifically specified as "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.

[0058] 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-.

[0059] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well 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 base 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, substituted amines, including naturally occurring substituted amines, cyclic amines, base 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.

[0060] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect the 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 doses will vary depending on the particular compound chosen, the dosing regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system by which the compound is delivered.

[0061] 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 preventative benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. A therapeutic benefit may also 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 preventative 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.

[0062] A "therapeutic benefit," as that term is used herein, encompasses therapeutic benefit and / or prophylactic benefit, 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.

[0063] 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.

[0064] 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 proteins). 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.

[0065] 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. The term "agonist" is therefore 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 the target polypeptide by interacting with other members of a signaling pathway in which the target polypeptide is a member.

[0066] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted to and within a cell to elicit an intracellular response. 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.

[0067] "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 cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of a suppository.

[0068] "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.

[0069] "Prodrug" is meant to indicate a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Formula (I) or (II)). 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 have advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124 (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 which is incorporated herein by reference in its entirety). The term "prodrug" is also meant 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, either by routine manipulation or in vivo, to the parent active compound, as described herein. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that cleaves to form the free hydroxy, amino, or 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 the active compound, and the like.

[0070] The term "in vivo" refers to events that take place in a subject's body.

[0071] The term "in vitro" refers to events that occur outside of a subject's body. For example, an in vitro assay includes any assay 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.

[0072] "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 or may not be substituted, and that the description includes both substituted aryl groups and aryl groups with no substitution.

[0073] 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.

[0074] 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. 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 interact non-covalently with menin and inhibit the interaction of menin with MLL.

[0075] The compounds of the present disclosure may be used in methods for treating a wide variety of diseases associated with MLL1, MLL2, MLL fusion proteins, and menin. 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.

[0076] In some aspects, 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 interfere with downstream signaling of menin or MLL (e.g., MLL1, MLL2, or MLL fusion proteins).

[0077] In certain aspects, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof:

[0078] [ka] During the ceremony, H is C 5-12 selected from carbocycles and 5- to 12-membered heterocycles, 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- to 12-membered heterocycles; B is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles; C is a 3- to 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(R51 )-, -N(R 51 )S(O)N(R 51 )-; 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 bonded 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 each independently, 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 each independently represent an integer of 0 to 6; R 50 is independent, 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[[ID=二十六]] 54 、 -P(O)(OR 52 )2、 -P(O)(R 52 )2、 =O、 =S、 =N(R 52 ); Each independently is 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)2NR 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 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one or more substituents selected from alkynyl; R 51 is independent, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently represents a halogen, -NO2, -CN, or -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, =O, =S, =N(R 52 ), C 3-12 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one or more substituents selected from alkynyl; R 52 are independently 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 at each occurrence, 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 teeth, Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -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[[ID=3)]])2 = S = N(R 52 ); and each independently, -NO2, -CN, -SR 52 [[ID=4))2 - NR 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)2NR 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, =S, and =N(R 52 substituted independently at each occurrence with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl selected from; and R 58 is hydrogen; and C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 a carbocycle, and a 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 (I), 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)-.

[0079] In certain aspects, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0080] [ka] During the ceremony: H is C 5-12 selected from carbocycles and 5- to 12-membered heterocycles, each of which is selected from one or more R50 optionally substituted with; A, B, and C are each independently 3-12 selected from carbocycles and 3- to 12-membered heterocycles; 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 )-; selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 or L 2 Two R's bonded to the same or different atoms of 50the groups together can optionally form a ring; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and one or more R 50 optionally substituted with; R A , R B , and R C are each independently, 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 each independently represent an integer of 0 to 6; R 50 is independent, 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, =O, =S, =N(R 52 ); Each independently is 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)2NR 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 3-12C optionally substituted at each occurrence 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 are selected at each occurrence from where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 optionally substituted with one or more substituents selected from alkynyl; R 51 is independent, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently represents a halogen, -NO2, -CN, or -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 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 optionally substituted with one or more substituents selected from alkynyl; R 52 are independently 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 at each occurrence, 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 is independent, -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)OR52 , -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, C 2-10 Alkynyl, C 3-12 selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Each alkynyl is independently selected from halogen, -NO2, -CN, and -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(R52 )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 optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle at each occurrence; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 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, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one or more substituents selected from alkynyl; and Furthermore, here, 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 Carbocycle and 3- to 12-membered heterocycle at each occurrence, 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 (II), R 56 When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0081] In certain aspects, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof:

[0082] [ka] During the ceremony, H is C 5-12selected from carbocycles and 5- to 12-membered heterocycles, 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- to 12-membered heterocycles; B is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles; C is a 3- to 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)-; 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 bonded 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 each independently, 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 each independently represent an integer of 0 to 6; R 50 is independent, 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 ); Each is independently halogen, -NO2, -CN, -OR 52 、 -SR 52 、 -N(R 52 )2、 -NR 53 [[ID=⑤5]]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)2NR<� 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 (注:原文中“<� 53 ”疑似有误,按照规则保留原样未修改。)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 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one substituent selected from alkynyl; R 51 is independent, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently represents a halogen, -NO2, -CN, or -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 C optionally substituted at each occurrence 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 3-12Carbocycles and 3- to 12-membered heterocycles are selected at each occurrence from where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one substituent selected from alkynyl; R 52 are independently 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 at each occurrence, 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 teeth, Halogen, -NO2, -CN, -SR 52 , -NR 53 R 54 , -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(ONR 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 Each independently: -NO2, -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, -NR52 C(O)NR 53 R 54 , -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 ), -NR 52 P(O)(R53), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =S, and =N(R 52 ) C, substituted at each occurrence with one or more substituents selected from 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl selected from; and R 58 is hydrogen; and C 1-20 Alkyl, C 3-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 a carbocycle, and a 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 (I), 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)-.

[0083] In certain aspects, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0084] [ka] During the ceremony: H is C 5-12 selected from carbocycles and 5- to 12-membered heterocycles, each of which is selected from one or more R 50 optionally substituted with; A, B, and C are each independently 3-12 selected from carbocycles and 3- to 12-membered heterocycles; 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)-; selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R 50 where L 1 or L 2 Two R's bonded to the same or different atoms of 50 the groups together can optionally form a ring; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is selected from one or more R 56 and one or more R 50 optionally substituted with; R A , R B , and R C are each independently, 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 each independently represent an integer of 0 to 6; R 50 is independent, 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[[ID=�3]] 52 )2, -P(O)(OR 52 [[ID=ģ6]])(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 ); Each is independently 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)2NR<| 53 R<| 54 , -C(O)R<| 52 , -C(O)OR<| 52 , -OC(O)R<| 52 , -OC(O)OR<| 52 , -OC(O)N(R<| 52 It should be noted that there are some unclear or potentially incorrect tags in the original text (such as <| 52 , <| 52 , <| 53 , <| 54 , <| 54 , <| 52 , <| 54 , <| 52 , <| 52 , <| 52 , <| 52 , <| 52 which might be misformatted). This translation is done based on the best understanding of the original text with the given rules.)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 C optionally substituted at each occurrence 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 are selected at each occurrence from where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 optionally substituted with one substituent selected from alkynyl; R 51 is independent, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently, 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)2NR 53 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​C optionally substituted at each occurrence 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 are selected at each occurrence from where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted with one substituent selected from alkynyl; R 52 are independently 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 at each occurrence, 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 is independent, -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 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 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected at each occurrence from a carbocycle, and a 3- to 12-membered heterocycle; where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Each alkynyl is independently selected from halogen, -NO2, -CN, and -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 optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle at each occurrence; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring each independently represent a 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, -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 optionally substituted with one substituent selected from alkynyl; and Furthermore, here, R 56optionally 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 Carbocycle and 3- to 12-membered heterocycle at each occurrence, 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 (II), R 56 When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0085] In some embodiments, for compounds of Formula (I) or (II), H is selected from one or more R 50 In some embodiments, H is a 5- to 12-membered heterocycle, such as a 6- to 12-membered bicyclic heterocycle optionally substituted with R. In some embodiments, H contains one or more heteroatoms, such as 1, 2, 3, 4, 5, or 6 ring heteroatoms. In some embodiments, H contains at least 1, 2, 3, 4, or 5 ring nitrogen atoms. ... one, two, three, four, or five ring nitrogen atoms. In some embodiments, H is a 5- to 12-membered heterocycle, such as a 6- to 12-membered bicyclic heterocycle optionally substituted with R. 50 In some embodiments, H is optionally substituted with C, such as —CHCF. 1-4 In some embodiments, H is substituted with one or more R 50 (e.g., R 50 (by replacing a hydrogen atom connected to a ring atom by a single bond to R). H may be 0, 1, 2, 3, 4, 5, or 6 or more R 50 H may be substituted with one or two R groups. 50 1, 2, 3, 4, 5, or 6 R, such as H substituted with a group 50 In some embodiments, H can be substituted with at least 1, 2, 3, 4, 5, or 6 R groups. 50In some embodiments, H is substituted with up to 6, 5, 4, 3, 2, or 1 R 50 The group is substituted.

[0086] In some embodiments, for compounds of formula (I) or (II), H is

[0087] [ka] where 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 is selected at each occurrence from; 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 alkynyl, e.g., R 2 -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, and C 1-2In some embodiments, R 2 is methyl or -NHCH. In some embodiments, R 2 is H. In some embodiments, X 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, Y is selected from haloalkyl. 1 is S. In some embodiments, Y 1 and Y 2 At least one of these is N, NR 4 , O, and S. In some embodiments, R 1 is C such as -CH2CF3 1-3 In some embodiments, X is haloalkyl. 1 is CR 2 and X 2 is N and X 3 and X 4 are C and Y respectively. 1 is S and Y 2 is CR 3 and R 1 is R 50 In some embodiments, X 1 is CR 2 and X 2 is N;X 3 and X 4 are C and Y respectively. 1 is S;Y 2 is CH;R 1 is C 1-3 haloalkyl; and R 2 is hydrogen, halogen, -OH, -OR 52 , -NH2, -N(R 52 )2, -CN, C 1-3 Alkyl, -CH2OH, -CH2OR 52 , -CH2NH2, -CH2N(R52 )2, C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 In some embodiments, H is selected from alkynyl.

[0088] [ka] In some embodiments, H is

[0089] [ka] etc.

[0090] [ka] In some embodiments, H is

[0091] [ka] and R 2 is hydrogen, halogen, -OH, -OR 52 , -NH, -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 hydrogen, halogen, -OH, alkoxy (e.g., -OR 52 , -OCH3, -OCH2CH3), aminoalkyl, alkylamino, -N(R 52 )2 (e.g., -NH2, -NHCH3, -NHCH2CH3), -N(CH3)2, -CN, C 1-3Alkyl (e.g. -CH3), cyclopropyl, C 1-3 Alkyl-OR 52 (e.g., -CH2OH, -CH2OC(O)CH3), C 1-3 Alkyl-N(R 52 )2, C 1-3 Haloalkyl, C 2-3 Alkenyl, and C 2-3 alkynyl.

[0092] In some embodiments, for compounds of formula (I) or (II), H is

[0093] [ka] and R 1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, and haloalkyl, such as from alkyl and haloalkyl; R 2 is selected from H, halo, hydroxyl, and amino, such as from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino; and Y 1 and Y 2 Each of these is S, CR 3 , N, NR 4 and O. In certain embodiments, Y 1 and Y 2 At most one of is O or S.

[0094] In some embodiments, for compounds of Formula (I) or (II), L 1 In some embodiments, L contains fewer than 20 atoms, such as fewer than 10 atoms. 1 In some embodiments, L contains less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. 1In some embodiments, L contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. 1 contains at least one heteroatom, e.g., L 1 contains at least one nitrogen. In some embodiments, L 1 is one or more R 50 In some embodiments, L 1 is unsubstituted. In some embodiments, L 1 represents a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 In some embodiments, L is selected from alkylene, alkenylene, heteroalkenylene, and heteroalkenylene. 1 represents a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, C 1-6 Alkylene, and C 2-6 alkenylene, wherein C 1-6 Alkylene and C 2-6 Each alkenylene independently represents one or more R 50In some embodiments, L 1 is -N(R) such as -NH- 51 In some embodiments, L 1 is -O-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -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, C 2-4 Alkenylene, and C 1-4 In some embodiments, L is selected from heteroalkylene. 1 -N(R 51 )-, where R 51 is selected from hydrogen and alkyl.

[0095] In some embodiments, for compounds of Formula (I) or (II), A is a 3- to 12-membered heterocycle, such as 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 contains at least one ring nitrogen. In some embodiments, A is

[0096] [ka] In some embodiments, A is selected from piperidinylenes and piperazinylenes such as

[0097] [ka] In some embodiments, A is an aromatic, non-aromatic, saturated, or unsaturated ring. In some embodiments, A is selected from arylene, cycloalkylene, heterocycloalkylene, N-heterocycloalkylene, heteroarylene, and N-heteroarylene. In some embodiments, A is a 5-8 membered heterocycle, wherein the heterocycle contains at least 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S.

[0098] In some embodiments, A is

[0099] [ka] is selected from.

[0100] In some embodiments, A is substituted with one or more R A (e.g., by replacing a hydrogen attached to a ring atom by a single bond to R A). A is 0, 1, 2, 3, 4, 5, or 6 or more R A A may be substituted with one or two R groups. A 1, 2, 3, 4, 5, or 6 R, such as A substituted with a group A In some embodiments, A may be substituted with at least 1, 2, 3, 4, 5, or 6 R A In some embodiments, A is substituted with m R groups. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with m R groups. A group, and m is an integer from 0 to 6. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is at least 1, 2, 3, 4, 5, or 6. In some embodiments, m is at most 6, 5, 4, 3, 2, or 1. In some embodiments, m is 0.

[0101] In some embodiments, R ais independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. In some embodiments, two R attached to the same atom or different atoms A The groups can be joined to form a ring.

[0102] In some embodiments, for compounds of Formula (I) or (II), L 2 In some embodiments, L contains fewer than 20 atoms, such as fewer than 10 atoms. 2 In some embodiments, L contains less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. 2 In some embodiments, L contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. 2 contains at least one heteroatom, e.g., L 2 contains at least one nitrogen. In some embodiments, L 2 is one or more R 50 C optionally substituted with 1-4 Alkylene, etc., C 1-10 In some embodiments, L is alkylene. 2 is one or more R 50 In some embodiments, L 2 is unsubstituted. In some embodiments, L 2represents a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 In some embodiments, L is selected from alkylene, alkenylene, heteroalkenylene, and heteroalkenylene. 2 represents a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, C 1-6 Alkylene, and C 2-6 alkenylene, wherein C 1-6 Alkylene and C 2-6 Each alkenylene independently represents one or more R 50 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 -CH2-, -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)2-. In some embodiments, L 2 is -CH2-.

[0103] In some embodiments, for compounds of Formula (I) or (II), B is a 3- to 12-membered heterocycle, such as a 6- to 12-membered bicyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, B is a 6- to 12-membered heterocycle, wherein the heterocycle contains at least 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, B is a 6,5- or 6,6-bicyclic heterocycle. In some embodiments, B contains at least one ring nitrogen. In some embodiments, B is selected from one or more R B optionally substituted with

[0104] [ka] In some embodiments, B is an indolylene such as

[0105] [ka] etc.

[0106] [ka] is.

[0107] In some embodiments, B is

[0108] [ka] where Z is selected from 1 , Z 2 , Z 3, and Z 4 are each independently, CR 7 , N, and NR 9 Selected from Z 5 is selected from C and N; Z 6 , Z 7 , and Z 8 are each independently, CR 8 , N, NR 9 , O, and S; Z 9 , Z 10 , and Z 11 are each independently, CR 10 , C.R. 11 R 12 , N.R. 13 , O, and S; R 7 , R 8 , R 10 , R 11 , and R 12 are independently hydrogen and R 50 and R 9 and R 13 are each independently R 51 wherein B is selected from L at any ring atom 2 or L 3 (e.g., L 2 or L 3 by replacing a hydrogen attached to a ring atom by a single bond to

[0109] In some embodiments, B is

[0110] [ka]

[0111] [ka] is selected from.

[0112] In some embodiments, B is one or more R BB is substituted with 0, 1, 2, 3, 4, 5, or 6 or more R B B may be substituted with one or two R B 1, 2, 3, 4, 5, or 6 R, such as B substituted with a group B In some embodiments, B may be substituted with at least 1, 2, 3, 4, 5, or 6 R B In some embodiments, B is substituted with n R groups. B group, where n is an integer from 0 to 6. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is at least 1, 2, 3, 4, 5, or 6. In some embodiments, n is at most 6, 5, 4, 3, 2, or 1. In some embodiments, n is an integer from 1 to 3.

[0113] In some embodiments, R B is independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. Bis independently selected at each occurrence from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl, and heteroarylalkyl. In some embodiments, two R attached to the same atom or different atoms are B The groups can be joined to form a ring.

[0114] In some embodiments, for compounds of Formula (II), L 3 In some embodiments, L contains fewer than 30 atoms, such as fewer than 20 atoms. 3 In some embodiments, L contains less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. 3 In some embodiments, L contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. 3 contains at least one heteroatom, e.g., L 3 contains at least one nitrogen. In some embodiments, L 3 is one or more R 50 C optionally substituted with 1-4 Alkylene, etc., C 1-10 In some embodiments, L is alkylene. 3 is one or more R 50 In some embodiments, L 3 is unsubstituted. In some embodiments, L 3 represents a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R51 )S(O)2N(R 51 In some embodiments, L is selected from alkylene, alkenylene, heteroalkenylene, and heteroalkenylene. 3 is one or more R 50 C optionally substituted with 1-6 alkylene, where R 50 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 52 In some embodiments, L 3 is -CH2CH(R such as -CH2CH(CH3)- 50 In some embodiments, L 3 Two R's bonded to the same or different atoms of 50 The group optionally forms a bridge or a ring, such as a cyclopropyl ring. 3 is R 50 where R 50 forms a single bond to Ring C. In some embodiments, L 3 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 52 In some embodiments, L is substituted with one or more groups selected from 3 is substituted with -CH3. In some embodiments, L 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, and optionally one or more R 50 In some embodiments, L is a C alkylene further 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 alkyl).

[0115] In some embodiments, for compounds of Formula (I), L 3 teeth,

[0116] [ka] Optionally, R 50 is methyl. 3 teeth

[0117] [ka] In some embodiments, L 3 teeth

[0118] [ka] In some embodiments, L 3 teeth

[0119] [ka] In some embodiments, L 3 contains a stereocenter. In some embodiments, the stereocenter is in the R configuration. In some embodiments, the stereocenter is in the S configuration. In some embodiments, L 3 The R-isomer of L is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the S-isomer. 3 The S-isomer of is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the R-isomer.

[0120] In some embodiments, for compounds of Formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 and L 3 is one or more R 50 where L 3 is not —CHCH(OH)—. In some embodiments, C is azetidinylene, piperidinylene, or piperazinylene; R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 and L 3 is C 1-4 Alkyl or C 1-4 Substituted with haloalkyl.

[0121] In some embodiments, for compounds of Formula (I), L 3 teeth,

[0122] [ka] and any combination thereof. In some embodiments, for compounds of formula (I), L 3 teeth,

[0123] [ka] is selected from.

[0124] In some embodiments, for compounds of Formula (II), L 3 In some embodiments, L contains fewer than 30 atoms, such as fewer than 20 atoms. 3 In some embodiments, L contains less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. 3In some embodiments, L contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. 3 is one or more R 56 and one or more R 50 C optionally substituted with 1-4 C, such as alkylene 1-10 In some embodiments, L is alkylene. 3 is one or more R 50 In some embodiments, L 3 is R 56 In some embodiments, L 3 is selected from alkylene and alkenylene. 3 is one or more R 56 C replaced by 1-6 alkylene, where R 56 is deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 59 In some embodiments, L 3 is R 56 C replaced by 1-4 alkylene, where R 56 forms a single bond to Ring C. In some embodiments, L 3 is -CH2CH(R such as -CH2CH(CH3)- 56 In some embodiments, L 3 Two R's bonded to the same or different atoms of 56 The group optionally forms a bridge or a ring, such as a cyclopropyl ring. 3 is R 56 where R 56 forms a single bond to Ring C. In some embodiments, L 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, and -OR 59 In some embodiments, L is substituted with one or more groups selected from 3 is substituted with -CH3. In some embodiments, L3 is substituted with -CH3 and further R 50 optionally substituted with C 1-4 alkylene, where R 50 is not —OH, —NH, or —CN. 3 has at least one C 1-3 Alkyl or C 1-3 haloalkyl, and optionally one or more R 50 In some embodiments, L is a C alkylene further 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 alkyl).

[0125] In some embodiments, with respect to compounds of formula (II), L 3 teeth,

[0126] [ka] Optionally, R 56 is methyl. 3 teeth,

[0127] [ka] In some embodiments, L 3 teeth,

[0128] [ka] In some embodiments, L 3 teeth,

[0129] [ka] In some embodiments, L 3 contains a stereocenter. In some embodiments, the stereocenter is in the R configuration. In some embodiments, the stereocenter is in the S configuration. In some embodiments, L 3 The R isomer of is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the S isomer. 3 The S isomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% excess over the R isomer. In some embodiments, with respect to compounds of formula (II), L 3 teeth,

[0130] [ka] and combinations thereof. In some embodiments, with respect to compounds of formula (II), L 3 teeth,

[0131] [ka] is selected from.

[0132] In some embodiments, with respect to compounds of Formula (I), 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

[0133] [ka] In some embodiments, C is selected from piperidinyl and piperazinyl, such as

[0134] [ka] In some embodiments, C is selected from:

[0135] [ka] In some embodiments, C is selected from one or more R C optionally substituted with

[0136] [ka] In some embodiments, C is selected from:

[0137] [ka] is selected from, 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 57is 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 is selected from.

[0138] In some embodiments, with respect to compounds of formula (I), C is

[0139] [ka] is selected from.

[0140] In some embodiments, with respect to compounds of formula (I), 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)NR 53 R 54, -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 In some embodiments, R is independently substituted at each occurrence 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 .

[0141] In some embodiments, with respect to compounds of Formula (I) or (II), C is a ring atom (e.g., a ring atom bonded to a hydrogen atom connected to R C by replacing a single bond to one or more R CC is substituted with 0, 1, 2, 3, 4, 5, 6 or more R C C may be substituted with one or two R groups. C 1, 2, 3, 4, 5, or 6 R groups, such as substituted C In some embodiments, C can be substituted with at least 1, 2, 3, 4, 5, or 6 R groups. C In some embodiments, C is substituted with a group. In some embodiments, C is unsubstituted. In some embodiments, C is substituted with a group. B group, where p is an integer from 0 to 6. In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, p is at least 1, 2, 3, 4, 5, or 6. In some embodiments, p is at most 6, 5, 4, 3, 2, or 1. In some embodiments, p is 0. In some embodiments, p is 1 or 2. In some embodiments, with respect to compounds of Formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 and p is an integer from 1 to 6.

[0142] 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 bases are together, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3haloalkyl.

[0143] In some embodiments, for compounds of formula (II), 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

[0144] [ka] piperidinyl and piperazinyl, such as, where R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0145] [ka] is selected from, where R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0146] [ka] is selected from, where R 57 is hydrogen and R 50 In some embodiments, C is selected from one or more R C optionally substituted with

[0147] [ka] is selected from, where R 57 is hydrogen and R 50In some embodiments, C is selected from:

[0148] [ka] is selected from, 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 is selected from.

[0149] In some embodiments, with respect to compounds of formula (II), C is

[0150] [ka] is selected from.

[0151] In some embodiments, with respect to compounds of formula (I) or (II), R C teeth, Halogen, -OR 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; and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which is selected from 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, =O, =S, =N(R 52 ), C 3-12 optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3-12 membered heterocycle; where R C C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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)NR53 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 independently with one or more substituents selected from:

[0152] 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 54In 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, and -C(O)NR 53 R 54 C replaced with 1-6 alkyl.

[0153] In some embodiments, C is

[0154] [ka] is selected from.

[0155] In some embodiments, with respect to compounds of formula (I) or (II), H is selected from one or more R 50 A is a 5-12 membered heterocycle optionally substituted with; A is a 3-12 membered heterocycle; and B is a 3-12 membered heterocycle. In some embodiments, H is selected from the group consisting of one or more R 50 A is a 6-12 membered bicyclic heterocycle optionally substituted with A; A is a 3-12 membered heterocycle; and B is a 3-12 membered heterocycle. In some embodiments, H is selected from the group consisting of one or more R 50 A is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R 50 A is a 5-12 membered heterocycle optionally substituted with A; A is a 3-12 membered heterocycle; and B is a 6-12 membered bicyclic heterocycle. In some embodiments, H is selected from the group consisting of one or more R 50 In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R 50 A is a 5-12 membered heterocycle optionally substituted with one or more R 50 A is a 5-12 membered heterocycle optionally substituted with; A is a 3-12 membered heterocycle; and B is indolylene. In some embodiments, H is selected from the group consisting of one or more R 50 A is selected from piperidinylene and piperazinylene; and B is indolylene.

[0156] In some embodiments, with respect to compounds of formula (I) or (II), H is selected from one or more R 50 A is a 5-12 membered heterocycle optionally substituted with; A is a 3-12 membered heterocycle; B is a 3-12 membered heterocycle; C is a 3-12 membered heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3. In some embodiments, H is selected from the group consisting of one or more R 50In some embodiments, H is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R 50 A is a 5-12 membered heterocycle optionally substituted with; A is a 3-12 membered heterocycle; B is a 3-12 membered heterocycle; and C is a 3-12 membered heterocycle. In some embodiments, H is selected from the group consisting of one or more R 50 A is a 6-12 membered bicyclic heterocycle optionally substituted with; A is a 3-12 membered heterocycle; B is a 6-12 membered bicyclic heterocycle; and C is a 3-12 membered heterocycle. In some embodiments, H is selected from the group consisting of one or more R 50 A is a 6-12 membered bicyclic heterocycle optionally substituted with one or more R 50 A is selected from piperidinylene and piperazinylene; B is a 6-12 membered bicyclic heterocycle optionally substituted with m; m is an integer from 0 to 3; and n is an integer from 1 to 3. In some embodiments, H is selected from one or more R 50 In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R 50 In some embodiments, H is thienopyrimidinyl optionally substituted with one or more R 50 In some embodiments, H is a 9-10 membered bicyclic heterocycle optionally substituted with one or more R 50A is a 9-10 membered bicyclic heterocycle optionally substituted with; A is a 5-7 membered heterocycle; B is a 9 membered bicyclic heterocycle; and n is an integer from 1 to 3, wherein each of said heterocycles contains at least one nitrogen atom.

[0157] In some embodiments, with respect to compounds of formula (I), L 1 contains less than 10 atoms, and L 2 contains less than 10 atoms, and L 3 contains less than 20 atoms. In some embodiments, L 1 , L 2 and L 3 Each of L includes at least one atom, such as at least two atoms. 1 , L 2 and L 3 are a single bond, -O-, -S-, and -N(R 51 ), -N(R 51 )CH2-, -C(O), -C(O)O, -OC(O), -C(O)N(R 51 ), -N(R 51 )C(O), -N(R 51 )C(O)N(R 51 ), -S(O)2, -S(O), -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene. In some embodiments, L 1 , L 2 and L 3 are -CH2-, -CH2CH2-, -CH2CH(CH3)-, and -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)-. In some embodiments, L 1 -O-, S-, -N(R 51 ), -N(R 51)CH2-, -C(O), -C(O)O, -OC(O), -C(O)N(R 51 ), -N(R 51 )C(O), -N(R 51 )C(O)N(R 51 ), -S(O)2, -S(O), -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; and L 2 and L 3 is one or more R 50 optionally substituted with C 1-4 In some embodiments, L is independently selected from alkylene. 1 , L 2 and L 3 are -O-, -S-, and -N(R 51 );C 1-4 alkylene and 1-4 membered heteroalkylene, each of which is independently selected from one or more R 50 In some embodiments, L 1 is -NH, and L 2 is -CH2-, and L 3 is one or more R 50 optionally substituted with C 1-4 It is alkylene.

[0158] In some embodiments, with respect to compounds of formula (II), L 1 contains less than 10 atoms, and L 2 contains less than 10 atoms, and L 3 contains less than 20 atoms. In some embodiments, L 1 , L 2 and L 3 Each of L includes at least one atom, such as at least two atoms. 1 and L 2 are a single bond, -O-, -S-, and -N(R 51 ), -N(R 51)CH2-, -C(O), -C(O)O, -OC(O), -C(O)N(R 51 ), -N(R 51 )C(O), -N(R 51 )C(O)N(R 51 ), -S(O)2, -S(O), -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; L 3 is one or more R 56 and optionally further substituted with one or more R 50 Replaced by C 1-10 Alkylene and C 2-10 In some embodiments, L is selected from the group consisting of alkyl, alkynylene ... 1 and L 2 are -CH2- and -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)2-, and L 3 is one or more R 56 and optionally further substituted with one or more R 50 Replaced by C 1-10 Alkylene and C 2-10 In some embodiments, L is selected from the group consisting of alkyl, alkynylene ... 1 -O-, S-, -N(R 51 ), -N(R 51 )CH2-, -C(O), -C(O)O, -OC(O), -C(O)N(R 51 ), -N(R 51 )C(O), -N(R 51 )C(O)N(R 51 ), -S(O)2, -S(O), -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; L2 is one or more R 50 optionally substituted with C 1-4 alkylene, and L 3 is one or more R 56 and optionally further substituted with one or more R 50 Replaced by C 1-4 In some embodiments, L is alkylene. 1 and L 2 are -O-, -S-, and -N(R 51 );C 1-4 alkylene and 1-4 membered heteroalkylene, each of which is independently selected from one or more R 50 optionally substituted with L 3 is one or more R 56 and optionally further substituted with one or more R 50 Replaced by C 1-4 In some embodiments, L is alkylene. 1 is -NH, and L 2 is -CH2-, and L 3 is one or more R 56 and optionally further substituted with one or more R 50 Replaced by C 1-4 It is alkylene.

[0159] In certain embodiments, with respect to compounds of formula (I): H is one or more R 50 a 5-12 membered bicyclic heterocycle optionally substituted with A, B, and C are each independently selected from a 3- to 12-membered heterocycle; L 1 , L 2 and L 3 are single bonds, -O-, -S, and -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 ring; R A , R B and R C are R 50 or two R attached to the same or different atoms, independently selected at each occurrence from 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 50 teeth, 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)2NR 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 ); each being independently 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, =O, =S, =N(R 52 ), C 3-12 C optionally substituted with one or more substituents independently at each occurrence 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 independently selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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)2NR53 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 optionally substituted independently with one or more substituents selected from alkynyl; R 51 teeth, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each of them is 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, =O, =S, =N(R 52 ), C 3-12 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle and 3-12 membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 independently selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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 optionally substituted independently with one or more substituents selected from alkynyl; R 52 is hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12and a 3- to 12-membered heterocycle, each of which is independently selected at each occurrence from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted by a carbocyclic or 3-6 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 teeth, -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, -P(O)(R 52 )2; and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which 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, -NR52 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 ) is substituted independently at each occurrence with one or more substituents selected from: 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 with respect to the compounds or salts of formula (I), 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)-.

[0160] In a particular embodiment, with respect to compounds of formula (II): H is one or more R 50 a 5-12 membered bicyclic heterocycle optionally substituted with A, B, and C are each independently selected from a 3- to 12-membered heterocycle; L 1 and L 2 are single bonds, -O-, -S, and -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 or L 2 Two R's attached to the same or different atoms of 50 The groups together can optionally form a ring; L 3 is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6alkynylene, 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, independently selected at each occurrence from 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 50 teeth, 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, -NR52 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 ); each independently being 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)2NR 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 3-12C optionally substituted with one or more substituents independently at each occurrence 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 independently selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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(R52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted independently with one or more substituents selected from alkynyl; R 51 teeth, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each of them is 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)(OR52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle and 3-12 membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 independently selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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 53R 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 optionally substituted independently with one or more substituents selected from alkynyl; R 52 is hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 and a 3- to 12-membered heterocycle, each of which is independently selected at each occurrence from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted by a carbocyclic or 3-6 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 teeth, -OR 59 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 independently selected at each occurrence from alkynyl, where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is 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 , -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, =O, =S, =N(R 52 ), C 3-12 optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3-12 membered heterocycle; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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)NR53 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; and Furthermore, here R 56 optionally forms a single bond to ring C; and R 59 is C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 and a 3- to 12-membered heterocycle, each of which is independently 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, with respect to a compound or salt of formula (II), R 56 When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0161] In certain embodiments, with respect to compounds of formula (I): 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-, and -CH2-; L 3 is 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, independently selected at each occurrence from 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 teeth, -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, -P(O)(R 52 )2; and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10alkynyl, each of which 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 1-6 alkyl), -C(O)NR 53 R 54 , -P(O)(OR 52 )2, and -P(O)(R 52 ) is substituted independently at each occurrence with one or more substituents selected from: 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 with respect to the compounds or salts of formula (I), 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 50where L 3 is not -CHCH(OH)-.

[0162] In certain embodiments, with respect to compounds of formula (I): 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-, and -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, independently selected at each occurrence from 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 teeth, -OR 59 , =O, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 independently selected at each occurrence from alkynyl, where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is a halogen, -NO2, -CN, -OR59 , -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 optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3-12 membered heterocycle; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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; and Furthermore, here R 56 optionally forms a single bond to ring C; and R 59 is C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12and a 3- to 12-membered heterocycle, each of which is independently 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, with respect to a compound or salt of formula (II), R 56 When is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0163] In certain embodiments, the compound of formula (I) is

[0164] [ka] etc.

[0165] [ka] 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 1-2alkyl, 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 is selected from 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(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 But 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, L 3 teeth,

[0166] [ka] is selected from, where 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

[0167] [ka] In some embodiments, C is selected from piperidinyl and piperazinyl, such as

[0168] [ka] In some embodiments, C is selected from:

[0169] [ka] In some embodiments, C is selected from one or more R C optionally substituted with

[0170] [ka] In some embodiments, C is selected from:

[0171] [ka] is selected from, where R 57 is -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 ; 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:

[0172] [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, and -C(O)NR 53 R 54 C replaced with 1-6 alkyl.

[0173] In some embodiments, C is

[0174] [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 bases are together, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 haloalkyl. In some embodiments, p is selected from the integers 0 to 4, such as p is selected from the integers 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)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54In some embodiments, R is independently substituted at each occurrence 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 .

[0175] In certain embodiments, the compound of formula (I) is

[0176] [ka] etc.

[0177] [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 R54 , =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 But 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), 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,

[0178] [ka] is selected from, where 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

[0179] [ka] In some embodiments, C is selected from piperidinyl and piperazinyl, such as

[0180] [ka] In some embodiments, C is selected from:

[0181] [ka] In some embodiments, C is selected from one or more R C optionally substituted with

[0182] [ka] In some embodiments, C is selected from:

[0183] [ka] is selected from, 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:

[0184] [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)NR53 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, and -C(O)NR 53 R 54 C replaced with 1-6 In some embodiments, C is selected from:

[0185] [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 bases are together, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 haloalkyl. In some embodiments, p is selected from the integers 0 to 4, such as p is selected from the integers 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, -NR52 S(=O)NR 53 R 54 , -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 In some embodiments, R is independently substituted at each occurrence 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 .

[0186] In certain embodiments, the compound of formula (I) is

[0187] [ka] etc.

[0188] [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 C2-3 In some embodiments, R is selected from alkynyl. 2 is methyl or -NHCH. In some embodiments, R 2 is H.

[0189] In certain embodiments, the compound of formula (I) is

[0190] [ka] etc.

[0191] [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. 2is 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.

[0192] In certain embodiments, the compound of formula (II) is

[0193] [ka] etc.

[0194] [ka] 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 is selected from 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 C 1-10Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 In some embodiments, R is selected from alkynyl. B But 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 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 1-6Haloalkyl, 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,

[0195] [ka] is selected from, where 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] piperidinyl and piperazinyl, such as, where R 57 is hydrogen and R 50 In some embodiments, C is selected from:

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

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

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

[0200] [ka] is selected from, 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 bases are together, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 haloalkyl. In some embodiments, p is selected from the integers 0 to 4, such as p is selected from the integers 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 52S(=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, and -C(O)NR 53 R 54 C replaced with 1-6 alkyl.

[0202] In some embodiments, C is

[0203] [ka] is selected from.

[0204] In certain embodiments, the compound of formula (II) is

[0205] [ka] etc.

[0206] [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 , -NR52 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 But 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 1-3haloalkyl, 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,

[0207] [ka] is selected from, where 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

[0208] [ka] piperidinyl and piperazinyl, such as, where R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0209] [ka] is selected from, where R 57 is hydrogen and R 50In some embodiments, C is selected from:

[0210] [ka] is selected from, where R 57 is hydrogen and R 50 In some embodiments, C is selected from one or more R C optionally substituted with

[0211] [ka] is selected from, where R 57 is hydrogen and R 50 In some embodiments, C is selected from:

[0212] [ka] is selected from, 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(R52 )2, and -NR 52 S(=O)2R 52 In some embodiments, C is selected from:

[0213] [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 bases are together, C 1-3 In some embodiments, R C is -CH3, etc., C 1-3 Alkyl and C 1-3 haloalkyl. In some embodiments, p is selected from the integers 0 to 4, such as p is selected from the integers 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 R54 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, and -C(O)NR 53 R 54 C replaced with 1-6 alkyl.

[0214] In some embodiments, C is

[0215] [ka] is selected from.

[0216] In certain embodiments, the compound of formula (II) is

[0217] [ka] etc.

[0218] [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.

[0219] In certain embodiments, the compound of formula (II) is

[0220] [ka] etc.

[0221] [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 Cis —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.

[0222] In certain embodiments, the disclosure provides stereoisomers of compounds of Formula (I) or (II). In some embodiments, the stereoisomers are present in enantiomeric excess. In some embodiments, the stereoisomers are provided in an enantiomeric excess of at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, the stereoisomers are provided in an enantiomeric excess of greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, the stereoisomers are present in an enantiomeric excess of greater than 95%, such as an enantiomeric excess of greater than 99%.

[0223] In certain embodiments, the present disclosure provides stereoisomers of compounds of Formula (I) or (II). In some embodiments, the stereoisomers are present in diastereomeric excess. In some embodiments, the stereoisomers are provided in diastereomeric excess of at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, the stereoisomers are provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% diastereomeric excess. In some embodiments, the stereoisomers are present in greater than 95% diastereomeric excess, such as greater than 99% diastereomeric excess.

[0224] In certain embodiments, compounds of formula (I) or (II) are preferably used as non-racemic mixtures, in which one enantiomer is present in excess of its corresponding enantiomer. Typically, such mixtures contain a mixture of two isomers in a ratio of at least about 9:1, preferably at least 19:1. In some embodiments, the compounds are provided in at least 96% enantiomeric excess, meaning that the compounds contain less than 2% of the corresponding enantiomer. In some embodiments, the compounds are provided in at least 96% diastereomeric excess, meaning that the compounds contain less than 2% of the corresponding diastereomer.

[0225] In certain embodiments, the compound of formula (I) or (II) is preferably used as a non-racemic mixture, wherein the (+)-isomer is the major component of the mixture. Typically, such a mixture contains about 10% or less of the (-)-isomer, meaning that the ratio of the (+)-isomer to the (-)-isomer is at least about 9:1, and preferably less than 5% of the (-)-isomer, also meaning that the ratio of the (+)-isomer to the (-)-isomer is at least about 19:1. In some embodiments, the compound used has less than 2% of the (-)-isomer, meaning that it has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.

[0226] In certain embodiments, the compound of formula (I) or (II) is preferably used as a non-racemic mixture, wherein the (-)-isomer is the major component of the mixture. Typically, such a mixture contains about 10% or less of the (+)-isomer, meaning that the ratio of the (-)-isomer to the (+)-isomer is at least about 9:1, and preferably less than 5% of the (+)-isomer, also meaning that the ratio of the (-)-isomer to the (+)-isomer is at least about 19:1. In some embodiments, the compound used has less than 2% of the (+)-isomer, meaning that it has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.

[0227] In certain aspects, the present disclosure provides a stereoisomer of a compound of formula (I), or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof:

[0228] [ka] During the ceremony, H is C 5-12carbocycle 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 single bonds, -O-, -S, and -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 R50 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, independently selected at each occurrence from 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 teeth, 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, =O, =S, =N(R 52 ) are independently selected at each occurrence; Each of them is 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 ), C3-12 C optionally substituted with one or more substituents independently at each occurrence 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 independently selected at each occurrence from: a carbocycle and a 3- to 12-membered heterocycle; where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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 optionally substituted independently with one or more substituents selected from alkynyl; R 51 teeth, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each of them is 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 3-12 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle and 3-12 membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 independently selected at each occurrence from: a carbocycle and a 3- to 12-membered heterocycle; where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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, =O, =S, =N(R 52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted independently with one or more substituents selected from alkynyl; R 52 is hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 and a 3- to 12-membered heterocycle, each of which is independently selected at each occurrence from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted by a carbocyclic or 3-6 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 teeth, 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, =S, =N(R 52 ); and C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, each of which is selected from -NO2, -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 R54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =S, and =N(R 52 ) independently selected at each occurrence; and 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 by a carbocyclic or 3-6 membered heterocyclic ring.

[0229] In some embodiments, stereoisomers of the compound of Formula (I) are provided in an enantiomeric excess of at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, stereoisomers are provided in an enantiomeric excess of greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, the stereoisomers are present in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.

[0230] In some embodiments, with respect to the stereoisomers of the compounds of formula (I), L 3 teeth,

[0231] [ka] Optionally, R 50 is methyl. In some embodiments, L 3 teeth,

[0232] [ka] In some embodiments, L 3 teeth,

[0233] [ka] In some embodiments, C is

[0234] [ka] In some embodiments, L 3 teeth,

[0235] [ka] and C is selected from

[0236] [ka] is selected from.

[0237] Combinations of the groups described above for the various variations of the compounds of formula (I) are contemplated herein for the stereoisomers of the compounds of formula (I).

[0238] In certain aspects, the present disclosure provides a stereoisomer of a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0239] [ka] During the ceremony: 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 C 3-12 independently selected from carbocycle and 3-12 membered heterocycle; L1 and L 2 are single bonds, -O-, -S, and -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 or L 2 Two R's attached to the same or different atoms of 50 The groups together can optionally form a ring; 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 50is replaced by; R A , R B and R C are R 50 or two R attached to the same or different atoms, independently selected at each occurrence from 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 teeth, 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)(OR52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ) are independently selected at each occurrence; Each of them is 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 3-12 optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3- to 12-membered heterocycle; C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl; and C 3-12 independently selected at each occurrence from: a carbocycle and a 3- to 12-membered heterocycle; where R 50 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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 2-6optionally substituted independently with one or more substituents selected from alkynyl; R 51 teeth, Hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each of them is 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 3-12C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle and 3-12 membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-12 independently selected at each occurrence from: a carbocycle and a 3- to 12-membered heterocycle; where R 51 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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(R52 ), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted independently with one or more substituents selected from alkynyl; R 52 is hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 and a 3- to 12-membered heterocycle, each of which is independently selected at each occurrence from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 optionally substituted by a carbocyclic or 3-6 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 teeth, -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 52C(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, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle and a 3- to 12-membered heterocycle; where R 56 C in 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl is 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 , -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, =O, =S, =N(R 52 ), C 3-12 optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3-12 membered heterocycle; where R 56 C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from 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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and Furthermore, here R 56 optionally forms a single bond to ring C; and R 59 is C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 and a 3- to 12-membered heterocycle, each of which is independently selected at each occurrence from halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C 3-12 It is optionally substituted by a carbocyclic or 3-6 membered heterocyclic ring.

[0240] In some embodiments, stereoisomers of the compound of Formula (II) are provided in an enantiomeric excess of at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, stereoisomers are provided in an enantiomeric excess of greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In some embodiments, the stereoisomers are present in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.

[0241] In some embodiments, with respect to the stereoisomers of the compound of formula (II), L 3 teeth,

[0242] [ka] Optionally, R 56 is methyl. In some embodiments, L 3 teeth,

[0243] [ka] In some embodiments, L 3 teeth,

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

[0245] [ka] In some embodiments, L 3 teeth,

[0246] [ka] and C is selected from

[0247] [ka] is selected from.

[0248] Combinations of the groups described above for the various variations of the compounds of formula (II) are contemplated herein for the stereoisomers of the compounds of formula (II).

[0249] In certain aspects, compounds of the present disclosure covalently bind to menin and inhibit the interaction of menin with MLL. Such binding can lead to increased affinity of the compound for menin, an advantageous property in many applications, including therapeutic and diagnostic uses. In some embodiments, compounds of the present disclosure contain an electrophilic group capable of reacting with a nucleophilic group present in the menin protein. Suitable electrophilic groups are described throughout this application, while suitable nucleophilic groups include, for example, a cysteine ​​moiety present in the binding domain of the menin protein. Without being bound by theory, a cysteine ​​residue in the binding domain of menin can react with an electrophilic group of a compound of the present disclosure, leading to the formation of a conjugate product. In some embodiments, compounds of the present disclosure can be covalently bound to the cysteine ​​residue at position 329 of menin isoform 2 (SEQ ID NO:2) or to cysteine ​​334 in menin isoform 1 (SEQ ID NO:1). In some embodiments, the present disclosure provides a conjugate of a compound of the present disclosure with a menin protein. For example, the present disclosure provides conjugates of compounds of the present disclosure with menin linked at cysteine ​​residue 329 in menin isoform 2 (SEQ ID NO:2) or at cysteine ​​334 in menin isoform 1 (SEQ ID NO:1).

[0250] In some embodiments, with respect to compounds of formula (I) or (II), R A , R B and R COne or more of the following, when present, comprise a functional group that covalently reacts with one or more residues on menin. In some embodiments, the functional group covalently reacts with one or more cysteine ​​residues on menin. In some embodiments, the functional group covalently reacts with a cysteine ​​on menin at position 329 relative to SEQ ID NO:2 when optimally aligned, or at position 334 relative to SEQ ID NO:1 when optimally aligned. In some embodiments, the functional group covalently reacts with one or more residues on menin selected from cysteine ​​329, cysteine ​​241, and / or cysteine ​​230 on menin relative to SEQ ID NO:2 when optimally aligned. In some embodiments, the functional group covalently reacts with cysteine ​​329 relative to SEQ ID NO:2 when optimally aligned.

[0251] In some embodiments, with respect to compounds of formula (I) or (II), R A , R B and R C When present, one or more of R comprises a moiety that covalently reacts with one or more residues on menin. A , R B and R C When present, one or more of R comprises a moiety that covalently reacts with one or more isoforms of menin, e.g., menin isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO:2), isoform 3 (SEQ ID NO:3). A , R B and R C wherein one or more of comprises a moiety that, when present, covalently reacts with menin, wherein the menin protein shares 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO:2), or isoform 3 (SEQ ID NO:3).

[0252] In some embodiments, with respect to compounds of formula (I) or (II), R A , R B and R C When present, one or more of R contains an electrophilic group that is susceptible to nucleophilic attack from a residue on menin. Suitable electrophilic moieties known to those of skill in the art to bind to nucleophilic residues, e.g., electrophilic moieties known to bind to cysteine ​​residues, are contemplated herein. In some embodiments, R A , R B and R C When present, one or more of the following moieties comprise a non-electrophilic moiety, wherein the moiety is capable of binding to or covalently reacting with a residue on menin: In some embodiments, a compound or salt of formula (I) or (II) is capable of (a) covalently binding to menin, and (b) inhibiting the interaction of menin with MLL.

[0253] In some embodiments, with respect to compounds of formula (I) or (II), R C comprises a functional group that covalently reacts with one or more residues on menin. In some embodiments, the functional group covalently reacts with one or more cysteine ​​residues on menin. In some embodiments, the functional group covalently reacts with a cysteine ​​on menin at position 329 relative to SEQ ID NO:2 when optimally aligned, or at position 334 relative to SEQ ID NO:1 when optimally aligned.

[0254] In some embodiments, with respect to compounds of formula (I) or (II), R C is a moiety that contains an α,β-unsaturated carbonyl; an α,β-unsaturated sulfonyl; an epoxide; an aldehyde; a sulfonyl fluoride; a halomethylcarbonyl, a dihalomethylcarbonyl, or a trihalomethylcarbonyl.

[0255] In some embodiments, with respect to compounds of formula (I) or (II), R C teeth,

[0256] [ka] Selected from; During the ceremony, L 5 is a single bond; and C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is selected from one or more R 32 independently and optionally substituted with; R 22 and R 23 are respectively, Hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, and -CN; Each is a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 3-10 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3- to 10-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-10 carbocycle and 3-10 membered heterocycle; where R 22 and R 23 C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each substituted with a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; or R 22 and R 23 together with the carbon atoms to which they are attached form a carbocyclic ring; R 24 teeth, Hydrogen, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R20 , and -S(O)N(R 20 )2; Each is a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 3-10 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3- to 10-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-10 carbocycle and 3-10 membered heterocycle; where R 24 C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each substituted with a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, P(O)(R20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 optionally substituted independently with one or more substituents selected from alkynyl; R 20 is R 52 are independently selected at each occurrence from R 32 is R 50 are selected independently at each occurrence.

[0257] In some embodiments, L 5 is a single bond. In some embodiments, L 5 is an optionally substituted C 1-6 In some embodiments, L is alkylene. 5 is selected from methylene, ethylene, or propylene. 5 is halogen, -NO2, =O, =S, -OR 20 , -SR 20 , and -N(R 20 ) substituted with one or more substituents selected from 2.

[0258] In some embodiments, R 23 teeth, hydrogen; Each is a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20)2, -OP(O)(OR 20 )2, -CN, C 3-10 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle, and 3- to 10-membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-10 carbocycle and 3-10 membered heterocycle; Here, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each substituted with a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted independently with one or more substituents selected from:

[0259] In some embodiments, R 23 teeth, hydrogen; Halogen, -OR 20 , -SR 20 , -N(R 20 )2, =O, =S, =N(R 20 ), and —CN, 1-6 alkyl; and Halogen, -OR 20 , -SR20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C3- and 3-10 membered heterocycle optionally substituted with one or more substituents selected from alkynyl.

[0260] In some embodiments, R 23 is hydrogen, and halogen, -OR 20 , -SR 20 , -N(R 20 )2, =O, =S, =N(R 20 ), and —CN, optionally substituted with one or more substituents selected from 1-6 alkyl.

[0261] In some embodiments, R 22 teeth, hydrogen and -CN; Each is a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20)2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 3-10 C optionally substituted with one or more substituents independently at each occurrence selected from carbocycle and 3-10 membered heterocycle; 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; and C 3-10 carbocycle and 3-10 membered heterocycle; Here, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each substituted with a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, optionally substituted independently with one or more substituents selected from:

[0262] In some embodiments, R 22 is hydrogen, -CN; and halogen, -OR 20 , -SR 20 , and -N(R 20)2, optionally substituted with one or more substituents selected from 1-6 alkyl.

[0263] In some embodiments, R 22 and R 23 together with the carbon atom to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring.

[0264] In some embodiments, R 24 is hydrogen, and halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 1-6 alkyl.

[0265] In some embodiments, R 21 teeth,

[0266] [ka] is selected from.

[0267] Combinations of the above groups for various variations are contemplated herein. Throughout the specification, groups and their substituents may be chosen to provide stable moieties and compounds.

[0268] The chemical compounds described herein 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 1-5, although in some cases the steps may be performed in an order different from that shown in Scheme 1 and Examples 1-6. 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.

[0269] 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 approximately atmospheric pressure within a temperature range of about −10° C. to about 110° C. for about 1 hour to about 24 hours; remaining reactions are run overnight for an average of about 16 hours.

[0270] In general, the compounds of the present disclosure can be prepared by the following reaction schemes:

[0271] [ka] 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 aldehyde 1-4 to amine 1-5 can proceed in the presence of a suitable reducing agent, such as NaBH(OAc) to give compounds of formula 1-6. Addition of TFA can reveal the free amine, which can be converted to R 57 -LG, where LG is a suitable leaving group, to give compounds of formula 1-7.

[0272] In some embodiments, compounds of the present disclosure, e.g., compounds of the formulae given in Tables 1 or 2, are synthesized according to one of the general routes outlined in Scheme 1, Examples 1-5, or by methods generally known in the art. In some embodiments, exemplary compounds can include, but are not limited to, compounds selected from Table 1, or salts thereof.

[0273] [Table 1-1]

[0274] [Table 1-2]

[0275] [Table 1-3]

[0276] [Table 1-4]

[0277] [Table 1-5]

[0278] Table 1-6

[0279] Table 1-7

[0280] Table 1-8

[0281] Table 1-9

[0282] Table 1-10

[0283] Table 1-11

[0284] Table 1-12

[0285] Table 1-13

[0286] Table 1-14

[0287] Table 1-15

[0288] Table 1-16

[0289] Table 1-17

[0290] Table 1-18

[0291] Table 1-19

[0292] Table 1-20

[0293] Table 1-21

[0294] Table 1-22

[0295] Table 1-23

[0296] Table 1-24

[0297] Table 1-25

[0298] Table 1-26

[0299] Table 1-27

[0300] Table 1-28

[0301] Table 1-29

[0302] Table 1-30

[0303] Table 1-31

[0304] Table 1-32

[0305] Table 1-33

[0306] Table 1-34

[0307] Table 1-35

[0308] Table 1-36

[0309] Table 1-37

[0310] Table 1-38

[0311] Table 1-39

[0312] Table 1-40

[0313] Table 1-41

[0314] Table 1-42

[0315] Table 1-43

[0316] Table 1-44

[0317] Table 1-45

[0318] Table 1-46

[0319] [Table 1-47]

[0320] In some embodiments, exemplary compounds include, but are not limited to, compounds or salts selected from Table 2.

[0321] [Table 2-1]

[0322] [Table 2-2]

[0323] [Table 2-3]

[0324] [Table 2-4]

[0325] [Table 2-5]

[0326] [Table 2-6]

[0327] Pharmaceutical Composition

[0328] The compositions and methods of the present disclosure may be used to treat an individual in need thereof. In some 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 (I) or (II) and a pharmaceutically acceptable carrier.

[0329] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In even more 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.

[0330] 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. Further, 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.

[0331] In certain embodiments, compositions of compounds or salts of Formula (I) or (II) are administered locally rather than systemically, often as depot or sustained-release formulations, for example, via injection of the compound directly into an organ. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, compounds or salts of Formula (I) or (II) are delivered in targeted drug delivery systems, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In still other embodiments, the compositions are provided in the form of rapid-release, sustained-release, or intermediate-release formulations. In still other embodiments, the compositions are administered locally.

[0332] The compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof may be effective over a wide dosage range. For example, in treating adult humans, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are exemplary dosages that may be used in some embodiments. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician.

[0333] In some embodiments, a compound or salt of Formula (I) or (II) is administered in a single dose. Typically, such administration is by injection (e.g., intravenous injection) to rapidly introduce the drug. However, other routes may be used if desired. In some embodiments, a single dose of a compound or salt of Formula (I) or (II) is used to treat an acute illness.

[0334] In some embodiments, the compound or salt of Formula (I) is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once a week, once every two weeks, or once every other day. In another embodiment, the compound or salt of Formula (I) or (II) and the other agent are both administered about once a day to about six times a day. In another embodiment, administration of the compound or salt of Formula (I) or (II) and the other agent continues for less than about seven days. In yet another embodiment, administration continues for about six days or more, about ten days or more, about 14 days or more, about 28 days or more, about two months or more, about six months or more, or a year or more. In some cases, continuous dosing is achieved and maintained as needed.

[0335] If necessary, administration of a compound or salt of Formula (I) or (II) may be continued. In some embodiments, a compound of the present disclosure is administered for 1 or more days, 2 or more days, 3 or more days, 4 or more days, 5 or more days, 6 or more days, 7 or more days, 14 or more days, or 28 or more days. In some embodiments, a compound of the present disclosure is administered for 28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day or less, or a portion thereof. In some embodiments, a compound or salt of Formula (I) or (II) is administered chronically (e.g., for the treatment of chronic effects) on an ongoing basis.

[0336] In some embodiments, the compound or salt of formula (I) or (II) is administered in various dosages.It is known in the art that due to the variability between patients in the pharmacokinetics of compounds, individualized dosing regimens are necessary for optimal treatment.The dosage for the compound or salt of formula (I) or (II) can be found by routine experimentation in light of the present disclosure.

[0337] In some embodiments, the compound or salt of Formula (I) or (II) is formulated into a pharmaceutical composition. In certain embodiments, the pharmaceutical composition may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients found in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) may be used as suitable for formulating the pharmaceutical compositions described herein.

[0338] Provided herein are pharmaceutical compositions comprising a compound or salt of Formula (I) or (II) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the compounds or salts described herein are administered as pharmaceutical compositions in which the compound or salt of Formula (I) or (II) is mixed with other active ingredients, such as in combination therapy. All combinations of active ingredients described in the combination therapy section below and elsewhere herein are encompassed herein. In certain embodiments, the pharmaceutical composition comprises one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof.

[0339] As used herein, a pharmaceutical composition refers to a mixture of a compound or salt of Formula (I) or (II) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, a pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, in practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound or salt of Formula (I) or (II) is administered as a pharmaceutical composition to a mammal suffering from the disease, disorder, or medical condition being treated. In specific embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. A compound or salt of Formula (I) or (II) may be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0340] In one embodiment, the compound or salt of Formula (I) or (II) is formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from a physiologically compatible buffer, such as, by way of example only, Hank's solution, Ringer's solution, or physiological saline. In other embodiments, the compound or salt of Formula (I) or (II) is formulated for transmucosal administration. In certain embodiments, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated. In yet other embodiments, in which the compound or salt of Formula (I) or (II) is formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0341] In another embodiment, the compound or salt of Formula (I) or (II) is formulated for oral administration. The compound or salt of Formula (I) or (II) may be formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compound or salt of Formula (I) or (II) is formulated in oral dosage forms, including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0342] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with a compound or salt of Formula (I) or (II), optionally grinding the resulting mixture, and, if necessary, adding suitable excipients to obtain tablets or dragee cores, followed by processing the granular mixture. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0343] In one embodiment, dosage forms such as dragee cores or tablets are coated with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to characterize various combinations of active compound dosages.

[0344] In some embodiments, a therapeutically effective amount of a compound or salt of Formula (I) or (II) is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft gelatin capsules and a plasticizer, such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient in admixture with one or more fillers. The fillers may include, by way of example only, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0345] In other embodiments, a therapeutically effective amount of a compound or salt of Formula (I) or (II) is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In yet another embodiment, a compound or salt of Formula (I) or (II) is formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the injection formulation is provided in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are optionally added to the injection formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulatory agents, such as suspending agents, stabilizers, and / or dispersing agents. In certain embodiments, the pharmaceutical formulation comprises an aqueous solution of the active compound in water-soluble form. In additional embodiments, suspensions of the compound or salt of Formula (I) or (II) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension also contains suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. In certain embodiments, the active agent is in powder form, which is constituted with an appropriate vehicle (e.g., sterile, pyrogen-free water) before use.

[0346] In yet another embodiment, the compound or salt of Formula (I) or (II) is administered topically. The compound or salt of Formula (I) or (II) may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, soothing preparations, creams, or ointments. Such pharmaceutical compositions optionally include solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0347] In yet other embodiments, the compound or salt of Formula (I) or (II) is formulated for transdermal administration. Transdermal formulations utilize transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In additional embodiments, transdermal delivery of the compound or salt of Formula (I) or (II) is achieved by iontophoretic patches, etc. In certain embodiments, transdermal patches provide controlled delivery of the compound or salt of Formula (I) or (II). In certain embodiments, the absorption rate is slowed by using rate-limiting membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. The absorption enhancer or carrier includes pharmaceutically acceptable absorbable solvents that aid passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing a compound or salt of Formula (I) or (II) optionally with a carrier, optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0348] In other embodiments, the compound or salt of Formula (I) or (II) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. The pharmaceutical composition of the compound or salt of Formula (I) or (II) is conveniently delivered in the form of an aerosol spray display from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In specific embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges, such as gelatin, for use in an inhaler or insufflator, by way of example only, are formulated containing a powder mix of the compound or salt of Formula (I) or (II) and a suitable powder base, such as lactose or starch.

[0349] In yet other embodiments, the compounds or salts of formula (I) may be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides or synthetic polymers such as polyvinylpyrrolidone (PEG). In suppository forms of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0350] In certain embodiments, pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the route of administration selected. Any pharmaceutically acceptable techniques, carriers, and excipients may optionally be used appropriately. Pharmaceutical compositions containing a compound or salt of formula (I) or (II) may be prepared by conventional methods, such as, by way of example only, conventional mixing, dissolving, granulating, making dragees, gelling, emulsifying, encapsulating, entrapment, or compressing processes.

[0351] Pharmaceutical compositions contain at least one pharmaceutically acceptable carrier, diluent, or excipient and a compound or salt of Formula (I) or (II), often referred to herein as the active agent or active ingredient. The active ingredient may be in free acid or free base form, or in a pharmaceutically acceptable salt form. Furthermore, the compound or salt of Formula (I) or (II) may be in unsolvated or solvated form with a pharmaceutically acceptable solvent, such as water or ethanol. In addition, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, carriers, preservatives, stabilizers, adjuvants such as wetting agents or emulsifiers, solution enhancers, salts for regulating osmotic pressure, buffers, and / or other pharmaceutically valuable substances.

[0352] Methods for preparing compositions containing compounds or salts of Formula (I) or (II) include formulating the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form solids, semi-solids, or liquids. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are soluble, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing compounds or salts of Formula (I) or (II). Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Pharmaceutical compositions of compounds or salts of Formula (I) or (II) include liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or as emulsions. These compositions may also optionally contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0353] In some embodiments, pharmaceutical compositions comprising a compound or salt of Formula (I) or (II) are in the form of a liquid in which the drug is present in solution, suspension, or both. Generally, when the composition is administered as a solution or suspension, a first portion of the drug is present in solution and a second portion of the drug is present in particulate form in suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0354] In some embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers, such as cellulose polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers, such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0355] The pharmaceutical compositions optionally further include a solubilizing agent to aid in the solubility of the compounds described herein. The term "solubilizing agent" generally includes agents that result in a micellar or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0356] The pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0357] In addition, useful compositions optionally also contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0358] The pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridium chloride.

[0359] The pharmaceutical composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0360] Pharmaceutical compositions may optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium disulfite.

[0361] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0362] In some embodiments, a delivery system for hydrophobic pharmaceutical compounds is used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also utilized. In additional embodiments, the compound or salt of Formula (I) or (II) is delivered using a sustained-release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. A variety of sustained-release materials may be used herein. In some embodiments, sustained-release capsules release the compound for several weeks up to 100 days or more. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0363] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0364] In some embodiments, the concentration of the compound or salt of Formula (I) or (II) provided in the pharmaceutical composition is about 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39 ... %, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or less than 0.0001% w / w, w / v, or v / v.

[0365] In some embodiments, the concentration of the compound or salt of Formula (I) or (II) provided in the pharmaceutical composition is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%. 15.25%,15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2. 75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008% Greater than 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0366] In some embodiments, the concentration of the compound or salt of Formula (I) or (II) is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 29%, from about 0.09 ... % to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v, or v / v.

[0367] In some embodiments, the concentration of the compound or salt of Formula (I) or (II) ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0368] In some embodiments, the amount of the compound or salt of Formula (I) or (II) is about 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g , 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g or less.

[0369] In some embodiments, the amount of the compound or salt of Formula (I) or (II) is about 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.00 25g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.00 7g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0 .03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08 g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0. Greater than 5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g.

[0370] In some embodiments, the amount of one or more compounds of the present disclosure ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0371] Kits and articles of manufacture are also provided herein for use in the therapeutic applications described herein. In some embodiments, such kits include a carrier, packaging, or container that is partitioned to receive one or more containers, such as vials, tubes, etc., each of which contains one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers can be formed from a variety of materials, such as glass or plastic.

[0372] The products provided herein include packaging materials. Packaging materials used in packaging pharmaceutical products include, for example, those found in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material appropriate for the selected formulation and intended mode of administration or treatment. For example, a packaging container contains a compound or salt of Formula (I) or (II), optionally in a composition or in combination with another agent as disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). Such kits optionally contain a compound with an identifying description or label or instructions for its use in the methods described herein.

[0373] For example, a kit typically includes one or more additional containers, each containing one or more of various materials (e.g., reagents, optionally in concentrated form, and / or equipment) that are desirable from a commercial and user perspective for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, excipients, filters, needles, syringes; carriers, packaging, containers, vials, and / or tube labels listing the contents and / or instructions for use. A set of instructions is also typically included. The label is optionally on or associated with the container. For example, a label is on a container when letters, numbers, or other features forming the label are attached, molded, or etched onto the container itself, while a label is associated with a container when the label is present in a receptacle or carrier that holds the container, for example, as a package insert. In addition, the label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates instructions for using the contents, such as the methods described herein. In some embodiments, pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms comprising a compound provided herein. In embodiments, the pack comprises, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser device is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the government agency of the drug form for human or animal administration. In embodiments, such notice is, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or approved product inserts. In some embodiments, compositions comprising a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated disease.

[0374] method

[0375] The present disclosure provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a partial tandem duplication of MLL), the methods comprising contacting a cell with an effective amount of a compound or salt of formula (I) or (II). Inhibition of the interaction of menin with one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a partial tandem duplication of MLL) can be assessed and demonstrated by a wide variety of methods known in the art. Non-limiting examples include: (a) decreased menin binding to one or more proteins or protein fragments (e.g., MLL1, MLL2, MLL fusion proteins, partial tandem duplications of MLL, or peptide fragments thereof); (b) decreased cell proliferation and / or cell viability; (c) increased cell differentiation; (d) decreased levels of downstream targets of MLL1, MLL2, MLL fusion proteins, and / or partial tandem duplications of MLL (e.g., Hoxa9, DLX2, and Meis1); and (e) decreased tumor volume and / or tumor volume growth rate. Kits and commercially available assays are available for determining one or more of the above.

[0376] The present disclosure also provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease states, including, but not limited to, diseases associated with menin, MLL, MLL1, MLL2, and / or MLL fusion proteins (e.g., cancer).

[0377] In some embodiments, a method for treating cancer is provided, the method comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound or salt of Formula (I) or (II). In some embodiments, the cancer is mediated by an MLL fusion protein. In other embodiments, the cancer is leukemia, breast cancer, prostate cancer, pancreatic cancer, lung cancer, liver cancer, skin cancer, or brain cancer. In certain embodiments, the cancer is leukemia. In some embodiments, the cancer comprises a solid tumor.

[0378] In some embodiments, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising determining whether the subject has an MLL fusion protein, and administering to the subject a therapeutically effective amount of a compound or salt of formula (I) or (II) when the subject is determined to have an MLL fusion protein.

[0379] MLL fusion proteins have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments are directed to the administration of a compound or salt of Formula (I) or (II) to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), hairy cell leukemia, and / or other leukemias. In other embodiments, the compounds can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0380] Determining whether a tumor or cancer contains an MLL fusion protein can be done by evaluating the nucleotide sequence encoding the MLL fusion protein, by evaluating the amino acid sequence of the MLL fusion protein, or by evaluating the properties of a putative MLL fusion protein.

[0381] Methods for detecting MLL fusion protein nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant gene-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, MLL fusion proteins are identified using, for example, direct sequencing of specific regions (e.g., exon 2 and / or exon 3) in the MLL or fusion partner gene. This technique identifies any mutations in the sequenced region.

[0382] Methods for detecting MLL fusion proteins are known to those skilled in the art and include, but are not limited to, detection of MLL fusion proteins using binding agents (e.g., antibodies) specific for the fusion protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0383] The method for determining whether a tumor or cancer contains an MLL fusion protein can use a variety of samples. In some embodiments, the sample is obtained from a subject with a tumor or cancer. In some embodiments, the sample is obtained from a cancer or a subject with a tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0384] The present disclosure further relates to a method for treating a hyperproliferative disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or salt of Formula (I) or (II). In some embodiments, the method is for treating a hyperproliferative disease in a mammal, including acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, and the like. , colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic biliary intraepithelial carcinoma (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet tumor, pancreatic endocrine tumor, renal cancer, laryngeal cancer, lip and and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck of unknown primary origin, midline duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraneoplastic syndrome For the treatment of cancers such as ganglionoma, sinonasal and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disease such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)). Optionally, the method relates to the treatment of leukemia, hematological malignancies, solid tumor cancer, prostate cancer (e.g., castration-resistant prostate cancer), breast cancer, Ewing's sarcoma, osteosarcoma, primary osteosarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, liver cancer (e.g., hepatocellular carcinoma), or diabetes. Optionally, the leukemia comprises AML, ALL, mixed lineage leukemia, or leukemia with partial tandem duplication of MLL.

[0385] In certain embodiments, the present disclosure relates to a method for treating lung cancer, the method comprising administering to a subject in need thereof an effective amount of any of the above-mentioned compounds (or pharmaceutical compositions containing the same).In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.In other embodiments, the lung cancer is small cell lung cancer.Other lung cancers that can be treated with the disclosed compounds include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated carcinoma.

[0386] Subjects that can be treated with the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, stereoisomers, isotopic substitutions, hydrates, or derivatives of the compounds according to the methods of the present disclosure, include, for example, subjects diagnosed with acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, Atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic bile duct intraepithelial carcinoma (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, euthyroidism Ning's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet tumor, pancreatic endocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer , lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck of unknown primary origin, midline duct carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuro blastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach,Cancers include, but are not limited to, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, virally induced cancer, leukemia, hematological malignancies, solid tumor cancer, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, osteosarcoma, primary osteosarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, and diabetes. In some embodiments, subjects treated with the compounds of the present disclosure include those diagnosed with non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0387] The present disclosure further provides methods for modulating the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) by contacting menin with an effective amount of a compound or salt of Formula (I) or (II). The modulation can inhibit or activate the protein activity of menin, one or more of its binding partners, and / or one or more downstream targets of menin, or one or more of its binding partners. In some embodiments, the present disclosure provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) by contacting menin with an effective amount of a compound or salt of Formula (I) or (II). In some embodiments, the present disclosure provides methods for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) by contacting a cell, tissue, or organ expressing menin, MLL1, MLL2, an MLL fusion protein, and / or a partial tandem duplication of MLL. In some embodiments, the present disclosure provides methods for inhibiting protein activity in a subject, including but not limited to rodents and mammals (e.g., humans), by administering to the subject an effective amount of a compound or salt of Formula (I) or (II). In some embodiments, the modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0388] In some embodiments, the present disclosure provides methods of inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in the cell. In some embodiments, the present disclosure provides methods of inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in a tissue by contacting the tissue with a compound or salt of Formula (I) or (II) in an amount sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in the tissue. In some embodiments, the present disclosure provides methods of inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in vivo by contacting the organism with a compound or salt of Formula (I) or (II) in an amount sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in vivo. In some embodiments, the present disclosure provides methods of inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in the animal.In some embodiments, the present disclosure provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in a mammal by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in the mammal. In some embodiments, the present disclosure provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in the human. The present disclosure provides methods for treating a disease mediated by the interaction of menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) in a subject in need of such treatment.

[0389] The present disclosure further provides methods for treating disorders mediated by the interaction of menin with one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a partial tandem duplication of MLL) by contacting a subject in need thereof with a therapeutically effective amount of a compound or salt of Formula (I) or (II).

[0390] The present disclosure further provides a method of treating a disorder mediated by a chromosomal translocation at chromosome 11q23 in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or salt of Formula (I) or (II).

[0391] The present disclosure further provides methods for treating diseases by administering to a patient suffering from the disease or condition an effective amount of a compound or salt of formula (I) or (II).

[0392] The present disclosure further provides methods for treating a disease or condition by administering to a patient suffering from the disease or condition an effective amount of a compound or salt of Formula (I) or (II), wherein the compound binds to menin and inhibits the interaction of menin with one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a partial tandem duplication of MLL).

[0393] The present disclosure further provides methods of stabilizing menin, the methods comprising contacting menin with a compound or salt of Formula (I) or (II). In some embodiments, the contacting comprises contacting menin with the compound in an amount sufficient to stabilize menin. In some embodiments, the contacting is performed in vivo. In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in a cell.

[0394] The present disclosure further provides methods for combination therapy in which agents known to modulate other pathways, other components of the same pathway, or sets of overlapping target enzymes, etc., are combined with compounds or salts of Formula (I) or (II). In one aspect, such treatments include, but are not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide a synergistic or additive therapeutic effect.

[0395] If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with a Notch inhibitor and / or a c-Myb inhibitor.If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with an MLL-WDR5 inhibitor and / or a Dot11 inhibitor.

[0396] Many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present disclosure, hi some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0397] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as numerous other chemotherapy drugs. Non-limiting examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including altrateamine, triethylenemelamine, triethylenethiophosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembrine, phenesterine, prednisone, trofosfamide, nitrogen mustards such as uracil mustard; carmustine, chlorozotocin, fotemustine, lomustine, nimustine, Nitrosoureas such as ranimustine; aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin , epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin,Antibiotics such as zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; calsterone, dromostanolone propionate, and epithiosulfite. Androgens such as acetaminophen, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotein, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elfomithine; elliptinium acetate acetate); etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenameth; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts of any of the above.Acids or derivatives. Suitable chemotherapeutic cell modulating agents also include antihormonal drugs that act to regulate or inhibit hormone action on tumors, such as, for example, tamoxifen (Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY Antiestrogens, including 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; mitoxantrone (novantrone); teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS2000; and difluoromethylornithine (DMFO). If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, acridine carboxamide, adecatumumab, 17-N- Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 antitoxin, antineoplastic drugs, antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin,Non-cell cycle specific anticancer drugs, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucansone, lutecan, mafosf amide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0398] The present disclosure further relates to a method for using the compound or salt of formula (I) or (II) or the pharmaceutical composition provided herein in combination with radiation therapy to inhibit abnormal cell proliferation or treat hyperproliferative disorders in mammals.Technologies for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.The administration of the compound of the present disclosure in this combination therapy can be determined as described herein.

[0399] Radiation therapy can be administered by one or a combination of several methods, including, without limitation, external beam radiation therapy, internal beam radiation therapy, interstitial irradiation, stereotactic radiotherapy, whole-body radiotherapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially restricted radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, without limitation, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as cell regulators in the present disclosure include both solid and liquid forms. By way of non-limiting example, the radioactive source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192, or other radionuclide that emits photons, beta particles, gamma rays, or other therapeutic radiation, as a solid source of I-125. The radioactive material can also be a fluid made from a solution of the radionuclide, e.g., I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198, Y-90, etc. Additionally, the radionuclide can be embodied in a gel or radioactive microspheres.

[0400] The compounds or pharmaceutical compositions of the present disclosure can be used in combination with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[0401] Anti-angiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib.Examples of useful matrix metalloproteinase inhibitors are described in the following, which are incorporated herein by reference in their entireties: WO 96 / 33172 (published October 24, 1996), WO 96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98 / 104971.1 (filed October 10, 1999), WO 98 / 104971.2 (filed October 10, 1999), WO 98 / 104971.3 (filed October 10, 1999), WO 98 / 104971.4 (filed October 10, 1999), WO 98 / 104971.5 (filed October 10, 1999), WO 98 / 104971.6 (filed October 10, 1999), WO 98 / 104971.7 (filed October 10, 1999), WO 98 / 104971.8 (filed October 10, 1999), WO 98 / 104971.9 (filed October 10, 1999), WO 98 / 104971.1 ...2 (filed October 10, 1999), WO 98 / 1049 07697 (published February 26, 1998), WO 98 / 03516 (published January 29, 1998), WO 98 / 34918 (published August 13, 1998), WO 98 / 34915 (published August 13, 1998), WO 98 / 33768 (published August 6, 1998), WO 98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994) European Patent Publication No. 931,788 (published July 28, 1999), International Publication No. 90 / 05719 (published May 31, 1990), International Publication No. 99 / 52910 (published October 21, 1999), International Publication No. 99 / 52889 (published October 21, 1999), International Publication No. 99 / 29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Publication No. Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), Ming Provisional Patent Application No. 60 / 148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999), and European Patent Publication No. 780,386 (published June 25, 1997). Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and / or AMP-9 over other matrix metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0402] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, algal toxins that suppress autophagy and inhibit type 2A or type 1 protein phosphatases, cAMP analogs and drugs that increase cAMP levels, adenosine, LY204002, N6-mercaptopurine riboside, vinblastine, and the like. Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins, including, but not limited to, ATG5 (which is involved in autophagy), may also be used.

[0403] In some embodiments, the compounds described herein may be formulated or administered in conjunction with a liquid or solid tissue barrier, also known as a lubricant. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, Seprafilm, Interceed, and hyaluronic acid.

[0404] In some embodiments, the pharmaceutical agent administered in combination with a compound described herein includes a suitable drug that is effectively delivered by inhalation, such as an analgesic, e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine; an antianginal preparation, e.g., diltiazem; an antiallergic, e.g., cromoglycate, ketotifen, or nedocromil; an infectious disease medication, e.g., cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; an antihistamine, e.g., methapyrilene; an anti-inflammatory, e.g., beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone; an antitussive, e.g., noscapine; a bronchodilator, e.g., ephedrine, adrenaline, fenoterol, folic acid, or fluticasone. lumoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics such as amiloride; anticholinergics such as ipratropium, atropine, or oxitropium; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophylline, or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be clear to those skilled in the art to use, where appropriate, agents in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts), or as esters (e.g., lower alkyl group esters), or as solvates (e.g., hydrates) to optimize the activity and / or stability of the agents.

[0405] Other exemplary therapeutic agents useful in combination therapy include, but are not limited to, the agents listed above, radiation therapy, antihormones, hormones and their releasing factors, thyroid and antithyroid agents, estrogens and progestins, androgens, adrenocorticotropic hormones; corticosteroids and their synthetic analogs; inhibitors of corticosteroid synthesis and action, insulin, oral hypoglycemic agents, and agents affecting pancreatic endocrine pharmacology, mineralization, and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin. , water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins such as vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase drugs; agents acting at the neuromuscular junction and / or autonomic ganglia; catecholamines, sympathomimetics, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0406] Therapeutic agents may also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the biotransformation of products of selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, antipyretics, drugs that inhibit the synthesis of prostaglandins and thromboxanes, and derivatives. Selective inhibitors of cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines mediating interactions involved in humoral and cell-mediated immune responses, lipid-derived autacoids, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium antagonists, membrane stabilizers, and leukotriene inhibitors.

[0407] Additional therapeutic agents contemplated herein include: diuretics, vasopressin, agents that affect renal water conservation, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, beta-adrenergic receptor blockers, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.

[0408] Other therapeutic agents contemplated include: drugs used to control gastric acidity, drugs for the treatment of peptic ulcers, drugs for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, drugs used in irritable bowel syndrome, drugs used for diarrhea, drugs used for constipation, drugs used for inflammatory bowel disease, drugs used for biliary tract disease, drugs used for pancreatic disease, therapeutic agents used to treat protozoal diseases, drugs used to treat malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis, and / or leishmaniasis, and / or drugs used in the chemotherapy of helminthic diseases. Other treatments include: antibacterial agents, sulfonamides, trimethoprim-sulfamethoxazole combination drugs, quinolones, drugs for urinary tract infections, penicillins, cephalosporins, and other beta-lactam antibiotics, drugs containing aminoglycosides, protein synthesis inhibitors, drugs used in chemotherapy for tuberculosis, Mycobacterium avium complexosis, and leprosy, antifungals, and antivirals, including nonretrovirals and antiretrovirals.

[0409] Examples of therapeutic antibodies that can be used in combination with the compounds of the present disclosure include, but are not limited to, anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

[0410] Additionally, therapeutic agents used in immunomodulation, such as immunomodulators, immunosuppressants, tolerogens, and immunoenhancing agents, are contemplated by the methods herein, as well as therapeutic agents acting on the blood and blood-forming organs, antianemic agents, growth factors, minerals, and vitamins, anticoagulants, thrombolytic agents, and antiplatelet agents.

[0411] For the treatment of renal cancer, the compounds of the present disclosure may be combined with sorafenib and / or bevacizumab.For the treatment of endometrial disorders, the compounds of the present disclosure may be combined with doxorubicin, taxotere (taxol), and / or cisplatin (carboplatin).For the treatment of ovarian cancer, the compounds of the present disclosure may be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan, and / or tamoxifen.For the treatment of breast cancer, the compounds of the present disclosure may be combined with taxotere (taxol), gemcitabine (capecitabine), tamoxifen, letrozole, Tarceva, lapatinib, PD0325901, bevacizumab, Herceptin, OSI-906, and / or OSI-930. For the treatment of lung cancer, compounds of the present disclosure may be combined with taxotere (taxol), gemcitabine, cisplatin, pemetrexed, tarceva, PD0325901, and / or bevacizumab.

[0412] Additionally, therapeutic agents that can be used in combination with the compounds of the present disclosure can be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," Tenth Edition edited by Hardman, Limbird and Gilman, or the Physician's Package Insert, both of which are incorporated herein by reference in their entireties.

[0413] The compounds described herein can be used in combination with other suitable agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be administered with the other agent. When used in combination therapy, the compounds described herein can be administered simultaneously or separately with the second agent. This combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the agents described above can be administered simultaneously, where both agents are in separate formulations. In another alternative, the compounds of the present disclosure can be administered immediately after the agent, or vice versa. In some embodiments of separate administration protocols, the compounds of the present disclosure and any of the agents described above can be administered minutes, hours, or days apart.

[0414] The following examples are provided for the purpose of illustrating various embodiments of the present disclosure and are not intended to limit the disclosure in any manner. The examples, along with the methods and compositions described herein, are presently representative of preferred embodiments and are exemplary, but are not intended to limit the scope of the disclosure. Modifications therein and other uses that fall within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art. [Example]

[0415] Example 1: Synthesis of Compound 59 in Table 1

[0416] [ka]

[0417] Step A: Preparation of compound 59-2: To ethyl-2-(diethoxylphosphoryl)acetate (1.91 g, 8.5 mmol) in THF (30 mL) was added NaH (421 mg, 10.5 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 h before adding 59-1 (2 g, 8 mmol). The reaction mixture was stirred at room temperature for 5 h. Ice water (50 mL) was added, and the product was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (eluted with 20% EtOAc in petroleum ether) to give 2.15 g of 59-2 as a white solid (yield: 85%).

[0418] Step B: Preparation of compound 59-3: To a solution of 59-2 (905 mg, 2.85 mmol) in MeOH (20 mL), (Boc)O (1.24 g, 5.71 mmol) and Pd / C catalyst were added. The reaction mixture was stirred at room temperature for 8 h under H. TLC showed the reaction was complete. The reaction was filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 20% EtOAc in petroleum ether) to give 59-3 as a solid (740 mg, yield: 91%).

[0419] Step C: Preparation of compound 59-4: To a solution of 59-3 (670 mg, 2.35 mmol) in THF (20 mL) was added LiAlH (179 mg, 4.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h, then 0.2 mL of HO, 0.2 mL of 15% NaOH, and 0.5 mL of HO were added. The mixture was stirred at room temperature for 1 h. The mixture was filtered, and the organic solution was concentrated. The residue was purified by silica gel column chromatography (eluted with 40% EtOAc in p...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof: 【Chemistry 1】 During the ceremony, H is C ５－１２ carbocycle and 5- to 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 carbocycle, and 3- to 12-membered heterocycle; B is C ３－１２ selected from carbocycle, and 3- to 12-membered heterocycle; 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 ) CH ２ -, -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) ２ O-, -N(R ５１ ) S (O) ２ -, -S(O) ２ N (R ５１ ) -, -N(R ５１ )S(O)-, -S(O)N(R ５１ ) -, -N(R ５１ ) S (O) ２ N (R ５１ ) -, -N(R ５１ ) S ( O ) N ( R ５１ )-; selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R ５０ and optionally substituted with, wherein L １ , L ２ , or L ３ Two R's bonded to the same atom or different atoms in any one of ５０ the groups together can optionally form a bridge or a ring; R Ａ , R Ｂ , and R Ｃ are each independently R ５０ or two R attached to the same atom 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 each independently represent an integer from 0 to 6; R ５０ is independent, ハロゲン、-NO ２ 、-CN、-OR ５２ 、-SR ５２ 、-N(R ５２ ) ２ 、-NR ５３ R ５４ 、-S(=O)R ５２ 、-S(=O) ２ R ５２ 、-S(=O) ２ N(R ５２ ) ２ 、-S(=O) ２ NR ５３ R ５４ 、-NR ５２ S(=O) ２ R ５２ 、-NR ５２ S(=O) ２ N(R ５２ ) ２ 、-NR ５２ S(=O) ２ 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 ); Each independently, halogen, -NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ), -NR ２ R ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), -S(=O) ２ NR ２ R ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), -NR ２ S(=O) ５２ NR ２ R ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), -OC(O)NR ２ R ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), -NR ２ C(O)NR ５２ R ５３ R ５４ , -C(O)N(R ５２ ), -C(O)NR ２ R<s ５３ R ５４ , -P(O)(OR ５２ ), -P(O)(R ２ ), =O, =S, =N(R ５２ ), C ２ ５２ ), C ３－１２ ​C optionally substituted at each occurrence 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 are selected at each occurrence from Here, R ５０ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from alkynyl; R ５１ is independent, hydrogen, -C(O)R ５２ , -C(O)OR ５２ , -C(O)N(R ５２ ), ２ , -C(O)NR ５３ R ５４ ; Each independently, a halogen, -NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ), -NR ２ R ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), -S(=O) ２ NR ２ R ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), -NR ２ S(=O) ５２ NR ２ R ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), -OC(O)NR ２ R ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), -NR ２ C(O)NR ５２ R ５３ R ５４ , -C(O)N(R ５２ ), -C(O)NR ２ R ５３ R ５４ , -P(O)(OR ５２ ), -P(O)(R ２ ), =O, =S, =N(R ５２ ), C ２ ５２ ), C ３－１２ ​C optionally substituted at each occurrence 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 are selected at each occurrence from Here, R ５１ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from alkynyl; R ５２ are independently 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 at each occurrence, each of which is selected from halogen, —CN, —NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ optionally substituted with a carbocycle or a 3- to 6-membered heterocycle; 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 teeth, Halogen, -NO ２ , -CN, -SR ５２ , -NR ５３ R ５４ , -S(=O) ２ R ５８ , -S(=O) ２ N(R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ) ２ , -NR ５２ S(=O) ２ 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 , =S, =N(R ５２ ); and each independently -NO ２ , -CN, -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 , =S, and =N(R ５２ substituted at each occurrence independently with one or more substituents selected from １－１０ Alkyl, C ２－１０ Alkenyl, and C ２－１０ Alkynyl is selected from: R ５８ is hydrogen; and C １－２０ Alkyl, C ３－２０ Alkenyl, C ２－２０ alkynyl, 1-6 membered heteroalkyl, C ３－１２ a carbocycle, and a 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ optionally substituted with a carbocycle or a 3- to 6-membered heterocycle; wherein for a compound or salt of formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R ５７ But -S(=O) ２ R ５８ , -S(=O) ２ N (R ５２ ) ２ , or -NR ５２ S (= O) ２ R ５２ When: p is an integer from 1 to 6; and / or L ３ is one or more R ５０ where L ３ Ha-CH ２ Not CH(OH)- A compound characterized by:

2. A compound of formula (II), or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 During the ceremony: H is C ５－１２ carbocycle and 5- to 12-membered heterocycle, each of which is selected from one or more R ５０ optionally substituted with; A, B, and C are each independently C ３－１２ selected from carbocycle, and 3- to 12-membered heterocycle; L １ and L ２ are each independently a single bond, —O—, —S—, —N(R ５１ ) -, -N(R ５１ ) CH ２ -, -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) ２ O-, -N(R ５１ ) S (O) ２ -, -S(O) ２ N (R ５１ ) -, -N(R ５１ )S(O)-, -S(O)N(R ５１ ) -, -N(R ５１ ) S (O) ２ N (R ５１ ) -, -N(R ５１ ) S ( O ) N ( R ５１ )-; selected from 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 one or more R ５６ and further substituted with one or more R ５０ optionally substituted with; R Ａ , R Ｂ , and R Ｃ are each independently R ５０ or two R attached to the same atom 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 each independently represent an integer from 0 to 6; R ５０ is independent, ハロゲン、-NO ２ 、-CN、-OR ５２ 、-SR ５２ 、-N(R ５２ ) ２ 、-NR ５３ R ５４ 、-S(=O)R ５２ 、-S(=O) ２ R ５２ 、-S(=O) ２ N(R ５２ ) ２ 、-S(=O) ２ NR ５３ R ５４ 、-NR ５２ S(=O) ２ R ５２ 、-NR ５２ S(=O) ２ N(R ５２ ) ２ 、-NR ５２ S(=O) ２ 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 ); Each independently, a halogen, -NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ), -NR ２ R ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), -S(=O) ２ NR ２ R ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), -NR ２ S(=O) ５２ NR ２ R ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), -OC(O)NR ２ R ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), -NR ２ C(O)NR ５２ R ５３ R ５４ , -C(O)N(R ５２ ), -C(O)NR ２ R ５３ R ５４ , -P(O)(OR ５２ ), -P(O)(R ２ ), =O, =S, =N(R ５２ ), C ２ ５２ ３－１２ ​​C optionally substituted at each occurrence 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 are selected at each occurrence from Here, R ５０ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from alkynyl; R ５１ is independent, hydrogen, -C(O)R ５２ , -C(O)OR ５２ , -C(O)N(R ５２ ), ２ , -C(O)NR ５３ R ５４ ; Each independently, halogen, -NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ), -NR ２ R ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), -S(=O) ２ NR ２ R ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), -NR ２ S(=O) ５２ NR ２ R ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), -OC(O)NR ２ R ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), -NR ２ C(O)NR ５２ R ５３ R ５４ , -C(O)N(R ５２ ), -C(O)NR ２ R ５３ R ５４ , -P(O)(OR ５２ ), -P(O)(R ２ ), =O, =S, =N(R ５２ ), C ２ ５２ ), C ３－１２ ​C optionally substituted at each occurrence 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 are selected at each occurrence from Here, R ５１ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from alkynyl; R ５２ are independently 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 at each occurrence, each of which is selected from halogen, —CN, —NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ optionally substituted with a carbocycle or a 3- to 6-membered heterocycle; 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 is independent, -NO ２ 、-OR ５９ 、-SR ５２ 、-NR ５３ R ５４ 、-S(=O)R ５２ 、-S(=O) ２ R ５２ 、-S(=O) ２ N(R ５２ ) ２ 、-S(=O) ２ NR ５３ R ５４ 、-NR ５２ S(=O) ２ R ５２ 、-NR ５２ S(=O) ２ N(R ５２ ) ２ 、-NR ５２ S(=O) ２ 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 アルキル、C ２－１０ アルケニル、C ２－１０ アルキニル、C ３－１２ selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; Here, R ５６ C in １－１０ Alkyl, C ２－１０ Alkenyl, and C ２－１０ Each alkynyl is independently selected from halogen, —NO ２ , -CN, -OR ５９ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle at each occurrence; Here, R ５６ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from alkynyl; and Furthermore, here, R ５６ optionally forms a single bond to Ring C; and R ５９ is independent, 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 at each occurrence, each of which is selected from halogen, —CN, —NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ optionally substituted with a carbocycle or a 3- to 6-membered heterocycle; Here, for the compound or salt of formula (II), R ５６ Ga-CH ３ When L ３ -OH, -NH ２ or is not further substituted with —CN A compound characterized by:

3. R Ｃ is -C(O)R ５２ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , =O,C １－３ Alkyl, and C １－３ haloalkyl, or two R bonded to different atoms Ｃ The base is C １－３ 3. The compound according to claim 2, which is capable of forming crosslinks.

4. 4. The compound of claim 1, wherein C is a 5- to 12-membered heterocycle, wherein the heterocycle contains at least one nitrogen atom.

5. 5. The compound of claim 4, wherein the heterocyclic ring is saturated.

6. 6. The compound of claim 5, wherein the heterocycle is selected from piperidinyl and piperazinyl.

7. C is 【Transformation 3】 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

8. R ５７ is -S(=O)R ５２ , -S(=O) ２ R ５８ , -S(=O) ２ N (R ５２ ) ２ , and -NR ５２ S (= O) ２ R ５２ 8. The compound according to claim 1, wherein the compound is selected from the group consisting of:

9. C is 【Chemistry 4】 Selected from: Here, R ５７ is -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ and -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , and -NR ５２ S (= O) ２ R ５２ C substituted with one or more substituents selected from １－１０ selected from alkyl The compound according to claim 2 .

10. R ５７ is -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , and -NR ５２ S (= O) ２ R ５２ 10. The compound of claim 9, wherein the compound is selected from:

11. R ５７ is -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -NHS(=O) ２ CH ３ , and -S(=O) ２ NHCH ３ 11. The compound according to claim 1 or any one of claims 7 to 10, wherein the compound is selected from the group consisting of:

12. R Ｃ is C １－３ Alkyl and C １－３ 12. The compound according to any one of claims 1 to 11, wherein the compound is selected from haloalkyl.

13. H is one or more R ５０ is a 5-12 membered heterocycle optionally substituted with A is a 3- to 12-membered heterocycle; and B is a 3- to 12-membered heterocycle 13. A compound according to any one of claims 1 to 12.

14. H is one or more R ５０ 14. The compound of claim 1, wherein the compound is a 6-12 membered bicyclic heterocycle optionally substituted with:

15. H is one or more R ５０ 15. The compound of claim 14, wherein the compound is thienopyrimidinyl optionally substituted with:

16. H is 【Transformation 5】 and X １ and X ２ are each independently CR ２ and N; X ３ and X ４ are each independently selected from C and N; Y １ and Y ２ are each independently, CR ３ , N, N.R. ４ , O, and S; R １ , R ２ , and R ３ are each independently hydrogen and R ５０ selected at each occurrence from R ４ is R ５１ Selected from 15. The compound of claim 14.

17. X ３ and X ４ 17. The compound of claim 16, wherein each is C.

18. X １ is CR ２ and R ２ represents hydrogen, halogen, —OH, —OR ５２ , -NH ２ , -N(R ５２ ) ２ , -CN,C １－３ Alkyl, C １－３ Alkyl-N(R ５２ ) ２ , C １－３ Haloalkyl, C ２－３ Alkenyl, and C ２－３ 18. The compound according to claim 16 or 17, characterized in that it is selected from alkynyl.

19. X １ is CR ２ and R ２ represents hydrogen, halogen, —OH, —OR ５２ , -NH ２ , -N(R ５２ ) ２ , -CN,C １－３ Alkyl, —CH ２ OH, -CH ２ OR ５２ , -CH ２ NH ２ , -CH ２ N (R ５２ ) ２ , C １－３ Alkyl-N(R ５２ ) ２ , C １－３ Haloalkyl, C ２－３ Alkenyl, and C ２－３ 18. The compound according to claim 16 or 17, characterized in that it is selected from alkynyl.

20. X ２ 20. The compound according to any one of claims 16 to 19, wherein is N.

21. 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 21. The compound of any one of claims 16 to 20, wherein the alkyl is selected from haloalkyl.

22. R １ is C １－３ 22. The compound of any one of claims 16 to 21, which is haloalkyl.

23. 23. The compound according to any one of claims 1 to 22, wherein A is a 5- to 8-membered heterocycle.

24. 24. The compound of claim 23, wherein A is a 6-membered monocyclic heterocycle.

25. 25. The compound of claim 23 or 24, wherein the heterocycle contains at least one nitrogen atom.

26. 26. The compound of claim 25, wherein A is selected from piperidinylene and piperazinylene.

27. A is 【Transformation 6】 27. The compound of claim 26, wherein:

28. 28. The compound of any one of claims 1 to 27, wherein B is a 6- to 12-membered bicyclic heterocycle.

29. 30. The compound of claim 28, wherein the heterocycle contains at least one nitrogen atom.

30. 30. The compound of claim 29, wherein B is indolylene.

31. B is one or more R Ｂ optionally substituted with 【Transformation 7】 31. The compound of claim 30, wherein:

32. H is one or more R ５０ thienopyrimidinyl substituted with A is selected from piperidinylene and piperazinylene; and B is indolylene 14. The compound of claim 13.

33. H is -CH ２ CF ３ 33. The compound of any one of claims 1 to 32, substituted with:

34. 34. The compound of any one of claims 1 to 33, wherein m is 0.

35. 35. The compound according to any one of claims 1 to 34, wherein n is an integer from 1 to 3.

36. L １ 36. The compound of claim 1, wherein contains less than 10 atoms.

37. L １ HA-N(R ５１ 37. The compound according to any one of claims 1 to 36, wherein:

38. L ２ 38. The compound of claim 1, wherein contains less than 10 atoms.

39. L ２ is one or more R ５０ C optionally substituted with １－４ 39. The compound of any one of claims 1 to 38, which is alkylene.

40. L ２ is -CH ２ -, -N(R ５１ ) -, -N(R ５１ ) CH ２ -, -N(R ５１ )C(O)—, and —N(R ５１ ) S (O) ２ 39. The compound according to any one of claims 1 to 38, wherein the compound is selected from the group consisting of:

41. L ３ 41. The compound of claim 1, wherein contains less than 20 atoms.

42. L ３ is one or more R ５０ C optionally substituted with １－６ 42. The compound of any one of claims 1 to 41, which is alkylene.

43. L ３ is at least one C １－３ Alkyl or C １－３ haloalkyl, and optionally one or more R ５０ Further substituted with C ２ 43. The compound of claim 42, which is an alkylene.

44. L 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 44. The compound of claim 1, wherein the compound is substituted with (alkyl).

45. L ３ Ha-CH ３ 45. The compound of claim 44, substituted with:

46. L ３ teeth 【Transformation 8】 43. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of:

47. R ５０ 47. The compound of claim 46, wherein is methyl.

48. L ３ teeth 【Chemistry 9】 43. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of:

49. R ５６ 49. The compound of claim 48, wherein is methyl.

50. H is one or more R ５０ thienopyrimidinyl optionally substituted with A is a 3- to 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 3. The compound according to claim 1 or 2.

51. 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 —O—, —S—, —NH—, or —CH ２ - selected from; L ３ represents a single bond, —O—, —S—, —N(R ５１ ) -, -N(R ５１ ) CH ２ -, -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) ２ O-, -N(R ５１ ) S (O) ２ -, -S(O) ２ N (R ５１ ) -, -N(R ５１ )S(O)-, -S(O)N(R ５１ ) -, -N(R ５１ ) S (O) ２ N (R ５１ ) -, -N(R ５１ ) S ( O ) N ( R ５１ )-; selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is selected from one or more R ５０ wherein L is optionally substituted with ３ Two R's bonded to the same atom or different atoms of ５０ the groups together can optionally form a ring; R Ａ , R Ｂ , and R Ｃ are each independently R ５０ or two R attached to the same atom or different atoms, Ａ group, two R Ｂ group, or two R Ｃ the groups can optionally be joined to 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 teeth, -S(=O)R ５２ , -S(=O) ２ R ５８ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 , -P(O)(R ５２ ) ２ and each independently represents -S(=O)R ５２ , -S(=O) ２ R ５８ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 C is substituted at each occurrence with one or more substituents selected from １－１０ Alkyl, C ２－１０ Alkenyl, and C ２－１０ Alkynyl is selected from: R ５８ is hydrogen; and C １－２０ Alkyl, C ３－２０ Alkenyl, C ２－２０ alkynyl, 1-6 membered heteroalkyl, C ３－１２ a carbocycle, and a 3- to 12-membered heterocycle, each of which is selected from halogen, —CN, —NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ Optionally substituted by a carbocyclic or 3- to 6-membered heterocyclic ring The compound according to claim 1 .

52. 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 —O—, —S—, —NH—, or —CH ２ - selected from; 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 further substituted with one or more R ５０ optionally substituted with; R Ａ , R Ｂ , and R Ｃ are each independently R ５０ or two R attached to the same atom 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 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 is independent, -OR ５９ , =O,C １－１０ Alkyl, C ２－１０ Alkenyl, and C ２－１０ selected at each occurrence from alkynyl, Here, R ５６ C in １－１０ Alkyl, C ２－１０ Alkenyl, and C ２－１０ Each alkynyl is independently selected from halogen, —NO ２ , -CN, -OR ５９ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from carbocycle, and 3- to 12-membered heterocycle at each occurrence; Here, R ５６ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S (= O) ２ R ５２ , -NR ５２ S (= O) ２ N (R ５２ ) ２ , -NR ５２ S (= O) ２ 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 optionally substituted with one or more substituents selected from alkynyl; and Furthermore, here, R ５６ optionally forms a single bond to Ring C; and R ５９ is independent, 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 at each occurrence, each of which is selected from halogen, —CN, —NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ Optionally substituted by a carbocyclic or 3- to 6-membered heterocyclic ring The compound according to claim 2 .

53. R ５７ is -S(=O) ２ R ５８ , -S(=O) ２ N (R ５２ ) ２ , and -S(=O) ２ NR ５３ R ５４ 52. The compound of claim 51, wherein the compound is selected from:

54. R ５７ is -S(=O) ２ CH ３ and -S(=O) ２ NHCH ３ 54. The compound of claim 53, wherein the compound is selected from:

55. C is -S(=O) ２ R ５８ , -S(=O) ２ N (R ５２ ) ２ , or -S(=O) ２ NR ５３ R ５４ 53. The compound of claim 52, substituted with:

56. H is 【Chemistry 10】 and R ２ represents hydrogen, halogen, —OH, —OR ５２ , -NH ２ , -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 56. The compound of any one of claims 50 to 55, wherein the compound is selected from alkynyl.

57. R ２ Ha-NH ２ , -CH ３ , and -NHCH ３ 57. The compound of claim 56, wherein the compound is selected from:

58. L ３ teeth 【Chemistry 11】 58. The compound according to any one of claims 50 to 57, wherein the compound is selected from the group consisting of:

59. 59. A substantially pure stereoisomer of a compound according to any one of claims 1 to 58.

60. 53. The compound of claim 52, wherein the stereoisomer is provided in at least 90% enantiomeric excess.

61. 61. The compound of any one of claims 1 to 60, wherein the compound is isotopically enriched.

62. A compound selected from Table 1 or Table 2.

63. 63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62 and a pharmaceutically acceptable carrier.

64. 64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is formulated for oral administration.

65. 64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is formulated for injection.

66. A method for inhibiting the interaction of menin with one or more of MLL1, MLL2, MLL fusion protein, and MLL partial tandem duplication, comprising contacting menin with an effective amount of a compound described in any one of claims 1 to 62.

67. 63. A method for inhibiting menin-MLL interaction, comprising contacting menin with an effective amount of a compound described in any one of claims 1 to 62, wherein inhibition of the interaction is evidenced by a decrease in expression of an MLL fusion protein target gene.

68. 68. The method of claim 67, wherein the MLL fusion protein target gene is HOXA9, DLX2, or MEIS1.

69. 63. A method of stabilizing menin, comprising contacting menin with a compound of any one of claims 1-62.

70. 70. The method of any one of claims 66 to 69, wherein the contacting step comprises contacting a cell that expresses menin.

71. 70. The method of any one of claims 66-69, further comprising administering a second therapeutic agent.

72. 70. The method of any one of claims 66 to 69, wherein the contacting step is performed in vivo.

73. 70. The method of any one of claims 66 to 69, wherein the contacting step is performed in vitro.

74. 63. A method for treating a disease or disorder associated with an MLL fusion protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-62.

75. 63. A method of treating a disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition of a therapeutically effective amount of a compound of any one of claims 1-62.

76. 76. The method of claim 74 or 75, wherein the disease or condition comprises leukemia, hematological malignancies, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain cancer, or diabetes.

77. 77. The method of claim 76, wherein the leukemia comprises AML, ALL, mixed lineage leukemia, or leukemia with MLL partial tandem duplication.

78. A method for treating a disorder mediated by chromosomal rearrangement on chromosome 11q23 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 62.

79. A method for treating a disorder mediated by the interaction of menin with another protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in any one of claims 1 to 62.

80. 80. The method of any one of claims 74 to 79, wherein the subject is a human.

81. 64. A kit comprising the pharmaceutical composition of claim 63 and instructions for using the composition to treat a subject suffering from a disease or disorder mediated by the interaction of menin with other proteins.

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