Substituted menin-mll inhibitors and methods of use

Abstract

The present invention provides methods of inhibiting the interaction of menin with MLL1, MLL2, and MLL-fusion oncoproteins. The methods can be used to treat leukemia, solid cancers, diabetes, and other diseases that depend on MLL1, MLL2, MLL fusion protein, and / or menin activity. The present invention also provides compositions for use in the methods.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780030597.6, filed on March 15, 2017, entitled "Substituted MENIN-MLL Inhibitor and Method of Use" (the corresponding PCT application was filed on March 15, 2017, and has the application number PCT / US2017 / 022564).

[0002] Cross-references

[0003] This application claims the benefits of the following applications: U.S. Provisional Application No. 62 / 309,372, filed March 16, 2016; U.S. Provisional Application No. 62 / 334,369, filed May 10, 2016; U.S. Provisional Application No. 62 / 431,389, filed December 7, 2016; and U.S. Provisional Application No. 62 / 446,640, filed January 16, 2017, which are incorporated herein by reference. Background Technology

[0004] Mixed lineage leukemia (MLL) proteins are histiprotein methyltransferases that are crucial for the epigenetic regulation of gene transcription. Many acute leukemias (including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed lineage leukemia (MLL)) are characterized by the presence of chimeric MLL fusion proteins, which are generated from a translocation of the MLL gene located on chromosome 11 q23 (11q23). The chimeric MLL fusion protein retains approximately 1,400 amino acids from the N-terminus of the MLL gene but fuses with one of approximately 80 mate proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). The MLL fusion protein lacks the original histiprotein methyltransferase activity from the MLL L-terminus and gains the ability to regulate the transcription of numerous oncogenes, including HOX and MEIS1, thereby increasing cell proliferation and decreasing cell differentiation, ultimately leading to leukemia.

[0005] The menin protein, encoded by the multiple endocrine neoplasm (MEN) gene, is a ubiquitously expressed nuclear protein involved in interactions with DNA processing and repair proteins, chromatin modification proteins, and numerous transcription factors (Agarwal et al., HormMetab Res, 2005, 37(6):369-374). The binding of menin to the N-terminus of the MLL fusion protein is required for the observed oncogenic activity of the MLL fusion protein. This binding has been shown to constitutively upregulate the expression of the HOX and MEIS1 oncogenes and impair hematopoietic cell proliferation and differentiation, leading to leukemia. Since menin has been shown to function as a general oncogenic cofactor in MLL-related leukemia, the interaction between menin and the MLL fusion protein, and between menin and MLL, represents a potential target for chemotherapy.

[0006] Leukemia patients with MLL gene chromosomal translocations, especially infants, have an extremely poor prognosis, with a 5-year survival rate of less than 40% (Slany; Haematologica, 2009, 94(7):984-993). Novel treatment strategies for this type of leukemia are urgently needed. Therefore, small molecule inhibitors that block the menin-MLL interaction are valuable targets for treating diseases involving MLL fusion proteins. Summary of the Invention

[0007] This invention addresses an industry need by providing compositions and methods for inhibiting protein-protein interactions between menin and MLL1, MLL2, and MLL-fusion oncogenic proteins. The compositions and methods described herein can be used to treat diseases dependent on the activity of MLL1, MLL2, MLL fusion proteins, and / or menin, such as leukemia, solid tumors, and diabetes. In some embodiments, the compounds of this invention interact with menin non-covalently and inhibit the interaction between menin and MLL. In some embodiments, the compounds of this invention covalently bind to menin and inhibit the interaction between menin and MLL.

[0008] In some embodiments of the compounds provided herein, the compounds are bound 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) of menin). In some 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).

[0009] In one aspect, the present invention provides a compound of formula (I):

[0010]

[0011] Or its pharmaceutically acceptable salt, isotopic form, or prodrug, wherein:

[0012] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0013] A is selected from key, C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0014] B is selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0015] C is a heterocyclic ring ranging from 3 to 12 members;

[0016] L 1 L 2 and L 3 Each is independently selected from the 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(R51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 L 2 or L 3 R on one of the same or different atoms 50 The groups can optionally form bridges or rings together;

[0017] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0018] m, n, and p are each an independent integer from 0 to 6;

[0019] R 50 Selected independently each time it appears:

[0020] 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 );

[0021] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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)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 3-12 Carbon rings and 3- to 12-membered heterocycles; and

[0022] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0023] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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、-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 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0024] R 51 Selected independently each time it appears:

[0025] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0026] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 R54 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles; and

[0027] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0028] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 -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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0029] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0030] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0031] R 57 Selected from:

[0032] 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)2NR 53 R54 -C(O)OR 52 -OC(O)R 52 -OC(O)OR 52 -OC(O)N(R) 52 )2、-OC(O)NR 53 R 54 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)NH(C 1-6 Alkyl), -C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=S、=N(R 52 );and

[0033] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of the groups is independently substituted with one or more substituents selected from the following groups each time it appears: -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)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 -NR52 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 );and

[0034] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0035] For compounds or salts of formula (I), where C is azapyridine, piperidinyl, or piperazine and R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 hour:

[0036] p is an integer from 1 to 6; and / or

[0037] L 3 via one or more R 50 Replace, where L 3 It is not -CH2CH(OH)-.

[0038] In one aspect, the present invention provides compounds of formula (II):

[0039]

[0040] Or its pharmaceutically acceptable salt, wherein:

[0041] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0042] A, B, and C are each independently selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0043] L 1 and L 2 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 replace;

[0044] L 3 Selected from alkylene, alkenylene, and ynylene groups, each of which is derived from one or more R groups. 56 Replace and optionally further via one or more R 50 replace;

[0045] R A R B and R C Each occurrence is independently selected from R. 50Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0046] m, n, and p are each an independent integer from 0 to 6;

[0047] R 50 Selected independently each time it appears:

[0048] 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 );

[0049] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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)NR53R 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 Carbon rings and 3- to 12-membered heterocycles; and

[0050] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0051] Where R 50 Each C in 3-12The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0052] R 51 Selected independently each time it appears:

[0053] Hydrogen, -C(O)R 52 -C(O)OR 52-C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0054] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0055] C3-12 Carbon rings and 3- to 12-membered heterocycles,

[0056] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0057] R 52Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0058] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0059] R 56 Selected independently each time it appears:

[0060] -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)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 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0061] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 R54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0062] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group; and

[0063] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0064] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0065] For compounds or salts of formula (II), in R 56 When it is -CH3, L 3 It is not further substituted by -OH, -NH2 or -CN.

[0066] In some implementations, for compounds of formula (II), R C Selected from -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 atoms attached to different atoms C Groups can form C together 1-3 bridge.

[0067] For compounds of formula (I) or (II), C may be a 5- to 12-membered heterocycle, wherein the heterocycle includes at least one nitrogen atom. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is selected from piperidinyl and piperazineyl groups.

[0068] In some embodiments, for compounds of formula (I), C is selected from... and In some implementation schemes, R 57 Selected from -S(=O)R 52-S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 .

[0069] In some embodiments, for compounds of formula (II), C is selected from... and Where R 57 Selected from -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 C 1-10 Alkyl groups, which are derived from one or more of the following groups: -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 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 In some implementations, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3 and -S(=O)2NHCH3.

[0070] For compounds of formula (I) or (II), R C Optional from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0071] In some embodiments, for compounds of formula (I) or (II), H is optionally derived from one or more R... 50 The substituted 5- to 12-membered heterocycles; A is a 3- to 12-membered heterocycle; and B is a 3- to 12-membered heterocycle.

[0072] For compounds of formula (I) or (II), H may optionally be derived from one or more R groups.50 Replaces the 6- to 12-membered bicyclic heterocycle. In some embodiments, H is optionally derived from one or more R... 50 Substituted thiophenepyrimidine group. In some embodiments, H is... X 1 and X 2 Each independently selected from CR 2 and N; X 3 and X 4 Each is independently selected from C and N; Y 1 and Y 2 Each independently selected from CR 3 , N, NR 4 O and S;R 1 R 2 and R 3 Each time it appears, it is independently selected from hydrogen and R. 50 And R 4 Selected from R 51 In some implementations, X 3 and X 4 Each is designated C. In some implementations, X... 1 For CR 2 And R 2 Selected from hydrogen, halogens, -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 Alkyne group. In some implementations, X 1 For CR 2 And R 2 Selected from hydrogen, halogens, -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 Alkyne group. In some implementations, X 2 For N. In some implementations, Y 2 For CR 3 And R 3 Selected from hydrogen, halogen, -OH, -N(R)52 )2、-CN、-C(O)OR 52 C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 1 C 1-3 Halogenated alkyl groups.

[0073] 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 includes at least one nitrogen atom. In some embodiments, A is selected from piperidinyl and piperazineyl groups, for example...

[0074] For compounds of formula (I) or (II), B may be a 6- to 12-membered bicyclic heterocycle. In some embodiments, the heterocycle includes at least one nitrogen atom. In some embodiments, B is optionally radiated by one or more R atoms. B Substituted indoles, for example

[0075] In some embodiments, for compounds of formula (I) or (II), H is derived from one or more R... 50 The substituted thiophene-pyrimidinyl group; A is selected from piperidinyl and piperazineyl; and B is indoleyl.

[0076] For compounds of formula (I) or (II), H may be substituted with -CH2CF3. In some embodiments, m is 0. In some embodiments, n is an integer from 1 to 3. In some embodiments, L 1 Including fewer than 10 atoms. In some implementations, L 1 -N(R) 51 In some implementations, L 2 Including fewer than 10 atoms. In some implementations, L 2 For optional access via one or more R 50 Replacement C 1-4 Alkylene. In some embodiments, L 2 Selected from -CH2-, -N(R) 51 )-、-N(R 51 CH2-、-N(R) 51 C(O)- and -N(R) 51 )S(O)2-. In some implementations, L 3 Includes fewer than 20 atoms. In some implementations, L 3 For optional access via one or more R 50 Replacement C 1-6 Alkylene. In some embodiments, L 3For at least C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Substituted C2 alkylene groups. In some embodiments, L 3 = 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) substitution. In some embodiments, L 3 Substitution with -CH3. In some embodiments, the compounds of formula (I) or (II) are selected from Table 1.

[0077] For compounds of formula (I), L 3 Optional and Optional, R 50 It is a methyl group. In some embodiments, for compounds of formula (II), L 3 Selected from and Optional, R 56 The methyl group is used. In some aspects, the present invention provides substantially pure stereoisomers of compounds of formula (I) or (II). Optionally, the stereoisomer system is provided in an excess of at least 90% enantiomers.

[0078] In some embodiments, for compounds of formula (I) or (II), H is optionally derived from one or more R... 50 Substituted thiophenepyrimidine group; A is a 3- to 12-membered heterocycle; B is a 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3.

[0079] In some implementations, for compounds of formula (I):

[0080] H is an optional location via one or more R. 50 Substituted thiophenepyrimidine group;

[0081] A is selected from piperidinyl and piperazineyl;

[0082] B is an indolide;

[0083] L 1 and L 2 Each is independently selected from -O-, -S-, -NH-, and -CH2-;

[0084] L 3 Selected from key, -O-, -S-, -N(R)51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 3 R on the same atom or different atoms 50 The groups may optionally form a ring together;

[0085] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups may optionally form a ring together;

[0086] m is an integer from 0 to 3;

[0087] n is an integer from 1 to 3;

[0088] p is an integer from 0 to 6;

[0089] R 57 Selected from:

[0090] -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)2NR 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

[0091] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of them is independently substituted by one or more substituents selected from the following groups each time it appears: -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)2NR 53 R 54 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R54 -C(O)NH(C 1-6 Alkyl), -C(O)NR 53 R 54 -P(O)(OR) 52 )2 and -P(O)(R 52 )2; and

[0092] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0093] In some implementations, for compounds of formula (II):

[0094] H is an optional location via one or more R. 50 Substituted thiophenepyrimidine group;

[0095] A is selected from piperidinyl and piperazineyl;

[0096] B is an indolide;

[0097] L 1 and L 2 Each is independently selected from -O-, -S-, -NH-, and -CH2-;

[0098] L 3 Selected from C 1-6 Alkylene, C 2-6 alkenyl and C 2-6 alkyne group, wherein each is derived from one or more R groups 56 Replace and optionally further via one or more R 50 replace;

[0099] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0100] m is an integer from 0 to 3;

[0101] n is an integer from 1 to 3;

[0102] p is an integer from 0 to 6;

[0103] R 56 Selected independently each time it appears:

[0104] -OR 59 =O,C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group,

[0105] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 R54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0106] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group; and

[0107] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0108] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0109] For compounds of formula (I), R 57 Optional from -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -S(=O)2NR 53 R 54 For example, -S(=O)2CH3 and -S(=O)2NHCH3. For compounds of formula (II), C can be converted via -S(=O)2R. 58 -S(=O)2N(R) 52 )2 or -S(=O)2NR 53 R 54 replace.

[0110] In some embodiments, for compounds of formula (I) or (II), H is And R 2 Selected from hydrogen, halogens, -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 Alkyne group. Optionally, R 2 Selected from -NH2, -CH3, and -NHCH3. In some embodiments, for compounds of formula (I) or (II), H is... And R 2 Selected from hydrogen, halogens, -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 Alkyne group. Optionally, R 2 Selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. For compounds of formula (I) or (II), L 3 Optional and

[0111] In some aspects, the present invention 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.

[0112] In some aspects, the present invention provides a method for inhibiting the interaction of menin with one or more of MLL1, MLL2, MLL fusion proteins, and MLL partial tandem repeats, comprising contacting menin with an effective amount of a compound or salt of formula (I) or (II). In some aspects, the present invention provides a method for inhibiting menin-MLL interaction, comprising contacting menin with an effective amount of a compound or salt of formula (I) or (II), wherein inhibition of the interaction is confirmed by a reduction in the expression of the MLL fusion protein target gene. In some aspects, the present invention provides a method for stabilizing menin, comprising contacting menin with a compound or salt of formula (I) or (II).

[0113] In practicing any of the target methods, the target gene for the MLL fusion protein may be HOXA9, DLX2, or MEIS1. Contact may include contact with cells expressing menin. In some embodiments, the method includes administration of a second therapeutic agent. In some embodiments, contact occurs in vivo. In some embodiments, contact occurs in vitro.

[0114] In some aspects, the present invention provides a method for treating a disease or condition associated with an MLL fusion protein, comprising administering to an individual in need an effective amount of a compound or salt of formula (I) or (II). In some aspects, the present invention provides a method for treating a disease or condition in an individual, comprising administering to the individual 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 includes leukemia, hematologic malignancies, solid tumor cancers, prostate cancer, breast cancer, liver cancer, brain tumors, or diabetes. In some embodiments, leukemia includes AML, ALL, mixed lineage leukemia, or leukemia with partial tandem repeats of MLL.

[0115] In some aspects, the present invention provides a method for treating a condition mediated by chromosomal rearrangement on chromosome 11q23 in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound or salt of formula (I) or (II). In some aspects, the present invention provides a method for treating a condition mediated by the interaction between menin and another protein, comprising administering to the individual in need a therapeutically effective amount of a compound or salt of formula (I) or (II). In some embodiments, the individual is a human.

[0116] In some aspects, the present invention provides a kit comprising the pharmaceutical composition set forth herein and instructions for use (which instruct the use of the composition to treat an individual suffering from a disease or symptom mediated by the interaction between menin and another protein).

[0117] Incorporation

[0118] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application were expressly and individually incorporated by reference. Attached Figure Description

[0119] The novel features of the invention are set forth in detail in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings of illustrative embodiments utilizing the principles of the invention, in which:

[0120] Figure 1 It is the amino acid sequence of human menin isotype 1 (SEQ ID NO:1).

[0121] Figure 2 It is the amino acid sequence of human menin isotype 2 (SEQ ID NO:2).

[0122] Figure 3It is the amino acid sequence of human menin isotype 3 (SEQ ID NO:3).

[0123] Figure 4 Describe the volume changes of MV4;11 tumors in mice treated with mediators and compounds.

[0124] Figure 5 The luminescence of MV4;11-luc tumors in a xenograft mouse model of MLL leukemia treated with mediators and compounds 6 days after treatment was depicted.

[0125] Figure 6 Describing oneself Figure 5 The changes in gene expression of DLX2, HOXA9, MEIS1, and CD11B in bone marrow samples obtained from mice treated with the mediators and compounds are shown in the figure.

[0126] Figure 7 Survival curves were plotted for mice with MV4;11-luc tumors treated with mediators and compounds.

[0127] Figure 8 Describe the volume changes of MV4;11 tumors in mice treated with mediators and compounds.

[0128] Figure 9 The gene expression changes of HOXA9, MEIS1, and CD11B in bone marrow samples obtained from mice treated with self-mediators and compounds were depicted.

[0129] Figure 10 Survival curves of mice with MOLM13 tumors treated with mediators and compounds were plotted.

[0130] Figure 11 The luminescence of MV4;11-luc tumors in a xenograft mouse model of MLL leukemia treated with mediators and compounds 6 days after treatment was depicted.

[0131] Figure 12 Describing oneself Figure 11 The changes in gene expression of HOXA9, MEIS1, and CD11B in bone marrow samples obtained from mice treated with the mediators and compounds are shown in the figure.

[0132] Figure 13 Survival curves of mice with MOLM13 tumors treated with mediators and compounds were plotted. Invention Details

[0133] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0134] "MLL fusion protein" refers to a protein fused with a partner protein and possessing the N-terminal fragment of MLL. 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, and EPS15. 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 be generated by conjugating a fusion gene to produce a fusion gene. Translation of this fusion gene can produce one or more polypeptides with functional properties derived from each of the original proteins.

[0135] When used in conjunction with a chemical moiety (e.g., alkyl, alkenyl, or ynyl), the term "C" is used. x-y "or "C x -C y "Intended 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 containing x to y carbons in its chain, including straight-chain alkyl and branched alkyl groups. The term "C"... x-y "Alkenyl" and "C" x-y "Alkyne" refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon group containing at least one double or triple bond. Unless otherwise specified in the specification, C x-y Alkyl, C x-y alkenyl or C x-y The alkynyl group may optionally be substituted by one or more substituents (such as those described herein).

[0136] "Carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each ring atom is a carbon atom. A carbocyclic ring may comprise a 3- to 10-membered monocyclic ring, a 6- to 12-membered bicyclic ring, and a 6- to 12-membered bridging ring. Each ring of a bicyclic carbocyclic ring may be selected from a saturated, unsaturated, or aromatic ring. In some embodiments, the carbocyclic ring is aryl. In some embodiments, the carbocyclic ring is cycloalkyl. In some embodiments, the carbocyclic ring is cycloalkenyl. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings (where valence allows) is included in the definition of a carbocyclic ring. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, dihydroindenyl, and naphthyl. Unless otherwise specifically stated in the specification, the carbocyclic ring may optionally be substituted with one or more substituents (e.g., those described herein).

[0137] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridging rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the remainder of the molecule via any atom of the heterocycle (e.g., a carbon or nitrogen atom of the heterocycle), where the valence allows. In some embodiments, the heterocycle is a heteroaryl group. In some embodiments, the heterocycle is a heterocyclic alkyl group. In an exemplary embodiment, the heterocycle (e.g., a pyridyl group) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene).

[0138] "Heteroaryl" refers to a 3- to 12-membered aromatic ring comprising at least one heteroatom, wherein each heteroatom may be independently selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, wherein at least one ring system is aromatic, i.e., it contains a cyclic, nonlocal (4n+2) (π-electron system according to Hückel theory) ring. The heteroatom in the heteroaryl ring may optionally be oxidized. One or more nitrogen atoms may optionally be quaternized in the presence of the heteroaryl ring. The heteroaryl ring may be attached to the remainder of the molecule by any atom of the heteroaryl ring (e.g., a carbon or nitrogen atom of the heteroaryl ring) when the valence allows. Examples of heteroaryl rings include (but are not limited to) nitrogen-containing heteroaryl rings. 1,3-benzodioxane-1, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxane Benz[b][1,4]oxazinyl, 1,4-benzodioxane-hexyl, benzonaphthofuranyl, benzooxazolyl, benzodioxanepentyl, benzodioxane-hexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl (benzothienyl, benzothiophenyl), benzothien[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, Phinyl, cyclopentan[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentan[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h] Linyl, 6,7-dihydro-5H-benzo[6,7]cycloheptane[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctyl[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctyl[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctyl[d]pyridyl, isothiazolyl, imidazolyl, indazole, indoleyl, indazole, isoindoleyl, dihydroindoleyl, isodihydroindoleyl, isoquinolinyl, inazinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphridinoneyl, oxadiazolyl, 2-oxazaza 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenoxazinyl, terazinyl, pteridinyl, purinyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyridinyl, pyrroleyl, quinazolinyl, quinoxalinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8 -Tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptane[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridino[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, thienyl. Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups optionally substituted with one or more substituents (such as those described herein) as defined above.

[0139] The compounds of the invention also include the crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of the compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0140] The compounds described herein may exhibit their natural isotopic abundances or may be artificially enriched in one or more atoms with specific isotopes having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention. For example, hydrogen has three natural isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as an extended in vivo half-life and / or exposure, or can provide compounds useful for studying in vivo drug elimination and metabolic pathways. Isotope-enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0141] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms. "Enantiomers" are a pair of stereoisomers that are not mirror images of each other. A 1:1 mixture of enantiomer pairs is a "racemic" mixture. The term "(±)" is used, where appropriate, to indicate a racemic mixture. "Diastereoisomers" are stereoisomers having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified as R or S. Resolved compounds with unknown absolute configurations can be specified as (+) or (-) depending on the direction (dextrorotatory or levorotatory) of the plane-polarized light at the sodium D line wavelength. Some of the compounds described herein contain one or more asymmetric centers and can thereby produce enantiomers, diastereomers, and other stereoisotopic forms, wherein the asymmetric center can be defined by absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of this invention are intended to encompass all such possible stereoisomers, including racemic mixtures, optically pure forms, diastereomer mixtures, 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 the compounds can be analyzed by any suitable method (including, but not limited to, chiral chromatography and optical rotation determination), and the dominance of one stereoisomer relative to another can be determined.

[0142] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E form (or cis or trans form). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the chemical entities described herein are intended to include all Z, E, and tautomeric forms.

[0143] The term "substituted" refers to a portion having a hydrogen substituent on one or more carbon or heteroatoms having a substituted structure. It should be understood that "substituted" or "substituted" implies the following conditions: the substitution is based on the permissible valence of the substituted atom and the substituent, and the substitution produces a stable compound that, for example, cannot be spontaneously transformed by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to encompass all permissible substituents of organic compounds. In a broad aspect, permissible substituents encompass acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents of suitable organic compounds can be one or more and can be the same or different. For the purposes of this invention, heteroatoms (e.g., nitrogen) may have hydrogen substituents and / or any permissible substituent of the organic compounds described herein that satisfies the heteroatom valence. Substituents may include any of the substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, thiohydrogen groups, alkylthio groups, sulfate groups, sulfonates, aminesulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, carbocyclic groups, heterocyclic groups, cycloalkyl groups, heterocyclic alkyl groups, aromatic and heteroaromatic moieties. In some embodiments, substituents may include any of the substituents described herein, such as: halogens, hydroxyl groups, oxo (=O), side thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=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(Ra )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, arylenyl, arynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which may optionally be substituted with the following groups: alkyl, alkenyl, alkynyl, halogen, hydroxyl, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), side thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=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 (where t is 1 or 2), -R b -S(O)t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a When the valence allows, the following groups may be optionally substituted: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), side thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -Rb -S(O) t N(R a )2 (where t is 1 or 2); and each R b Independently selected from direct-chain or straight-chain or branched alkylene, alkenyl, or ynylene chains, and each R c It is a straight chain or a branched alkylene, alkenylene, or ynylene chain.

[0144] Those skilled in the art will understand that substituents may themselves be substituted where appropriate. Unless specifically stated as “unsubstituted,” the chemical references herein should be understood to include substituted variants. For example, the reference to “heteroaryl” groups may implicitly include both substituted and unsubstituted variants.

[0145] In cases where the substituents are specified from left to right in their conventional chemical formula, it also covers chemically identical substituents derived from structures written from right to left, such as -CH2O- being equivalent to -OCH2-.

[0146] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic relative ions known in the trade. Pharmaceutically acceptable acid addition salts can be formed using both 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, phenylethanolic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using both 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 their derivatives 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, pharmaceutically acceptable base addition salts are selected from salts of ammonium, potassium, sodium, calcium, and magnesium.

[0147] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound described herein that is sufficient to affect the intended application (including, but not limited to, the treatment of a disease as defined below). Therapeutic effective amounts can vary depending on factors such as the intended therapeutic application (in vivo) or the individual being treated and the condition of the disease (e.g., the individual's weight and age), the severity of the disease, the method of administration, and such factors, which can be readily determined by those skilled in the art. The term also applies to doses that induce specific responses in target cells (e.g., reduced platelet attachment and / or cell migration). Specific doses will vary depending on factors such as the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is intended, and the physical delivery system carrying it.

[0148] As used herein, “treatment” refers to a means of obtaining a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventative benefits) with respect to a disease, condition, or medical symptom. A therapeutic benefit means the elimination or improvement of the underlying condition being treated. Additionally, a therapeutic benefit can be achieved by eliminating or improving one or more physiological symptoms associated with an underlying condition, thereby observing improvement in an individual, although the individual may still have the underlying condition. In some embodiments, for preventative benefits, the composition is administered to an individual at risk of developing a specific disease or to an individual reporting one or more physiological symptoms of the disease, even if the disease may not be diagnosable.

[0149] The term "therapeutic effect" as used herein encompasses the therapeutic and / or preventative benefits described above. A preventative effect includes delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing the progression of a disease or symptom, or any combination thereof.

[0150] The terms “co-administration,” “combination administration,” and their grammatical equivalents as used herein encompass the administration of two or more agents to an animal (including a human) such that the agent and / or its metabolites are simultaneously present in the individual. Co-administration includes administration of separate compositions simultaneously, administration of separate compositions at different times, or administration of a composition in the presence of two agents.

[0151] The terms “antagonist” and “inhibitor” are used interchangeably and refer to compounds that can inhibit the biological functions (e.g., activity, expression, binding, protein-protein interactions) of target proteins (e.g., menin, MLL1, MLL2, and / or MLL fusion proteins). Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. Although preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway (of which the target protein is a member) are also specifically included in this definition. Preferred biological activity inhibited by antagonists is associated with tumor development, growth, or spread.

[0152] As used herein, the term "agonist" refers to a compound capable of inducing or enhancing the biological function of a target protein (whether by inhibiting the activity or expression of the target protein). Therefore, the term "agonist" is defined in the context of the biological action of the target polypeptide. Although preferred agonists in this document specifically interact with (e.g., bind to) the target, compounds that induce or enhance the biological activity of the target polypeptide by interacting with other members of a signal transduction pathway (of which the target polypeptide is a member) are also specifically included within this definition.

[0153] "Signal transduction" refers to the process by which signals are stimulated or inhibited to reach and within the cell to induce intracellular responses. Regulators of signal transduction pathways are compounds that regulate the activity of one or more cellular proteins localized to the same specific signal transduction pathway. Regulators can increase (agonists) or inhibit (antagonists) the activity of signal transduction molecules.

[0154] "Anticancer agent," "antitumor agent," or "chemotherapy agent" refers to any drug that can be used to treat neoplastic symptoms. An anticancer agent includes a chemotherapy agent. "Chemotherapy" means the administration of one or more chemotherapeutic agents and / or other drugs to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, percutaneous, buccal, or inhalation or suppository form.

[0155] “Individual” refers to an animal, such as a mammal, such as a human. The methods described herein can be used for human treatment and veterinary applications. In some embodiments, the individual is a mammal, and in some embodiments, the individual is a human. “Mammalian” includes humans and domesticated animals (e.g., laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits)) and non-domesticated animals (e.g., wild animals and the like).

[0156] “Prodrug” means a compound that can be converted into a bioactive compound (e.g., a compound of formula (I) or (II)) under physiological conditions or by solvent degradation. Thus, the term “prodrug” refers to a pharmaceutically acceptable precursor of a bioactive compound. In some respects, a prodrug is inert when administered to an individual, but can be converted into an active compound in vivo (e.g.) by hydrolysis. Prodrug compounds generally offer advantages regarding solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7–9, 21–24 (Elsevier, Amsterdam); Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems”, (1987) ACSSymposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, 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 intended to encompass any covalently bonded carrier that, when administered to a mammalian individual, releases the active compound in vivo. Prodrugs of active compounds, as described herein, are prepared by modifying functional groups present in the active compound, in which the modified group dissociates from the parent active compound during conventional processing or in vivo. Prodrugs comprise compounds in which a hydroxyl, amino, or thiol group is bonded to any of the following groups: upon administration of the prodrug of the active compound to a mammalian individual, the hydroxyl, amino, or thiol group cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include (but are not limited to) acetate, formate, and benzoate derivatives of the hydroxyl functional group in the active compound, or acetamide, formamide, and benzamide derivatives of the amine functional group, and the like.

[0157] The term "in vivo" refers to events that occur within an individual's body.

[0158] The term "in vitro" refers to events that occur outside an individual's body. For example, in vitro analysis encompasses any analysis performed outside of an individual. In vitro analysis includes cell-based analyses, which use either live or dead cells. In vitro analysis also includes cell-free analyses, which do not use intact cells.

[0159] "Optional" or "optionally" means that the event or situation described below may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted and unsubstituted aryl groups.

[0160] "Pharmaceutically acceptable carriers, diluents, or excipients" include (but are not limited to) any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the United States Food and Drug Administration for acceptable use in humans or domestic animals.

[0161] This invention provides compounds for regulating the interaction of menin with proteins such as MLL1, MLL2, and MLL-fusion oncogenic proteins. In some embodiments, this invention 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 oncogenic proteins. The compounds of this invention can be used in methods for treating a wide variety of cancers and other diseases related to one or more of MLL1, MLL2, MLL fusion proteins, and menin. In some embodiments, the compounds of this invention covalently bind to menin and inhibit the interaction between menin and MLL. In some embodiments, the compounds of this invention interact non-covalently with menin and inhibit the interaction between menin and MLL.

[0162] The compounds of this invention can be used in numerous methods for treating diseases related to MLL1, MLL2, MLL fusion proteins, and menin. In some embodiments, the compounds of this invention interact with menin non-covalently and inhibit the interaction between menin and MLL. In some embodiments, the compounds of this invention covalently bind to menin and inhibit the interaction between menin and MLL.

[0163] In some aspects, the present invention provides compounds or salts that selectively bind to menin proteins and / or regulate the interaction of menin with MLL proteins (e.g., MLL1, MLL2, or MLL fusion proteins). In some embodiments, the compound regulates menin proteins by binding to or interacting with one or more amino acids and / or one or more metal ions. Some compounds may occupy the F9 and / or P13 pockets of menin. Binding of the compounds disclosed herein may disrupt downstream signaling of menin or MLL (e.g., MLL1, MLL2, or MLL fusion proteins).

[0164] In some aspects, the present invention provides compounds of formula (I):

[0165]

[0166] Or its pharmaceutically acceptable salt, isotopic form, or prodrug, wherein:

[0167] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0168] A is selected from key, C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0169] B is selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0170] C is a heterocyclic ring ranging from 3 to 12 members;

[0171] L 1 L 2 and L 3 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51)-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 L 2 or L 3 R on one of the same or different atoms 50 The groups can optionally form bridges or rings together;

[0172] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0173] m, n, and p are each an independent integer from 0 to 6;

[0174] R 50 Selected independently each time it appears:

[0175] 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)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 );

[0176] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)2NR 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、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles; and

[0177] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0178] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0179] R 51 Selected independently each time it appears:

[0180] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0181] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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 -NR52 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 Carbon rings and 3- to 12-membered heterocycles; and

[0182] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0183] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52S(=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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0184] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0185] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0186] R 57 Selected from:

[0187] 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)2NR 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

[0188] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of the groups is independently substituted with one or more substituents selected from the following groups each time it appears: -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 52S(=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 );and

[0189] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0190] For compounds or salts of formula (I), where C is azapyridine, piperidinyl, or piperazine and R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 hour:

[0191] p is an integer from 1 to 6; and / or

[0192] L 3 via one or more R 50 Replace, where L 3 It is not -CH2CH(OH)-.

[0193] In some aspects, the present invention provides compounds of formula (II):

[0194]

[0195] Or its pharmaceutically acceptable salt, wherein:

[0196] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0197] A, B, and C are each independently selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0198] L 1 and L 2 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R50 Replacement, two of which are attached to L 1 or L 2 R on the same atom or different atoms 50 The groups may optionally form a ring together;

[0199] L 3 Selected from alkylene, alkenylene, and ynylene groups, each of which is derived from one or more R groups. 56 Replace and optionally further via one or more R 50 replace;

[0200] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0201] m, n, and p are each an independent integer from 0 to 6;

[0202] R 50 Selected independently each time it appears:

[0203] 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)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、=O、=S、=N(R 52 );

[0204] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 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 Carbon rings and 3- to 12-membered heterocycles; and

[0205] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0206] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 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 alkynyl group;

[0207] R 51 Selected independently each time it appears:

[0208] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0209] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 -NR52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles; and

[0210] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0211] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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)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 group;

[0212] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0213] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0214] R 56 Selected independently each time it appears:

[0215] -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)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 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0216] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 Carbon rings and 3- to 12-membered heterocycles;

[0217] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 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 alkynyl group; and

[0218] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0219] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0220] For compounds or salts of formula (II), in R 56 When it is -CH3, L 3 It is not further substituted by -OH, -NH2 or -CN.

[0221] In some aspects, the present invention provides compounds of formula (I):

[0222]

[0223] Or its pharmaceutically acceptable salt, isotopic form, or prodrug, wherein:

[0224] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0225] A is selected from key, C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0226] B is selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0227] C is a heterocyclic ring ranging from 3 to 12 members;

[0228] L 1 L 2 and L 3 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 L 2 or L 3 R on one of the same or different atoms 50 The groups can optionally form bridges or rings together;

[0229] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0230] m, n, and p are each an independent integer from 0 to 6;

[0231] R 50 Selected independently each time it appears:

[0232] 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、-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 );

[0233] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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、-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 Carbon rings and 3- to 12-membered heterocycles; and

[0234] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0235] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 52C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0236] R 51 Selected independently each time it appears:

[0237] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0238] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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 52S(=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、-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 Carbon rings and 3- to 12-membered heterocycles; and

[0239] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0240] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54-S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0241] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0242] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0243] R 57 Selected from:

[0244] 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)2NR 53 R 54 -C(O)OR 52 -OC(O)R 52 -OC(O)OR 52 -OC(O)N(R) 52 )2、-OC(O)NR 53 R 54 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)NH(C 1-6 Alkyl), -C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、-P(O)(OR 52(R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=S、=N(R 52 );and

[0245] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of the groups is independently substituted with one or more substituents selected from the following groups each time it appears: -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)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、-P(O)(OR 52 (R) 52 ), -P(O)(NR52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=S and=N(R 52 );and

[0246] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0247] For compounds or salts of formula (I), where C is azapyridine, piperidinyl, or piperazine and R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 hour:

[0248] p is an integer from 1 to 6; and / or

[0249] L 3 via one or more R 50 Replace, where L 3 It is not -CH2CH(OH)-.

[0250] In some aspects, the present invention provides compounds of formula (II):

[0251]

[0252] Or its pharmaceutically acceptable salt, wherein:

[0253] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0254] A, B, and C are each independently selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0255] L 1 and L 2Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 or L 2 R on the same atom or different atoms 50 The groups may optionally form a ring together;

[0256] L 3 Selected from alkylene, alkenylene, and ynylene groups, each of which is derived from one or more R groups. 56 Replace and optionally further via one or more R 50 replace;

[0257] R A R B and RC Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0258] m, n, and p are each an independent integer from 0 to 6;

[0259] R 50 Selected independently each time it appears:

[0260] 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、-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 );

[0261] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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、-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 Carbon rings and 3- to 12-membered heterocycles; and

[0262] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0263] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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(R52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0264] R 51 Selected independently each time it appears:

[0265] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0266] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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(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、-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 Carbon rings and 3- to 12-membered heterocycles; and

[0267] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0268] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52-S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0269] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0270] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0271] R 56 Selected independently each time it appears:

[0272] -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)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)(R52 )2、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0273] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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(R52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0274] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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)R52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、-P(O)(OR 52 (R) 52 ), -P(O)(NR 52 (R) 52 -NR 52 P(O)(R 52 ), -P(O)(NR 52 (OR) 52 ), -P(O)(NR 52 )2、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group; and

[0275] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0276] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0277] For compounds or salts of formula (II), in R 56 When it is -CH3, L 3 It is not further substituted by -OH, -NH2 or -CN.

[0278] In some embodiments, for compounds of formula (I) or (II), H is optionally derived from one or more R... 50The substituted 5- to 12-membered heterocycle, such as a 6- to 12-membered bicyclic heterocycle. In some embodiments, H contains one or more heteroatoms, such as 1, 2, 3, 4, 5, or 6 cyclic heteroatoms. In some embodiments, H contains at least 1, 2, 3, 4, or 5 cyclic nitrogen atoms. In some embodiments, H is optionally substituted with one or more R... 50 Substituted thiophene-pyrimidine group. In some embodiments, H is substituted with C. 1-4 Halogenated alkyl groups (e.g., -CH2CF3) are substituted. In some embodiments, H is substituted with one or more R groups. 50 Replace (e.g., by using R) 50 (The hydrogen atom is replaced by a bond that is linked to a ring atom). H can be linked by 0, 1, 2, 3, 4, 5, 6 or more R atoms. 50 Group substitution. H can be substituted by 1, 2, 3, 4, 5, or 6 R groups. 50 Group substitution, for example, H via one or two R groups. 50 Group substitution. In some embodiments, H is substituted with at least 1, 2, 3, 4, 5, or 6 R groups. 50 Group substitution. In some embodiments, H is substituted with up to 6, 5, 4, 3, 2, or 1 R group. 50 Group substitution.

[0279] In some embodiments, for compounds of formula (I) or (II), H is Where X 1 and X 2 Each independently selected from CR 2 and N; X 3 and X 4 Each is independently selected from C and N; Y 1 and Y 2 Each independently selected from CR 3 , N, NR 4 O and S;R 1 R 2 and R 3 Each time it appears, it is independently selected from hydrogen and R. 50 And R 4 Selected from R 51 .

[0280] In some implementation schemes, X 3 and X 4 Each is designated C. In some implementations, X... 1 For CR 2 And R 2 Selected from hydrogen, halogens, -OH, -OR 52 -NH2, -N(R) 52 )2、-CN、C 1-3 Alkyl, -CH2OH, -CH2OR52 -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. In some embodiments, R 2 It is methyl or -NHCH3. In some embodiments, R 2 For H. In some implementations, X 2 For N. In some implementations, Y 2 For CR 3 And R 3 Selected from hydrogen, halogen, -OH, -N(R) 52 )2、-CN、-C(O)OR 52 C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, Y 1 System S. In some implementations, Y 1 and Y 2 At least one of them is selected from N and NR. 4 O and S. In some implementation schemes, R 1 C 1-3 Halogenated alkyl groups, such as -CH2CF3. In some embodiments, X 1 For CR 2 X 2 Let N, X 3 and X 4 Each is C, Y 1 S, Y 2 For CR 3 And R 1 Selected from R 50 In some implementations, X 1 For CR 2 ;X 2 For N; X 3 and X 4 Each is C; Y 1 System S; Y 2 For CH; R 1 C 1-3 Halogenated alkyl; and R 2 Selected from hydrogen, halogens, -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 Alkyne group. In some embodiments, H is... In some implementations, H is For example In some implementations, H is And R 2 Selected from hydrogen, halogens, -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 Alkyne group. In some embodiments, R 2 Selected from hydrogen, halogen, -OH, alkoxy (e.g., -OR) 52 -OCH3, -OCH2CH3), aminoalkyl, alkylamino, -N(R 52 -NH2 (e.g., -NH2, -NHCH3, -NHCH2CH3), -N(CH3)2, -CN, C 1-3 Alkyl (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 Alkyne group.

[0281] In some embodiments, for compounds of formula (I) or (II), H is Where R 1 Selected from H, halogen, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amide, acyl, alkyl, cycloalkyl, heteroalkyl, and haloalkyl, for example selected from alkyl and haloalkyl; R 2Selected from H, halogen, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amide, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino, for example selected from H, halogen, hydroxyl, and amino; and Y 1 and Y 2 Each of them is independently selected from S, CR 3 , N, NR 4 And O. In some implementations, Y 1 and Y 2 The most common type is O or S.

[0282] In some embodiments, for compounds of formula (I) or (II), L 1 This includes fewer than 20 atoms, for example, fewer than 10 atoms. In some embodiments, L 1 This includes fewer than 20, 15, 10, 9, 8, 7, 6, 5, 4, or fewer than 3 atoms. In some embodiments, L 1 It includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L 1 Includes at least one heteroatom, for example, L 1 Includes at least one nitrogen. In some embodiments, L 1 Optionally via one or more R 50 Replacement. In some implementations, L 1 Unreplaced. In some implementations, L 1 Selected from key, -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 heteroalkylene. In some embodiments, L 1 Selected from key, -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 alkenyl groups, of which C 1-6 Alkylene and C 2-6 Each of the sub-alkenyl groups is optionally derived from one or more R groups. 50 Replacement. In some implementations, L 1 -N(R) 51 -, for example -NH-. In some implementations, L 1 Selected from -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 imide and C 1-4 Heteroalkyl groups. In some embodiments, L 1 -N(R) 51 )-, where R 51 Selected from hydrogen and alkyl groups.

[0283] 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 includes at least one nitrogen atom. In some embodiments, A includes at least one cyclic nitrogen atom. In some embodiments, A is selected from piperidinyl and piperazineyl groups, for example... In some implementation schemes, A is In some embodiments, A is an aromatic, non-aromatic, saturated, or unsaturated ring. In some embodiments, A is selected from arylene, cycloalkylene, heteroalkylene, N-heteroalkylene, heteroarylene, and N-heteroarylene. In some embodiments, A is a 5- to 8-membered heterocycle, wherein the heterocycle comprises at least 1, 2, 3, or 4 cyclic heteroatoms selected from N, O, and S.

[0284] In some implementation schemes, A is selected from and

[0285] In some implementations, A is transmitted via one or more R A Replace (e.g., by using R) A (The hydrogen atoms that are linked to the ring atoms are replaced by bonds). A can be linked by 0, 1, 2, 3, 4, 5, 6 or more R atoms. A Group substitution. A can be substituted by 1, 2, 3, 4, 5, or 6 R groups. A Group substitution, for example, A via 1 or 2 R groups A Group substitution. In some embodiments, A is substituted with at least 1, 2, 3, 4, 5, or 6 R groups. A Group substitution. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with m R groups. A Group substitution, where 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.

[0286] In some implementation schemes, R A Each time it appears, it is independently selected from halogen, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amide, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclic, heterocyclic alkyl, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heterocyclic amino, heterocyclic alkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. In some embodiments, two R groups attached to the same or different atoms... A Groups can form rings together.

[0287] In some embodiments, for compounds of formula (I) or (II), L 2 This includes fewer than 20 atoms, for example, fewer than 10 atoms. In some embodiments, L 2 This includes fewer than 20, 15, 10, 9, 8, 7, 6, 5, 4, or fewer than 3 atoms. In some embodiments, L 2 It includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L 2 Includes at least one heteroatom, for example, L2 Includes at least one nitrogen. In some embodiments, L 2 For optional access via one or more R 50 Replacement C 1-10 Alkylene, such as C 1-4 Alkylene. In some embodiments, L 2 Optionally via one or more R 50 Replacement. In some implementations, L 2 Unreplaced. In some implementations, L 2 Selected from key, -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 heteroalkylene. In some embodiments, L 2 Selected from key, -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 alkenyl groups, of which C 1-6 Alkylene and C 2-6 Each of the sub-alkenyl groups is optionally derived from one or more R groups. 50 Replacement. In some implementations, L 2 Selected from -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 Heteroalkyl groups. In some embodiments, L 2 Selected from -CH2-, -N(R) 51 )-、-N(R 51 CH2-、-N(R) 51 C(O)- and -N(R) 51 )S(O)2-. In some implementations, L 2 It is -CH2-.

[0288] 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 includes at least one nitrogen atom. In some embodiments, B is a 6- to 12-membered heterocycle, wherein the heterocycle includes at least 1, 2, 3, or 4 cyclic heteroatoms selected from N, O, and S. In some embodiments, B is a 6,5- or 6,6-bicyclic heterocycle. In some embodiments, B includes at least one cyclic nitrogen atom. In some of these embodiments, B is optionally cyclically oxidized via one or more R atoms. B Substituted indoles, for example In some implementation schemes, B is For example

[0289] In some implementation schemes, B is selected from and Z 1 Z 2 Z 3 and Z 4 Each independently selected from CR 7 , N and NR 9 Z 5 Selected from C and N; Z 6 Z 7 and Z 8 Each independently selected from CR 8 , N, NR 9 O and S; Z 9 Z 10 and Z 11 Each independently selected from CR 10 CR 11 R 12 NR 13 O and S;R 7 R 8 R 10R 11 and R 12 Each is independently selected from hydrogen and R 50 And R 9 and R 13 Each independently selected from R 51 B can be linked to L at any ring atom. 2 or L 3 (For example, by using L) 2 or L 3 The hydrogen atoms that are linked to the ring atoms are replaced by bonds.

[0290] In some implementation schemes, B is selected from

[0291]

[0292] and

[0293] In some implementations, B is transmitted via one or more R B Replace (e.g., by using R) B (The bond replaces the hydrogen atoms linked to the ring atom). B can be linked by 0, 1, 2, 3, 4, 5, 6 or more R atoms. B Group substitution. B can be substituted by 1, 2, 3, 4, 5 or 6 R groups. B Group substitution, for example, B via 1 or 2 R groups B Group substitution. In some embodiments, B is substituted with at least 1, 2, 3, 4, 5, or 6 R groups. B Group substitution. In some embodiments, B is substituted with n R groups. B Group substitution, 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.

[0294] In some implementation schemes, R BEach time it appears, it is independently selected from halogen, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amide, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclic, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkyloxy, heterocyclic alkyloxy, heterocyclic amino, heterocyclic alkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. In some embodiments, R B Each R group is independently selected from halogen, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amide, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclic alkyl, and heteroarylalkyl groups, each time it appears. In some embodiments, two R groups are attached to the same or different atoms. B Groups can form rings together.

[0295] In some implementations, for compounds of formula (I), L 3 This includes fewer than 30 atoms, for example, fewer than 20 atoms. In some embodiments, L 3 This includes fewer than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or fewer than 3 atoms. In some embodiments, L 3 It includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L 3 Includes at least one heteroatom, for example, L 3 Includes at least one nitrogen. In some embodiments, L 3 For optional access via one or more R 50 Replacement C 1-10 Alkylene, such as C 1-4 Alkylene. In some embodiments, L 3 Optionally via one or more R 50 Replacement. In some implementations, L 3 Unreplaced. In some implementations, L 3 Selected from key, -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 heteroalkylene. In some embodiments, L 3 For optional access via one or more R 50 Replacement C 1-6 Alkylene, wherein R 50 Selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 52 In some implementations, L 3 -CH2CH(R) 50 -, for example -CH2CH(CH3)-. In some implementations, both are attached to L 3 R on the same atom or different atoms 50 The groups optionally form bridges or rings, such as cyclopropyl rings. In some embodiments, L 3 via R 50 Replace, where R 50 A bond is formed to the ring C. In some implementations, L 3 Through one or more selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 52 The group is substituted. In some embodiments, L 3 Replaced by -CH3. In some implementations, L 3 For at least C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Substituted C2 alkylene groups. In some embodiments, L 3 = 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) substitution.

[0296] In some implementations, for compounds of formula (I), L 3 Selected from and Optional, R 50 It is a methyl group. L 3 Optional and In some implementations, L 3 Tie In some implementations, L 3 Tie In some implementations, L 3 Including a stereocentric center. In some embodiments, the stereocentric system has an R-configuration. In some embodiments, the stereocentric system has an S-configuration. In some embodiments, L... 3 The R-isomer is provided in excess of the S-isomer by 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, L... 3 The S-isomer is provided in excess of the R-isomer by 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%.

[0297] In some embodiments, for compounds of formula (I), C is aziridine, piperidinyl, or piperazine; R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 And L 3 via one or more R 50 Replace, where L 3 Not -CH2CH(OH)-. In some embodiments, C is azapyrobutyl, piperidinyl, or piperazine; R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 And L 3 via C 1-4 Alkyl or C 1-4 Halogenated alkyl substitution.

[0298] In some implementations, for compounds of formula (I), L 3 Selected from And any combination thereof. In some embodiments, for compounds of formula (I), L 3 Selected from and

[0299] In some implementations, for compounds of formula (II), L 3 This includes fewer than 30 atoms, for example, fewer than 20 atoms. In some embodiments, L 3 This includes fewer than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or fewer than 3 atoms. In some embodiments, L 3 It includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or at least 20 atoms. In some embodiments, L 3 For one or more R 56 Replace and optionally further via one or more R 50 Replacement C 1-10 Alkylene, such as C 1-4 Alkylene. In some embodiments, L 3 Optionally via one or more R 50 Replacement. In some implementations, L 3 via R 56 Replacement. In some implementations, L 3 Selected from alkylene and alkenylene groups. In some embodiments, L 3 For one or more R 56 Replacement C 1-6 Alkylene, wherein R 56 Selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 59 In some implementations, L 3 For R 56 Replacement C 1-4 Alkylene, wherein R 56 A bond is formed to the ring C. In some implementations, L 3 -CH2CH(R) 56 -, for example -CH2CH(CH3)-. In some implementations, both are attached to L 3 R on the same atom or different atoms 56 The groups optionally form bridges or rings, such as cyclopropyl rings. In some embodiments, L 3 via R 56 Replace, where R 56 A bond is formed to the ring C. In some implementations, L 3 Through one or more selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 59 The group is substituted. In some embodiments, L 3Replaced by -CH3. In some implementations, L 3 For -CH3 substitution and optionally further R 50 Replacement C 1-4 Alkylene, wherein R 50 Not -OH, -NH2, or -CN. In some implementations, L 3 For at least C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Substituted C2 alkylene groups. In some embodiments, L 3 = 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) substitution.

[0300] In some implementations, for compounds of formula (II), L 3 Selected from and Optional, R 56 It is a methyl group. L 3 Optional and In some implementations, L 3 Tie In some implementations, L 3 Tie In some implementations, L 3 Including a stereocentric center. In some embodiments, the stereocentric system has an R-configuration. In some embodiments, the stereocentric system has an S-configuration. In some embodiments, L... 3 The R-isomer is provided in excess of the S-isomer by 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, L... 3 The S-isomer is provided in excess of the R-isomer by 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%.

[0301] In some implementations, for compounds of formula (II), L 3 Selected from And any combination thereof. In some embodiments, for compounds of formula (II), L 3 Selected from and

[0302] In some embodiments, for compounds of formula (I), C is a 3- to 12-membered heterocycle, such as a 5- to 12-membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, 8- to 10-membered fused bicyclic heterocycles, and 7- to 12-membered spirocyclic heterocycles. In some embodiments, the heterocycle includes at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C includes at least one cyclic nitrogen atom. In some embodiments, C is selected from piperidinyl and piperazineyl groups, for example... and In some implementations, C is selected from and In some implementations, C is selected from and In some implementations, C is selected from and It is optionally transmitted via one or more R C Replacement. In some implementations, C is selected from... and Where R 57 Selected from -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 C 1-10 Alkyl groups via one or more selected from -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 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52)2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3 and -S(=O)2NHCH3.

[0303] In some embodiments, for compounds of formula (I), C is selected from... and

[0304] In some implementations, for compounds of formula (I), R 57 Selected from -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)2NR 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 groups, wherein each one is independently substituted with one or more substituents selected from the following group each time it appears: -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)2NR 53 R 54 -C(O)NH(C 1-6 Alkyl), -C(O)NR 53 R 54 In some implementations, R 57 Selected from -S(=O)2R 58 -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)2NR 53 R 54 and C 1-6 Alkyl groups (via one or more of the following) selected from -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)2NR 53 R 54 (Substituent substitution). In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 In some implementations, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3 and -S(=O)2NHCH3.

[0305] In some embodiments, for compounds of formula (I) or (II), C is via one or more R C Replace (e.g., by using R) C (The hydrogen atoms are replaced by bonds that link to the ring atoms). C can be linked by 0, 1, 2, 3, 4, 5, 6 or more R atoms. C Group substitution. C can be substituted by 1, 2, 3, 4, 5 or 6 R groups. C Group substitution, for example, C via one or two R groups. C Group substitution. In some embodiments, C is substituted with at least 1, 2, 3, 4, 5, or 6 R groups. C Group substitution. In some embodiments, C is unsubstituted. In some embodiments, C is substituted with p R groups. CGroup substitution, wherein 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, for compounds of formula (I), C is aziridine, piperidinyl, or piperazine; 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.

[0306] In some implementation schemes, R C Selected from -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 atoms attached to different atoms C Groups can form C together 1-3 Bridge. In some implementations, R C Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups (e.g., -CH3).

[0307] In some embodiments, for compounds of formula (II), C is selected from C6. 3-12 The carbon ring and 3- to 12-membered heterocycles, such as 5- to 12-membered heterocycles. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, 8- to 10-membered fused bicyclic heterocycles, and 7- to 12-membered spirocyclic heterocycles. In some embodiments, the heterocycle includes at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C includes at least one cyclic nitrogen atom. In some embodiments, C is selected from piperidinyl and piperazineyl groups, for example... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from hydrogen and R 50In some implementations, C is selected from... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from one or more R... C Replacement and and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from -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 C1- 10 Alkyl groups, which are derived from one or more of the following groups: -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 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3 and -S(=O)2NHCH3.

[0308] In some embodiments, for compounds of formula (II), C is selected from... and

[0309] In some implementations, for compounds of formula (I) or (II), R C Selected from: halogen, -OR 52 -N(R) 52 )2、-NR53 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; and

[0310] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles;

[0311] Where R C Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)2NR 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、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0312] In some implementation schemes, R C Selected from -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 implementations, R C Selected from -N(R) 52 )2、-NR 53 R 54 -NR52 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 groups and those via -N(R) 52 )2、-NR 53 R 54 -NR 52 S(=O)2R 52 -C(O)R 52 -C(O)OR 52 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2 or -C(O)NR 53 R 54 Replacement C 1-6 alkyl.

[0313] In some implementations, C is selected from and

[0314] In some embodiments, for compounds of formula (I) or (II), H is optionally derived from one or more R... 50 The substituted 5- to 12-membered heterocycles; A is a 3- to 12-membered heterocycle; and B is a 3- to 12-membered heterocycle. In some embodiments, H is optionally substituted with one or more R... 50 The substituted 6- to 12-membered bicyclic heterocycles; A is a 3- to 12-membered heterocycle; and B is a 3- to 12-membered heterocycle. In some embodiments, H is optionally derived from one or more R... 50The substituted 6- to 12-membered bicyclic heterocycles; A is a 3- to 12-membered heterocycle; and B is a 6- to 12-membered bicyclic heterocycle. In some embodiments, H is optionally derived from one or more R... 50 The substituted 5- to 12-membered heterocycles; A is a 3- to 12-membered heterocycle; and B is a 6- to 12-membered bicyclic heterocycle. In some embodiments, H is optionally substituted via one or more R... 50 The substituted thiophene-pyrimidinyl group; A is a 3- to 12-membered heterocycle; and B is a 3- to 12-membered heterocycle. In some embodiments, H is optionally substituted with one or more R groups. 50 The substituted 5- to 12-membered heterocycle; A is selected from piperidinyl and piperazineyl; and B is a 3- to 12-membered heterocycle. In some embodiments, H is optionally substituted with one or more R... 50 The substituted 5- to 12-membered heterocycle; A is a 3- to 12-membered heterocycle; and B is an indoleyl group. In some embodiments, H is a substituted heterocycle derived from one or more R groups. 50 The substituted thiophene-pyrimidinyl group; A is selected from piperidinyl and piperazineyl; and B is indoleyl.

[0315] In some embodiments, for compounds of formula (I) or (II), H is optionally derived from one or more R... 50 The substituted 5- to 12-membered heterocycles; A is a 3- to 12-membered heterocycle; B is a 3- to 12-membered heterocycle; C is a 3- to 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 optionally substituted via one or more R 50 The replacement is a 6- to 12-membered bicyclic heterocycle; A is a 3- to 12-membered heterocycle; B is a 6- to 12-membered bicyclic heterocycle; C is a 3- to 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 optionally derived from one or more R... 50 The substituted 5- to 12-membered heterocycles; A is a 3- to 12-membered heterocycle; B is a 3- to 12-membered heterocycle; and C is a 3- to 12-membered heterocycle. In some embodiments, H is optionally substituted via one or more R... 50 The alternatives are 6- to 12-membered bicyclic heterocycles; A is a 3- to 12-membered heterocycle; B is a 6- to 12-membered bicyclic heterocycle; and C is a 3- to 12-membered heterocycle. In some embodiments, H is optionally derived from one or more R... 50 The substituted 6- to 12-membered bicyclic heterocycle; A is selected from piperidinyl and piperazineyl; B is a 6- to 12-membered bicyclic heterocycle; and C is a 3- to 12-membered heterocycle. In some embodiments, H is optionally substituted with one or more R... 50 The substituted 6- to 12-membered bicyclic heterocycle; A is selected from piperidinyl and piperazineyl; B is a 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3. In some embodiments, H is optionally substituted with one or more R... 50The substituted thiophene-pyrimidinyl group; A is a 3- to 12-membered heterocycle; and B is a 6- to 12-membered bicyclic heterocycle. In some embodiments, H is optionally substituted with one or more R groups. 50 The substituted thiophene-pyrimidinyl group; A is a 3- to 12-membered heterocycle; B is a 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to 3; and n is an integer from 1 to 3. In some embodiments, H is optionally substituted with one or more R groups. 50 The substituted 9- to 10-membered bicyclic heterocycle; A is a 5- to 7-membered heterocycle; and B is a 9-membered bicyclic heterocycle, wherein each of the heterocycles comprises at least one nitrogen atom. In some embodiments, H is optionally derived from one or more R... 50 The substituted 9- to 10-membered bicyclic heterocycles; A is a 5- to 7-membered heterocycle; B is a 9-membered bicyclic heterocycle; and n is an integer from 1 to 3, wherein each of the heterocycles includes at least one nitrogen atom.

[0316] In some implementations, for compounds of formula (I), L 1 Including fewer than 10 atoms, L 2 Including fewer than 10 atoms, and L 3 Includes fewer than 20 atoms. In some implementations, L 1 L 2 and L 3 Each comprises at least one atom, for example, at least two atoms. In some embodiments, L 1 L 2 and L 3 Each is independently selected from the 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 )-, alkylene, alkenylene, heteroalkylene, and heteroalkylene. In some embodiments, L 1 L 2 L 3 Each is independently selected from -CH2-, -CH2CH2-, -CH2CH(CH3)-, -N(R) 51 )-、-N(R 51 CH2-、-N(R)51 C(O)- and -N(R) 51 )S(O)2-. In some implementations, L 1 Selected from -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 heteroalkylene; and L 2 and L 3 Independently selected from, optionally via, one or more R 50 Replacement C 1-4 Alkylene. In some embodiments, L 1 L 2 and L 3 Each is independently selected from -O-, -S-, -N(R) 51 )-;C 1-4 Alkylenes and 1 to 4 heteroalkylenes, wherein each is optionally derived from one or more R 50 Replacement. In some implementations, L 1 For -NH-, L 2 It is -CH2-, and L 3 For optional access via one or more R 50 Replacement C 1-4 Alkylene.

[0317] In some implementations, for compounds of formula (II), L 1 Including fewer than 10 atoms, L 2 Including fewer than 10 atoms, and L 3 Includes fewer than 20 atoms. In some implementations, L 1 L 2 and L 3 Each comprises at least one atom, for example, at least two atoms. In some embodiments, L 1 and L 2 Each is independently selected from the 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 )-, alkylene, alkenylene, heteroalkylene, and heteroalkylene, and L 3 Selected from one or more R 56 Replace and optionally further via one or more R 50 Replacement C 1-10 Alkylene and C 2-10 Alkenyl group. In some embodiments, L 1 and L 2 Each is independently selected from -CH2-, -N(R) 51 )-、-N(R 51 CH2-、-N(R) 51 C(O)- and -N(R) 51 )S(O)2-, and L 3 Selected from one or more R 56 Replace and optionally further via one or more R 50 Replacement C 1-10 Alkylene and C 2-10 Alkenyl group. In some embodiments, L 1 Selected from -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 heteroalkylene; and L 2 For optional access via one or more R 50 Replacement C 1-4 Alkylene, and L3 For one or more R 56 Replace and optionally further via one or more R 50 Replacement C 1-4 Alkylene. In some embodiments, L 1 and L 2 Each is independently selected from -O-, -S-, -N(R) 51 )-;C 1-4 Alkylenes and 1 to 4 heteroalkylenes, wherein each is optionally derived from one or more R 50 Replace, and L 3 System base via one or more R 56 Replace and optionally further via one or more R 50 Replacement C 1-4 Alkane. In some embodiments, L 1 For -NH-, L 2 It is -CH2-, and L 3 For one or more R 56 Replace and optionally further via one or more R 50 Replacement C 1-4 Alkylene.

[0318] In some respects, for compounds of formula (I):

[0319] H is an optional location via one or more R. 50 Replacement of 5- to 12-membered heterocycles;

[0320] A, B, and C are each independently selected from heterocycles ranging from 3 to 12 members;

[0321] L 1 L 2 and L 3 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51)C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 L 2 or L 3 R on one of the same or different atoms 50 The groups may optionally form a ring together;

[0322] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups may optionally form a ring together;

[0323] m is an integer from 0 to 3;

[0324] n is an integer from 1 to 3;

[0325] p is an integer from 0 to 6;

[0326] R 50 Selected independently each time it appears:

[0327] 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)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 );

[0328] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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 -NR52 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 Carbon rings and 3- to 12-membered heterocycles; and

[0329] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0330] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52S(=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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0331] R 51 Selected independently each time it appears:

[0332] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0333] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0334] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0335] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52S(=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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0336] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0337] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0338] R 57 Selected from:

[0339] -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)2NR 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

[0340] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of them is independently substituted by one or more substituents selected from the following groups each time it appears: -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)2NR 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; and

[0341] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0342] For compounds or salts of formula (I), where C is azapyridine, piperidinyl, or piperazine and R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 hour:

[0343] p is an integer from 1 to 6; and / or

[0344] L 3 via one or more R 50 Replace, where L 3 It is not -CH2CH(OH)-.

[0345] In some respects, for compounds of formula (II):

[0346] H is an optional location via one or more R. 50 Replacement of 5- to 12-membered heterocycles;

[0347] A, B, and C are each independently selected from heterocycles ranging from 3 to 12 members;

[0348] L 1 and L 2 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51)C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 or L 2 R on the same atom or different atoms 50 The groups may optionally form a ring together;

[0349] L 3 Selected from C 1-6 Alkylene, C 2-6 alkenyl and C 2-6 alkyne group, wherein each is derived from one or more R groups 56 Replace and optionally further via one or more R 50 replace;

[0350] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0351] m is an integer from 0 to 3;

[0352] n is an integer from 1 to 3;

[0353] p is an integer from 0 to 6;

[0354] R 50 Selected independently each time it appears:

[0355] 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 );

[0356] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0357] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0358] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-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)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0359] R 51 Selected independently each time it appears:

[0360] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0361] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0362] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0363] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR.52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0364] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0365] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0366] R 56 Selected independently each time it appears:

[0367] -OR 59 =O,C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group,

[0368] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 -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 Carbon rings and 3- to 12-membered heterocycles;

[0369] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 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 alkynyl group; and

[0370] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0371] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0372] For compounds or salts of formula (II), in R 56 When it is -CH3, L 3 It is not further substituted by -OH, -NH2 or -CN.

[0373] In some respects, for compounds of formula (I):

[0374] H is an optional location via one or more R. 50 Substituted thiophenepyrimidine group;

[0375] A is selected from piperidinyl and piperazineyl;

[0376] B is an indolide;

[0377] L 1 and L 2 Each is independently selected from -O-, -S-, -NH-, and -CH2-;

[0378] L 3 Selected from key, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 3 R on the same atom or different atoms 50 The groups may optionally form a ring together;

[0379] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups may optionally form a ring together;

[0380] m is an integer from 0 to 3;

[0381] n is an integer from 1 to 3;

[0382] p is an integer from 0 to 6;

[0383] R 57 Selected from:

[0384] -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)2NR 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

[0385] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of them is independently substituted by one or more substituents selected from the following groups each time it appears: -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)2NR 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; and

[0386] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0387] For compounds or salts of formula (I), where C is azapyridine, piperidinyl, or piperazine and R 57 is -S(=O)2R 58 -S(=O)2N(R) 52 )2 or -NR 52 S(=O)2R 52 hour:

[0388] p is an integer from 1 to 6; and / or

[0389] L 3 via one or more R 50 Replace, where L 3 It is not -CH2CH(OH)-.

[0390] In some respects, for compounds of formula (II):

[0391] H is an optional location via one or more R. 50 Substituted thiophenepyrimidine group;

[0392] A is selected from piperidinyl and piperazineyl;

[0393] B is an indolide;

[0394] L 1 and L 2 Each is independently selected from -O-, -S-, -NH-, and -CH2-;

[0395] L 3 Selected from C 1-6 Alkylene, C 2-6 alkenyl and C 2-6 alkyne group, wherein each is derived from one or more R groups 56 Replace and optionally further via one or more R 50 replace;

[0396] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0397] m is an integer from 0 to 3;

[0398] n is an integer from 1 to 3;

[0399] p is an integer from 0 to 6;

[0400] R 56 Selected independently each time it appears:

[0401] -OR 59 =O,C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group,

[0402] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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)NR53 R 54 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0403] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 52C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 -P(O)(OR) 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group; and

[0404] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0405] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0406] For compounds or salts of formula (II), in R 56 When it is -CH3, L 3 It is not further substituted by -OH, -NH2 or -CN.

[0407] In some respects, compounds of formula (I) can be represented by the following formula:

[0408] For example In some implementation schemes, R 1 Selected from R 50 In some implementations, R 1 C 1-3 Halogenated alkyl groups, such as -CH2CF3. In some embodiments, R 2 Selected from R 50 In some implementations, R 2 Selected from hydrogen, halogens, -OH, -OR 52 -NH2, -N(R) 52 )2、-CN、C 1-3Alkyl, 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 Alkyne group. In some embodiments, R 2 Selected from halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. Optionally, R 2 Selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. In some embodiments, R 3 Selected from hydrogen, halogen, -OH, -N(R) 52 )2、-CN、-C(O)OR 52 C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 51 Selected from hydrogen and alkyl groups, for example, R 51 Hydrogen is involved. In some implementations, R... A Selected from 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 group, optionally substituted C1-10 Alkyl groups, optionally substituted C 2-10 alkenyl and optionally substituted C 2-10 Alkyne group. In some embodiments, m is 0. In some embodiments, L 2 Selected from -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 Heteroalkyl groups. In some embodiments, L 2 For optional access via one or more R 50 Replacement C 1-4 Alkylene. In some embodiments, L 2 For optional access via one or more R 50 Replacement C 1-2 Alkylene. In some embodiments, L 2 Selected from -CH2-, -N(R) 51 )-、-N(R 51 CH2-、-N(R) 51 C(O)- and -N(R) 51 )S(O)2-. In some implementations, L 2 For -CH2-. In some implementations, R B It is present at one or more positions in indole, for example, at positions 2, 3, 4, or 6 in indole. In some embodiments, R B Selected from 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 group, optionally substituted C 1-10 Alkyl groups, optionally substituted C 2-10 alkenyl and optionally substituted C 2-10Alkyne group. In some embodiments, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 C 1-3 Alkyl groups and optionally substituted C 1-3 Alkyl, for example, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 and C 1-2 Alkyl group. In some embodiments, n is an integer from 1 to 4 (e.g., an integer from 2 to 3). In some embodiments, n is 2. In some embodiments, L 3 Selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 alkyne group, wherein each is derived from one or more R groups 50 Replacement. In some implementations, L 3 For optional access via one or more R 50 Replacement C 1-6 Alkylene. In some embodiments, L 3 For at least C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Substituted C2 alkylene groups. In some embodiments, L 3 = 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) substitution. In some embodiments, L 3 Replaced by -CH3. In some implementations, L 3 Selected from and Where R 50Optionally, it is methyl. In some embodiments, C is a 3- to 12-membered heterocycle, such as a 5- to 12-membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, 8- to 10-membered fused bicyclic heterocycles, and 7- to 12-membered spirocyclic heterocycles. In some embodiments, the heterocycle includes at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C includes at least one cyclic nitrogen atom. In some embodiments, C is selected from piperidinyl and piperazineyl groups, for example... and In some implementations, C is selected from and In some implementations, C is selected from and In some implementations, C is selected from... and It is optionally transmitted via one or more R C Replacement. In some implementations, C is selected from... and Where R 57 Selected from -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 C 1-10 Alkyl groups, which are derived from one or more of the following groups: -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 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, C is selected from... and In some implementation schemes, RC Selected from -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 implementations, R C Selected from -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 groups and those via -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、-NR52 C(O)NR 53 R 54 -C(O)N(R) 52 )2 or -C(O)NR 53 R 54 Replacement C 1-6 Alkyl group. In some embodiments, C is selected from... and In some implementation schemes, R C Selected from -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 atoms attached to different atoms C Groups can form C together 1-3 Bridge. In some implementations, R C Selected from C 1-3 Alkyl and C 1-3 Haloalkyl (e.g., -CH3). In some embodiments, p is selected from integers 0 to 4, for example, p is selected from integers 0 to 2. In some embodiments, p is 0. In some embodiments, R 57 Selected from -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)2NR 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 groups, wherein each one is independently substituted with one or more substituents selected from the following group each time it appears: -S(=O)2R 58 -S(=O)2N(R) 52 )2、-S(=O)2NR 53R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)2NR 53 R 54 -C(O)NH(C 1-6 Alkyl), -C(O)NR 53 R 54 In some implementations, R 57 Selected from -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)2NR 53 R 54 and via one or more selected from -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)2NR 53 R 54 The substituents of C 1-6 Alkyl group. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 In some implementations, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3 and -S(=O)2NHCH3.

[0409] In some respects, compounds of formula (I) can be represented by the following formula:

[0410] For example In some implementation schemes, R 2 Selected from R 50 In some implementations, R 2 Selected from hydrogen, halogens, -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 Alkyne group. In some embodiments, R 2 Selected from halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. Optionally, R 2 Selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. In some embodiments, R B Selected from 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 group, optionally substituted C 1-10Alkyl groups, optionally substituted C 2-10 alkenyl and optionally substituted C 2-10 Alkyne group. In some embodiments, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 C 1-3 Alkyl groups and optionally substituted C 1-3 Alkyl, for example, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 and C 1-2 Alkyl group. In some embodiments, L 3 Selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 alkyne group, wherein each is derived from one or more R groups 50 Replacement. In some implementations, L 3 For optional access via one or more R 50 Replacement C 1-6 Alkylene. In some embodiments, L 3 For at least C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Substituted C2 alkylene groups. In some embodiments, L 3 = 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) substitution. In some embodiments, L 3 Replaced by -CH3. In some implementations, L 3 Selected from and Where R 50Optionally, it is methyl. In some embodiments, C is a 3- to 12-membered heterocycle, such as a 5- to 12-membered heterocycle. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, 8- to 10-membered fused bicyclic heterocycles, and 7- to 12-membered spirocyclic heterocycles. In some embodiments, the heterocycle includes at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C includes at least one cyclic nitrogen atom. In some embodiments, C is selected from piperidinyl and piperazineyl groups, for example... and In some implementations, C is selected from and In some implementations, C is selected from and In some implementations, C is selected from and Each of them may choose to pass through one or more R C Replacement. In some implementations, C is selected from... and Where R 57 Selected from -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 C 1-10 Alkyl groups, which are derived from one or more of the following groups: -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 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, C is selected from... and In some implementation schemes, R C Selected from -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 implementations, R C Selected from -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 groups and those via -N(R) 52 )2、-NR 53 R 54 -NR 52 S(=O)2R 52 -C(O)R 52 -C(O)OR 52 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52)2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2 or -C(O)NR 53 R 54 Replacement C 1-6 Alkyl group. In some embodiments, C is selected from... and In some implementation schemes, R C Selected from -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 atoms attached to different atoms C Groups can form C together 1-3 Bridge. In some implementations, R C Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl group (e.g., -CH3). In some embodiments, p is selected from integers 0 to 4, for example, p is selected from integers 0 to 2. In some embodiments, p is 0. In some embodiments, R 57 Selected from -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)2NR 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 groups, wherein each one is independently substituted with one or more substituents selected from the following group each time it appears: -S(=O)2R 58 -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)2NR 53 R 54 -C(O)NH(C 1-6 Alkyl), -C(O)NR 53 R 54 In some implementations, R 57 Selected from -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)2NR 53 R 54 and via one or more selected from -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)2NR 53 R 54 The substituents of C 1-6 Alkyl group. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 In some implementations, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3 and -S(=O)2NHCH3.

[0411] In some respects, compounds of formula (I) can be represented by the following formula:

[0412] For example In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, such as piperidinyl and piperazine. In some embodiments, R... 50 Selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 52 For example, R 50 It is methyl. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, R 57 The system is –S(=O)2CH3. In some implementations, R 50 It is methyl and R 57 For -S(=O)2CH3. In some implementations, R 2 Selected from hydrogen, halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. In some embodiments, R 2 It is methyl or -NHCH3. In some embodiments, R 2 For H.

[0413] In some respects, compounds of formula (I) can be represented by the following formula:

[0414] For example In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, such as piperidinyl and piperazine. In some embodiments, R...50 Selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 52 For example, R 50 It is methyl. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, R 57 The system is –S(=O)2CH3. In some implementations, R 50 It is methyl and R 57 For -S(=O)2CH3. In some implementations, R 2 Selected from hydrogen, halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. In some embodiments, R 2 It is methyl or -NHCH3. In some embodiments, R 2 For H.

[0415] In some respects, compounds of formula (II) can be represented by the following formula:

[0416] For example In some implementation schemes, R 1 Selected from R 50 In some implementations, R 1 C 1-3 Halogenated alkyl groups, such as -CH2CF3. In some embodiments, R 2Selected from R 50 In some implementations, R 2 Selected from hydrogen, halogens, -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 Alkyne group. In some embodiments, R 2 Selected from halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. Optionally, R 2 Selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. In some embodiments, R 3 Selected from hydrogen, halogen, -OH, -N(R) 52 )2、-CN、-C(O)OR 52 C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 51 Selected from hydrogen and alkyl groups, for example, R 51 Hydrogen is involved. In some implementations, R... A Selected from 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 group, optionally substituted C 1-10 Alkyl groups, optionally substituted C 2-10 alkenyl and optionally substituted C 2-10 Alkyne group. In some embodiments, m is 0. In some embodiments, L 2 Selected from -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 Heteroalkyl groups. In some embodiments, L 2 For optional access via one or more R 50 Replacement C 1-4 Alkylene. In some embodiments, L 2 For optional access via one or more R 50 Replacement C 1-2 Alkylene. In some embodiments, L 2 Selected from -CH2-, -N(R) 51 )-、-N(R 51 CH2-、-N(R) 51 C(O)- and -N(R) 51 )S(O)2-. In some implementations, L 2 For -CH2-. In some implementations, R B It is present at one or more positions in indole, for example, at positions 2, 3, 4, or 6 in indole. In some embodiments, R B Selected from 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 1-10Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, optionally substituted C 1-10 Alkyl groups, optionally substituted C 2-10 alkenyl and optionally substituted C 2-10 Alkyne group. In some embodiments, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 C 1-3 Alkyl groups and optionally substituted C 1-3 Alkyl, for example, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 and C 1-2 Alkyl group. In some embodiments, n is an integer from 1 to 4 (an integer from 2 to 3). In some embodiments, n is 2. In some embodiments, L 3 Selected from alkylene, alkenylene, and ynylene groups, each of which is derived from one or more R groups. 56 Replace and optionally further via one or more R 50 Replacement. In some implementations, L 3 Selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 alkyne group, wherein each is derived from one or more R groups 56 Replace and optionally further via one or more R 50 Replacement. In some implementations, L 3 Selected from C 1-6 Alkylene, which is derived from one or more R 56 Replace and optionally further via one or more R 50 Replacement. In some implementations, L 3 It is a C2 alkylene group, which has at least one C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Replacement. In some implementations, L 3 = 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) substitution. In some embodiments, L3 Replaced by -CH3. In some implementations, L 3 Selected from and Where R 56 Optionally, it is methyl. In some embodiments, C is selected from C6. 3-12 The carbon ring and 3- to 12-membered heterocycles, such as 5- to 12-membered heterocycles. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, 8- to 10-membered fused bicyclic heterocycles, and 7- to 12-membered spirocyclic heterocycles. In some embodiments, the heterocycle includes at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C includes at least one cyclic nitrogen atom. In some embodiments, C is selected from piperidinyl and piperazineyl groups, for example... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from one or more R... C Replacement ,and and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from -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 C 1-10 Alkyl groups, which are derived from one or more of the following groups: -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)2R52 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52 For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, C is selected from... and In some implementation schemes, R C Selected from -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 atoms attached to different atoms C Groups can form C together 1-3 Bridge. In some implementations, R C Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl group (e.g., -CH3). In some embodiments, p is selected from integers 0 to 4, for example, p is selected from integers 0 to 2. In some embodiments, p is 0. In some embodiments, R C Selected from -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 implementations, R C Selected from -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 groups and those via -N(R) 52 )2、-NR 53 R 54 -NR 52 S(=O)2R 52 -C(O)R 52 -C(O)OR 52 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2 or -C(O)NR 53 R 54 Replacement C 1-6 Alkyl group. In some embodiments, C is selected from... and .

[0417] In some respects, compounds of formula (II) can be represented by the following formula:

[0418] For example In some implementation schemes, R 2 Selected from R 50 In some implementations, R2 Selected from hydrogen, halogens, -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 Alkyne group. In some embodiments, R 2 Selected from halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. Optionally, R 2 Selected from -NH2, -CH3, -OCH3, -CH2OH, and -NHCH3. In some embodiments, R B Selected from 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 group, optionally substituted C 1-10 Alkyl groups, optionally substituted C 2-10 alkenyl and optionally substituted C 2-10 Alkyne group. In some embodiments, R BSelected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 C 1-3 Alkyl groups and optionally substituted C 1-3 Alkyl, for example, R B Selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 and C 1-2 Alkyl group. In some embodiments, L 3 Selected from alkylene, alkenylene, and ynylene groups, each of which is derived from one or more R groups. 56 Replace and optionally further via one or more R 50 Replacement. In some implementations, L 3 Selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 alkyne group, wherein each is derived from one or more R groups 56 Replace and optionally further via one or more R 50 Replacement. In some implementations, L 3 Selected from C 1-6 Alkylene, which is derived from one or more R 56 Replace and optionally further via one or more R 50 Replacement. In some implementations, L 3 It is a C2 alkylene group, which has at least one C 1-3 Alkyl or C 1-3 Halogenated alkyl and optionally further substituted with one or more R 50 Replacement. In some implementations, L 3 = 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) substitution. In some embodiments, L 3 Replaced by -CH3. In some implementations, L 3 Selected from and Where R 56 Optionally, it is methyl. In some embodiments, C is selected from C6. 3-12The carbon ring and 3- to 12-membered heterocycles, such as 5- to 12-membered heterocycles. In some embodiments, the heterocycle is saturated. In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, 8- to 10-membered fused bicyclic heterocycles, and 7- to 12-membered spirocyclic heterocycles. In some embodiments, the heterocycle includes at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C includes at least one cyclic nitrogen atom. In some embodiments, C is selected from piperidinyl and piperazineyl groups, for example... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from one or more R... C Replacement ,and and Where R 57 Selected from hydrogen and R 50 In some implementations, C is selected from... and Where R 57 Selected from -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 C 1-10 Alkyl groups, which are derived from one or more of the following groups: -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 Substituents are substituted. In some embodiments, R 57 Selected from -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R 52For example, R 57 Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, C is selected from... and In some implementation schemes, R C Selected from -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 atoms attached to different atoms C Groups can form C together 1-3 Bridge. In some implementations, R C Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl group (e.g., -CH3). In some embodiments, p is selected from integers 0 to 4, for example, p is selected from integers 0 to 2. In some embodiments, p is 0. In some embodiments, R C Selected from -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 implementations, R C Selected from -N(R) 52 )2、-NR 53 R 54 -NR 52 S(=O)2R 52 -C(O)R52 -C(O)OR 52 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 C 1-6 Alkyl groups and those via -N(R) 52 )2、-NR 53 R 54 -NR 52 S(=O)2R 52 -C(O)R 52 -C(O)OR 52 -NR 52 C(O)R 52 -NR 52 C(O)OR 52 -NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 -C(O)N(R) 52 )2 or -C(O)NR 53 R 54 Replacement C 1-6 Alkyl group. In some embodiments, C is selected from... and

[0419] In some respects, compounds of formula (II) can be represented by the following formula:

[0420] In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, such as piperidinyl and piperazine. In some embodiments, R... 56 Selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 59 For example, R 56 It is methyl. In some embodiments, R C Selected from -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52)2 and -NR 52 S(=O)2R 52 For example, R C Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, p is an integer from 1 to 3; for example, p is 1. In some embodiments, R C For -S(=O)2CH3. In some implementations, R 56 It is methyl and R C For -S(=O)2CH3. In some implementations, R 2 Selected from hydrogen, halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. In some embodiments, R 2 It is methyl or -NHCH3. In some embodiments, R 2 For H.

[0421] In some respects, compounds of formula (II) can be represented by the following formula:

[0422] For example In some embodiments, C is selected from 5- to 7-membered monocyclic heterocycles, such as piperidinyl and piperazine. In some embodiments, R... 56 Selected from deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR 59 For example, R 56 It is methyl. In some embodiments, R C Selected from -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2 and -NR 52 S(=O)2R52 For example, R C Selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3. In some embodiments, p is an integer from 1 to 3; for example, p is 1. In some embodiments, R C For -S(=O)2CH3. In some implementations, R 56 It is methyl and R C For -S(=O)2CH3. In some implementations, R 2 Selected from hydrogen, halogens, -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 Alkyne group, for example, R 2 Selected from -OH, -OR 52 -NH2, -N(R) 52 )2, -CN and C 1-2 Alkyl group. In some embodiments, R 2 It is methyl or -NHCH3. In some embodiments, R 2 For H.

[0423] In some embodiments, the present invention provides stereoisomers of compounds of formula (I) or (II). In some embodiments, the stereoisomer system is provided in excess of the enantiomer. In some embodiments, the stereoisomer system is provided in 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% enantiomer. In some embodiments, the stereoisomer system is provided in an enantiomer 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 stereoisomer system is provided in an enantiomer excess of greater than 95%, for example, greater than 99%.

[0424] In some embodiments, the present invention provides stereoisomers of compounds of formula (I) or (II). In some embodiments, the stereoisomeric system is provided in excess of diastereomers. In some embodiments, the stereoisomeric system is provided in 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% diastereomers. In some embodiments, the stereoisomer system is provided in an 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% diastereomers. In some embodiments, the stereoisomer system is provided in an excess of greater than 95% diastereomers, for example, greater than 99% diastereomers.

[0425] In some embodiments, the compound of formula (I) or (II) is preferably used as a non-racemic mixture, wherein one enantiomer is present in excess relative to its corresponding enantiomer. Typically, the mixture contains a mixture of the two isomers in a ratio of at least about 9:1, preferably at least 19:1. In some embodiments, the compound is provided in an excess of at least 96% enantiomer, meaning that the compound has less than 2% of the corresponding enantiomer. In some embodiments, the compound is provided in an excess of at least 96% diastereomer, meaning that the compound has less than 2% of the corresponding diastereomer.

[0426] In some embodiments, the compound of formula (I) or (II) is preferably used as a non-racemic mixture, wherein the (+)-isomer system mixture is the major component. Typically, the mixture contains no more than about 10% of the (-)-isomer, meaning the ratio of (+)-isomer to (-)-isomer is at least about 9:1, and preferably the mixture contains less than 5% of the (-)-isomer, meaning the ratio of (+)-isomer to (-)-isomer is at least about 19:1. In some embodiments, the compound used has less than 2% of the (-)-isomer, meaning it has an enantiomer excess of at least about 96%. In some embodiments, the compound has an enantiomer excess of at least 98%. In some embodiments, the compound has an enantiomer excess of at least 99%.

[0427] In some embodiments, the compound of formula (I) or (II) is preferably used as a non-racemic mixture, wherein the (-)-isomer system mixture is the major component. Typically, the mixture contains no more than about 10% of the (+)-isomer, meaning the ratio of (-)-isomer to (+)-isomer is at least about 9:1, and preferably the mixture contains less than 5% of the (+)-isomer, meaning the ratio of (-)-isomer to (+)-isomer is at least about 19:1. In some embodiments, the compound used has less than 2% of the (+)-isomer, meaning it has an enantiomer excess of at least about 96%. In some embodiments, the compound has an enantiomer excess of at least 98%. In some embodiments, the compound has an enantiomer excess of at least 99%.

[0428] In some respects, the present invention provides stereoisomers of compounds of formula (I):

[0429]

[0430] Or its pharmaceutically acceptable salt, isotopic form, or prodrug, wherein:

[0431] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0432] A is selected from key, C 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0433] B is selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0434] C is a heterocyclic ring ranging from 3 to 12 members;

[0435] L 1 L 2 and L 3 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51)C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 L 2 or L 3 R on one of the same or different atoms 50 The groups can optionally form bridges or rings together;

[0436] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0437] m, n, and p are each an independent integer from 0 to 6;

[0438] R 50 Selected independently each time it appears:

[0439] 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 );

[0440] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0441] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0442] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52S(=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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0443] R 51 Selected independently each time it appears:

[0444] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0445] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0446] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0447] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52S(=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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0448] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0449] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0450] R 57 Selected from:

[0451] 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)2NR 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

[0452] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group, wherein each of the groups is independently substituted with one or more substituents selected from the following groups each time it appears: -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 -NR52 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 );and

[0453] R 58 Selected from hydrogen; and C 1-20 Alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0454] In some embodiments, the stereoisomer system of the compound of formula (I) is provided in an enantiomer 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 stereoisomer system is provided in an enantiomer 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 implementations, the stereoisomer system has an enantiomer excess of more than 95%, for example, more than 99%.

[0455] In some implementations, for stereoisomers of compound (I), L 3 Selected from and Optional, R 50 It is methyl. In some embodiments, L 3 Tie In some implementations, L 3 Tie In some implementations, C is selected from and In some implementations, L 3 Selected from and And C is selected from and

[0456] Any combination of groups described above for the various variables of compound (I) is covered in this article for the stereoisomers of compound (I).

[0457] In some respects, the present invention provides stereoisomers of compounds of formula (II):

[0458]

[0459] Or its pharmaceutically acceptable salt, wherein:

[0460] H is selected from C 5-12 Carbon rings and 5- to 12-membered heterocycles, each optionally via one or more R... 50 replace;

[0461] A, B, and C are each independently selected from C. 3-12 Carbon rings and 3- to 12-membered heterocycles;

[0462] L 1 and L 2 Each is independently selected from the bond, -O-, -S-, -N(R) 51 )-、-N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 )-、-C(O)N(R 51 )C(O)-、-C(O)N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)-、-N(R 51 )C(O)N(R 51 )-、-N(R 51 )C(O)O-、-OC(O)N(R 51 )-、-C(NR 51 )-、-N(R 51 )C(NR 51 )-、-C(NR 51 )N(R 51 )-、-N(R 51 )C(NR 51 )N(R 51 )-、-S(O) 2- , -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 S(O)2-、-S(O)2N(R) 51 )-、-N(R 51 )S(O)-、-S(O)N(R 51 )-、-N(R 51 )S(O)2N(R 51 )-、-N(R 51 )S(O)N(R 51 )-; alkylene, alkenylene, ynylene, heteroalkylene, heteroalkenylene, and heteroynylene, each optionally derived from one or more R 50 Replacement, two of which are attached to L 1 or L 2 R on the same atom or different atoms 50 The groups may optionally form a ring together;

[0463] L 3 Selected from alkylene, alkenylene, and ynylene groups, each of which is derived from one or more R groups. 56 Replace and optionally further via one or more R 50 replace;

[0464] R A R B and R C Each occurrence is independently selected from R. 50 Or two R atoms attached to the same or different atoms A Group, two R B Group or two R C The groups can optionally form bridges or rings together;

[0465] m, n, and p are each an independent integer from 0 to 6;

[0466] R 50 Selected independently each time it appears:

[0467] 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 );

[0468] C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0469] C3-12 Carbon rings and 3- to 12-membered heterocycles,

[0470] Where R 50 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0471] R 51Selected independently each time it appears:

[0472] Hydrogen, -C(O)R 52 -C(O)OR 52 -C(O)N(R) 52 )2、-C(O)NR 53 R 54 ;

[0473] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each group is optionally substituted independently, each time it appears, by one or more substituents 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)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 Carbon rings and 3- to 12-membered heterocycles; and

[0474] C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0475] Where R 51 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0476] R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted;

[0477] R 53 and R 54 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or more R 50 Substituted heterocycles;

[0478] R 56 Selected independently each time it appears:

[0479] -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)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(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 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings and 3- to 12-membered heterocycles,

[0480] Where R 56 Each C in 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Each time the alkynyl group appears, it is independently and optionally substituted by one or more substituents selected from: halogen, -NO2, -CN, -OR. 59 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 52C(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 Carbon rings and 3- to 12-membered heterocycles;

[0481] Where R 56 Each C in 3-12 The carbocyclic ring and the 3- to 12-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: halogen, -NO2, -CN, -OR. 52 -SR 52 -N(R) 52 )2、-NR 53 R 54 -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group; and

[0482] In addition, R 56 Optionally, bonds are formed to the ring C; and

[0483] R 59 Each time it appears, it is independently selected from C. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally via halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted.

[0484] In some embodiments, the stereoisomer system of the compound of formula (II) is provided in an enantiomer 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 stereoisomer system is provided in an enantiomer 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 implementations, the stereoisomer system has an enantiomer excess of more than 95%, for example, more than 99%.

[0485] In some implementations, for stereoisomers of formula (II), L 3 Selected from and Optional, R 56 It is methyl. In some embodiments, L 3 Tie In some implementations, L 3 Tie In some implementations, C is selected from and In some implementations, L 3 Selected from and And C is selected from and .

[0486] Any combination of groups described above for each variable of compound (II) covers the stereoisomers of compound (II) used in this article.

[0487] In some aspects, the compounds of the present invention are covalently bound to menin and inhibit the interaction between menin and MLL. This binding can increase the affinity of the compound for menin, which is an advantageous property in many applications, including therapeutic and diagnostic applications. In some embodiments, the compounds of the present invention include an electrophilic group capable of reacting with a nucleophilic group present in the menin protein. Suitable electrophilic groups are described throughout the application, and suitable nucleophilic groups include, for example, cysteine ​​moieties present in the binding domain of the menin protein. It is not expected, however theoretically, that cysteine ​​residues in the menin binding domain can react with the electrophilic group of the compounds of the present invention to form a conjugate. In some embodiments, the compounds of the present invention are covalently bound to a cysteine ​​residue at position 329 of menin isoform 2 (SEQ ID NO: 2) or cysteine ​​residue 334 of menin isoform 1 (SEQ ID NO: 1). In some embodiments, the present invention provides conjugates of the compounds of the present invention with the menin protein. For example, the present invention provides a conjugate of the compound of the present invention with menin, the compound being bound to cysteine ​​residue 329 of menin isoform 2 (SEQ ID NO:2) or cysteine ​​residue 334 of menin isoform 1 (SEQ ID NO:1).

[0488] In some implementations, for compounds of formula (I) or (II), R A R B and R COne or more of the functional groups, when present, include functional groups that covalently react with one or more residues on the menin. In some embodiments, the functional group covalently reacts with one or more cysteine ​​residues on the menin. In some embodiments, the functional group covalently reacts with cysteine ​​at position 329 of SEQ ID NO:2 (in optimal alignment) or with position 334 of SEQ ID NO:1 (in optimal alignment). In some embodiments, in optimal alignment, the functional group covalently reacts with one or more menin residues selected from cysteine ​​329, cysteine ​​241, and / or cysteine ​​230 of SEQ ID NO:2. In some embodiments, in optimal alignment, the functional group covalently reacts with cysteine ​​329 of SEQ ID NO:2.

[0489] In some implementations, for compounds of formula (I) or (II), R A R B and R C One or more of these components, when present, include portions that covalently react with one or more residues on menin. In some embodiments, R A R B and R C One or more of the components, when present, include portions that covalently react with 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) of menin). In some embodiments, R A R B and R C One or more of the components, when present, include portions that covalently react 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 isotype 1 (SEQ ID NO:1), isotype 2 (SEQ ID NO:2), or isotype 3 (SEQ ID NO:3).

[0490] In some implementations, for compounds of formula (I) or (II), R A R B and R COne or more of the components, when present, include electrophilic groups that are susceptible to nucleophilic attacks from residues on the menin. Any suitable electrophilic motif known to those skilled in the art to bind to a nucleophilic residue (e.g., any electrophilic motif known to bind to a cysteine ​​residue) is included herein. In some embodiments, R A R B and R C One or more of the components, when present, include a portion other than an electrophile, wherein the portion is capable of binding to residues on menin or reacting covalently. In some embodiments, the compound or salt of formula (I) or (II) is capable of (a) covalently binding to menin and (b) inhibiting the interaction between menin and MLL.

[0491] In some implementations, for compounds of formula (I) or (II), R C This includes functional groups that covalently react with one or more residues on the menin. In some embodiments, the functional group covalently reacts with one or more cysteine ​​residues on the menin. In some embodiments, the functional group covalently reacts with the cysteine ​​residue at position 329 of SEQ ID NO:2 (in optimal alignment) or at position 334 of SEQ ID NO:1 (in optimal alignment).

[0492] In some implementations, for compounds of formula (I) or (II), R C The part includes the following groups: α,β-unsaturated carbonyl; α,β-unsaturated sulfonyl; epoxide; aldehyde; sulfonyl fluoride; halomethyl carbonyl, dihalomethyl carbonyl or trihalomethyl carbonyl.

[0493] In some implementations, for compounds of formula (I) or (II), R C Selected from:

[0494] and in:

[0495] L 5 Selected from key; and C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl and C 2-6 Alynyl group, wherein each is independently optionally derived from one or more R groups. 32 replace;

[0496] R 22 and R 23 Each is selected independently from:

[0497] 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;

[0498] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each of them, each in each occurrence, is independently and optionally substituted by one or more substituents selected from: halogens, -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 Carbon rings and 3 to 10-membered heterocycles; and

[0499] C 3-10 Carbon rings and 3 to 10-membered heterocycles,

[0500] Where R 22 and R 23Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: 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 group; or R 22 and R 23 Together with the carbon atoms to which they are attached, they form a carbon ring;

[0501] R 24 Selected from:

[0502] Hydrogen, -C(O)R 20 -C(O)OR 20 -C(O)N(R) 20 )2、-OC(O)R 20 -S(O)2R 20 and -S(O)2N(R 20 )2;

[0503] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each of them, each in each occurrence, is independently and optionally substituted by one or more substituents selected from: halogens, -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)R20 -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 Carbon rings and 3 to 10-membered heterocycles; and

[0504] C 3-10 Carbon rings and 3 to 10-membered heterocycles,

[0505] Where R 24 Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: 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 group;

[0506] R 20 Each time it appears, it is independently selected from R. 52 ;and

[0507] R 32 Each time it appears, it is independently selected from R. 50 .

[0508] In some implementations, L 5 As a key. In some implementations, L 5C is arbitrarily substituted 1-6 Alkylene. In some embodiments, L 5 Selected from methylene, ethylene, or propylene. In some embodiments, L 5 One or more of the following are selected from halogen, -NO2, =O, =S, -OR 20 -SR 20 and -N(R) 20 Substituents of )2.

[0509] In some implementation schemes, R 23 Selected from:

[0510] hydrogen;

[0511] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each of them, each in each occurrence, is independently and optionally substituted by one or more substituents selected from: halogens, -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 Carbon rings and 3 to 10-membered heterocycles; and

[0512] C 3-10 Carbon rings and 3 to 10-membered heterocycles,

[0513] Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: 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 Alkyne group.

[0514] In some implementation schemes, R 23 Selected from:

[0515] hydrogen;

[0516] C 1-6 Alkyl groups, optionally via one or more alkyl groups selected from halogens, -OR 20 -SR 20 -N(R) 20 )2、=O、=S、=N(R 20 Substitution of ) and -CN; and

[0517] 3 to 10-membered heterocyclic rings, optionally substituted by one or more substituents selected from: halogens, -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 C2-6 Alkyne group.

[0518] In some implementation schemes, R 23 Selected from hydrogen and optionally via one or more halogens, -OR 20 -SR 20 -N(R) 20 )2、=O、=S、=N(R 20 C substituents of ) and -CN 1-6 alkyl.

[0519] In some implementation schemes, R 22 Selected from:

[0520] Hydrogen and -CN;

[0521] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each of them, each in each occurrence, is independently and optionally substituted by one or more substituents selected from: halogens, -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 Carbon rings and 3 to 10-membered heterocycles; and

[0522] C 3-10 Carbon rings and 3 to 10-membered heterocycles,

[0523] Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocycle are independently and optionally substituted by one or more substituents selected from the following: 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 Alkyne group.

[0524] In some implementation schemes, R 22 Selected from hydrogen, -CN; and C 1-6 Alkyl groups, optionally via one or more alkyl groups selected from halogens, -OR 20 -SR 20 and -N(R) 20 Substituents of )2.

[0525] In some implementation schemes, R 22 and R 23 Together with the carbon atoms to which they are attached, they form 5-, 6-, or 7-membered carbon rings.

[0526] In some implementation schemes, R 24 Selected from hydrogen and optionally via one or more halogens, -OR 20 -SR 20 -N(R) 20 )2, C substituents of -NO2, =O and -CN 1-6 alkyl.

[0527] In some implementation schemes, R 21 Selected from and

[0528] All combinations of the groups described above for each variable are covered herein. Throughout the specification, groups and their substituents may be selected to provide stable moieties and compounds.

[0529] The chemical entities described herein can be synthesized using one or more illustrative reaction diagrams and / or techniques known in the art. The materials used herein are commercially available or prepared using synthetic methods generally known in the art. The reaction diagram is not limited to the compounds or any particular substituents listed in the examples; it is for illustrative purposes only. Although in the reaction… Figure 1 The steps described and illustrated in Examples 1-5 may differ from the reactions in some cases. Figure 1 The reaction shall be carried out in the order shown in Examples 1-5. Various modifications may be made to the reaction diagram of the synthesis reaction, and those skilled in the art who have referenced the disclosure contained herein are advised. The numbers or R groups in each reaction diagram need not correspond to those in the claims or other embodiments or tables herein.

[0530] Unless otherwise specified, the reactions described herein occur at atmospheric pressure and typically within a temperature range of -10°C to 200°C. Furthermore, unless otherwise specified, reaction times and conditions are intended to be approximate, for example, occurring over a period of approximately 1 hour to approximately 24 hours at approximately atmospheric pressure and within a temperature range of approximately -10°C to approximately 110°C; the reaction is maintained overnight (an average period of approximately 16 hours).

[0531] Generally, the compounds of the present invention can be prepared by the following reaction diagram:

[0532] reaction Figure 1

[0533]

[0534] In some implementation schemes, it can be based on the reaction Figure 1 Compounds of formulas 1-7 can be prepared. For example, methanesulfonyl chloride can be added to a solution of alcohol 1-1 and triethylamine to provide methanesulfonate 1-2. Adding sulfonate 1-2 to a solution of Cs2CO3 and amine 1-3 can provide compounds of formula 1-4. Aldehyde 1-4 can be coupled to amine 1-5 in the presence of a suitable reducing agent (e.g., NaBH(OAc)3) to give compounds of formula 1-6. Adding TFA reveals the free amine, which can optionally react with R 57 -LG reacts (where LG is a suitable leaving group) to provide compounds of formula 1-7.

[0535] In some implementation schemes, based on the reaction Figure 1 The compounds of the present invention (e.g., compounds given in Table 1 or 2) may be synthesized by the general approach outlined in Examples 1-5 or by one of the methods commonly known in the art. In some embodiments, exemplary compounds may comprise (but are not limited to) compounds selected from Table 1 or salts thereof.

[0536] Table 1

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603] In some embodiments, the exemplary compound may comprise (but is not limited to) compounds selected from Table 2 or their salts.

[0604] Table 2

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612] Pharmaceutical Composition

[0613] The compositions and methods of this invention can be used to treat individuals in need. In some embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal (e.g., a human), the composition or compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound or salt of formula (I) or (II) and a pharmaceutically acceptable carrier.

[0614] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In further embodiments, the pharmaceutical composition comprises a compound as disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of this therapeutic agent are described below.

[0615] Suitable routes of administration include (but are not limited to) oral, intravenous, rectal, aerosol, non-enteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nasal, and local administration. Additionally, by way of example only, non-enteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0616] In some embodiments, the composition of a compound or salt of formula (I) or (II) is administered locally rather than systemically, for example by direct injection of the compound into an organ. This composition is typically in the form of a storage formulation or a sustained-release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In other embodiments, the compound or salt of formula (I) or (II) is delivered using a targeted drug delivery system (e.g., in the form of liposomes coated with organ-specific antibodies). In this embodiment, the liposomes are targeted to the organ and selectively absorbed therefrom. In other embodiments, the composition is provided in the form of a rapid-release formulation, a delayed-release formulation, or an immediate-release formulation. In other embodiments, the composition is administered locally.

[0617] Compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, are effective over a wide dose range. For example, in treating adults, doses of 0.01 mg / day to 1000 mg / day, 0.5 mg / day to 100 mg / day, 1 mg / day to 50 mg / day, and 5 mg / day to 40 mg / day are dosage examples used in some implementation schemes. The exact dose depends on the route of administration, the form of the compound administered, the individual to be treated, the individual's weight, and the preferences and experience of the attending physician.

[0618] In some embodiments, a compound or salt of formula (I) or (II) is administered in a single dose. Typically, this administration is carried out by injection (e.g., intravenous injection) to rapidly introduce the drug. However, other routes may be used appropriately. In some embodiments, a single dose of a compound or salt of formula (I) or (II) is used to treat acute symptoms.

[0619] In some embodiments, the compound or salt of formula (I) or (II) is administered in multiple doses. In some embodiments, the compound or salt of formula (I) or (II) is administered about once, twice, three times, four times, five times, six times, or more than six times daily. In other embodiments, the compound or salt of formula (I) or (II) and another agent are administered together about once daily to about six times daily. In another embodiment, the compound or salt of formula (I) or (II) and the agent are continued for less than about 7 days. In yet another embodiment, the compound or salt of formula (I) or (II) is continued for more than about 6 days, more than about 10 days, more than about 14 days, more than about 28 days, more than about two months, more than about six months, or one year or longer. In some cases, continuous administration is performed and maintained as needed.

[0620] The compound or salt of formula (I) or (II) may be administered as needed. In some embodiments, the compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of the invention 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 a portion of 1 day. In some embodiments, the compound or salt of formula (I) or (II) is administered long-term and continuously for, for example, to treat chronic effects.

[0621] In some embodiments, a compound or salt of formula (I) or (II) is administered at a given dose. It is known in the art that due to inter-individual variability in the pharmacokinetics of compounds, dosing regimens need to be individualized for optimal therapy. The administration of a compound or salt of formula (I) or (II) according to the present invention can be determined by routine experiments.

[0622] In some embodiments, compounds or salts of formula (I) or (II) are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically applicable formulation. A suitable formulation depends on the chosen route of administration. The pharmaceutical compositions described herein were formulated using any pharmaceutically acceptable and suitable technology, carrier, and excipient: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999).

[0623] This document provides pharmaceutical compositions comprising compounds or salts of formula (I) or (II) and pharmaceutically acceptable diluents, excipients, or carriers. In some embodiments, the described compounds or salts are administered as pharmaceutical compositions containing a mixture of compounds or salts of formula (I) or (II) with other active ingredients (as in combination therapies). This document covers all combinations of active ingredients stated herein and throughout the invention. In specific embodiments, the pharmaceutical composition comprises one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof.

[0624] As used herein, a pharmaceutical composition refers to a mixture of a compound or salt of formula (I) or (II) with other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). In some embodiments, the pharmaceutical composition facilitates the delivery of the compound to an organism. In some embodiments, in the practice of the treatment methods or uses provided herein, a therapeutically effective amount of a compound of formula (I) or (II) or a salt thereof in the pharmaceutical composition is given to a mammal suffering from the disease, condition, or symptom to be treated. In a particular embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount varies depending on the severity of the disease, the individual's age and relative health status, the efficacy 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 components of a mixture).

[0625] In one embodiment, the compound or salt of formula (I) or (II) is formulated as an aqueous solution. In a specific embodiment, the aqueous solution is selected from physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer, by way of example only. In other embodiments, the compound or salt of formula (I) or (II) is formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation contains an permeabilizing agent suitable for permeable barriers. In other embodiments where the compound or salt of formula (I) or (II) is formulated for other non-intestinal injections, a suitable formulation contains an aqueous or non-aqueous solution. In a specific embodiment, the solution contains a physiologically compatible buffer and / or excipient.

[0626] 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) can 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 an oral dosage form, which includes, by way of example only, tablets, powders, pills, sugar-coated tablets, capsules, liquids, gels, syrups, elixirs, liquids, suspensions, and the like.

[0627] In some embodiments, the oral pharmaceutical preparation is obtained by mixing one or more solid excipients with a compound or salt of formula (I) or (II), optionally milling the resulting mixture, and, if necessary, treating the granular mixture after adding a suitable excipient to obtain a tablet or sugar-coated tablet core. Specifically, the suitable excipient is a filler, such as sugars including lactose, sucrose, mannitol, or sorbitol; a cellulose preparation, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. The disintegrant comprises (by way of example only) cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginate or a salt thereof (e.g., sodium alginate).

[0628] In one embodiment, a dosage form having one or more suitable coatings is provided, such as a sugar-coated tablet core and tablets. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional components, such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, a paint solution, and a suitable organic solvent or solvent mixture. Dyes and / or pigments are also optionally added to the coating for identification purposes. Additionally, dyes and / or pigments are optionally used to characterize different combinations of active compound dosages.

[0629] 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 compounded push-in capsules made of gelatin and soft-sealable capsules made of gelatin and a plasticizer (e.g., glycerin or sorbitol). In a specific embodiment, the compounded push-in capsule contains an active ingredient mixed with one or more fillers. The fillers include (by example only) lactose, a binder (e.g., starch) and / or a lubricant (e.g., talc or magnesium stearate) and optionally a stabilizer. In other embodiments, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. The suitable liquid includes (by example only) one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer is optionally added.

[0630] 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, rhomboid tablets, or gels. In other embodiments, a compound or salt of formula (I) or (II) is formulated for non-enteral injection, comprising a formulation suitable for concentrated injection or continuous infusion. In specific embodiments, the injectable formulation is present in a unit dosage form (e.g., in an ampoule) or in a multi-dose container. Optionally, a preservative is added to the injectable formulation. In other embodiments, the pharmaceutical composition is formulated as a sterile suspension, solution, or emulsion in an oily or aqueous medium in a form suitable for non-enteral injection. Non-enteral injection formulations optionally contain formulations such as suspending agents, stabilizers, and / or dispersants. In specific embodiments, pharmaceutical formulations for non-enteral administration comprise an aqueous solution of the active compound in a water-soluble form. In other embodiments, the suspension of the compound or salt of formula (I) or (II) is prepared into a suitable oily injectable suspension. Lipophilic solvents or mediators suitable for the pharmaceutical compositions described herein include (by example only) fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. In some specific embodiments, the aqueous injectable suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains a suitable stabilizer or agent that increases the solubility of the compound to allow for the preparation of a highly concentrated solution. In some embodiments, the active agent is in powder form for use with a suitable mediator (e.g., sterile, pyrogen-free water) prior to use.

[0631] In other embodiments, the compound or salt of formula (I) or (II) is administered topically. The compound or salt of formula (I) or (II) can be formulated into various topically applicable compositions, such as solutions, suspensions, lotions, gels, ointments, sticks, balms, creams, or ointments. The pharmaceutical composition optionally contains solubilizers, stabilizers, tension enhancers, buffers, and preservatives.

[0632] In other embodiments, the compound or salt of formula (I) or (II) is formulated for transdermal administration. The transdermal formulation may employ a transdermal delivery device and a transdermal delivery patch and may be a lipophilic emulsion or buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive. In various embodiments, the patch is configured for continuous, pulsed, or on-demand delivery of pharmaceutical agents. In other embodiments, the compound or salt of formula (I) or (II) is delivered transdermally using iontophoresis patches and the like. In some embodiments, the transdermal patch provides controlled delivery of the compound or salt of formula (I) or (II). In specific embodiments, the absorption rate is slowed by using a rate-controlled membrane or by trapping the compound in a polymer matrix or gel. In alternative embodiments, an absorption enhancer is used to increase absorption. The absorption enhancer or carrier comprises a pharmaceutically acceptable absorbable solvent that facilitates transdermal absorption. For example, in one embodiment, the transdermal device is in the form of a bandage, which includes a backing component; a reservoir containing a compound or salt of formula (I) or (II) (optionally having a carrier); optionally including a rate control barrier to deliver the compound to the host skin at a controlled and predetermined rate over a long period of time; and a component for securing the device to the skin.

[0633] 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, nebulizers, or powders. Pharmaceutical compositions of compounds or salts of formula (I) or (II) are conveniently delivered as a self-pressurized pack or nebulizer in the form of an aerosol spray, 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 may be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges (e.g., gelatin for inhalers or blowpipes, by way of example only) are formulated as a powder mixture containing a compound or salt of formula (I) or (II) and a suitable powder matrix (e.g., lactose or starch).

[0634] In other embodiments, the compound or salt of formula (I) or (II) is formulated for use in rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retention enemas, containing a conventional suppository base (e.g., cocoa butter or other glycerides) and a synthetic polymer (e.g., polyvinylpyrrolidone, PEG, and the like). In suppository compositions, a low-melting-point wax (e.g., (but not limited to) a mixture of fatty acid glycerides) is optionally melted first in combination with the cocoa butter.

[0635] In some embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically applicable formulation. The appropriate formulation depends on the chosen route of administration. Any suitable pharmaceutically acceptable technique, carrier, and excipient may optionally be used. Pharmaceutical compositions comprising compounds or salts of formula (I) or (II) are prepared in a conventional manner, for example, by means of conventional mixing, dissolving, granulation, coating, grinding, emulsification, encapsulation, embedding, or compression processes.

[0636] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient, and a compound or salt of formula (I) or (II) (sometimes referred to herein as an active agent or active ingredient). The active ingredient may be in the form of a free acid or free base or in the form of a pharmaceutically acceptable salt. Additionally, the compound or salt of formula (I) or (II) may be in an unsolvated or solvated form achieved using a pharmaceutically acceptable solvent (e.g., water and ethanol). Furthermore, the pharmaceutical composition optionally comprises other medical or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, buffers, and / or other substances of therapeutic value.

[0637] A method for preparing a composition comprising a compound or salt of formula (I) or (II) comprises formulating the compound with one or more pharmaceutically acceptable inert excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions comprise (but are not limited to) powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions comprise solutions containing the compound, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles comprising a compound or salt of formula (I) or (II). Semi-solid compositions comprise (but are not limited to) gels, suspensions, and creams. Pharmaceutical compositions of compounds or salts of formula (I) or (II) comprise liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to use, or emulsions. The composition may also optionally contain trace amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.

[0638] In some embodiments, the pharmaceutical composition comprising a compound or salt of formula (I) or (II) is in liquid form, wherein the pharmaceutical agent is present in solution, suspension, or both. Typically, when the composition is administered in solution or suspension form, a first portion of the pharmaceutical agent is present in solution and a second portion of the pharmaceutical agent is present in a suspension in particulate form within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0639] In some embodiments, the aqueous suspension contains one or more polymers as suspending agents. The polymers include water-soluble polymers (e.g., cellulose polymers, such as hydroxypropyl methylcellulose) and water-insoluble polymers (e.g., cross-linked carboxyl-containing polymers). Some pharmaceutical compositions described herein also include mucosal adhesion polymers selected from, for example, carboxymethyl cellulose, carbomer (an acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylate / butyl acrylate copolymer, sodium alginate, and dextran.

[0640] Similarly, pharmaceutical compositions may optionally contain a solubilizer to facilitate the dissolution of the compounds described herein. The term "sorlubilizer" generally includes an agent that causes the formation of a micelle solution or true solution of the pharmaceutical preparation. Certain acceptable nonionic surfactants (e.g., polysorbate 80) and ocularly acceptable glycols, polyethylene glycols (e.g., polyethylene glycol 400), and glycol ethers may be used as solubilizers.

[0641] The pharmaceutical composition optionally comprises one or more pH adjusters or buffers, 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 hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. The acid, base, and buffer are included in the amount necessary to maintain the pH of the composition within an acceptable range.

[0642] Additionally, the useful composition may optionally contain one or more salts in amounts required to bring the osmotic pressure of the composition within an acceptable range. These salts include those having 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.

[0643] The pharmaceutical composition optionally includes one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as phenylmercuric borate and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridinium chloride.

[0644] Pharmaceutical compositions 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, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0645] Pharmaceutical compositions may include one or more antioxidants as needed to enhance chemical stability. Suitable antioxidants include (by way of example only) ascorbic acid and sodium metabisulfite.

[0646] In some embodiments, the aqueous suspension composition is packaged in a single-dose, non-resealable container. Alternatively, a multi-dose, resealable container is used, in which case a preservative is typically included in the composition.

[0647] In some embodiments, a delivery system for hydrophobic pharmaceutical compounds is employed. Liposomes and emulsions are examples of delivery media or carriers used herein. In some embodiments, organic solvents (e.g., N-methylpyrrolidone) are also used. In other embodiments, a sustained-release system (e.g., a semi-permeable matrix of a solid hydrophobic polymer containing a therapeutic agent) is used to deliver compounds or salts of formula (I) or (II). Various sustained-release materials are available herein. In some embodiments, sustained-release capsules release the compound for several weeks to a maximum of 100 days. Other strategies for protein stabilization are employed, depending on the chemical properties and biological stability of the therapeutic agent.

[0648] In some embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol compounds and / or other general stabilizers. 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) cyclodextrin, (l) pentosan polysulfate and other heparin-like substances, (m) divalent cations (e.g. magnesium and zinc) or (n) combinations thereof.

[0649] In some embodiments, the concentration of the compound or salt of formula (I) or (II) provided in the pharmaceutical composition, on a w / w, w / v, or v / v basis, is less than 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%, 0.0%. 9%, 0.08%, 0.07%, 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 0.0001%.

[0650] In some embodiments, the concentration of the compound or salt of formula (I) or (II) provided in the pharmaceutical composition, on a w / w, w / v, or v / v basis, is greater than 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%, 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%.

[0651] In some embodiments, the concentration of the compound or salt of formula (I) or (II), expressed as w / w, w / v, or v / v, is within the following ranges: about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.0001% to about 27%, about 0.0001% to about 26%, about 0.0001% to about 25%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 27%, about 0.0001% to about 26%, about 0.0001% to about 25 ...6%, about 0.0001% to about 25%, about 0.07% to about 24%, about 0.08% 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%.

[0652] In some embodiments, the concentration of the compound or salt of formula (I) or (II), in w / w, w / v or v / v 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%, and about 0.1% to about 0.9%.

[0653] In some embodiments, the amount of the compound or salt of formula (I) or (II) is equal to or less than 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, 0.2 g. 5g, 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.

[0654] In some embodiments, the amount of the compound or salt of formula (I) or (II) is greater than 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, or 0.0025 g. ,0.003g,0.0035g,0.004g,0.0045g,0.005g,0.0055g,0.006g,0.0065g,0.007 g, 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 .08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.4 5g, 0.5g, 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.

[0655] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001-10g, 0.0005-9g, 0.001-8g, 0.005-7g, 0.01-6g, 0.05-5g, 0.1-4g, 0.5-4g or 1-3g.

[0656] For use in the therapeutic applications described herein, kits and articles are also provided. In some embodiments, the kit includes a carrier, packaging, or a spaced-out container to house one or more containers (e.g., vials, tubes, and the like), each container including a separate component intended for use in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers are formed from various materials (e.g., glass or plastic).

[0657] The articles described herein contain packaging materials. Packaging materials for packaging pharmaceutical products include those set forth in, for example, U.S. Patents 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 materials suitable for the selected formulation and the intended mode of administration and treatment. For example, a container contains a compound or salt of formula (I) or (II), which is optionally in the form of a composition or combination with another pharmaceutical agent as disclosed herein. The container optionally has a sterile inlet port (for example, an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). The container optionally includes identification instructions or markings or instructions relating to the compound and its use in the methods described herein.

[0658] For example, a medicine box typically includes one or more additional containers, each containing one or more materials (e.g., reagents and / or devices optionally in concentrated form) desired from a commercial and user perspective for the use of the compounds described herein. Non-limiting examples of such materials include (but are not limited to) buffers, diluents, filters, needles, syringes; carriers, packaging, containers, vials, and / or tubes; markings and / or instructions for use listing the contents and packaging inserts with instructions for use. A set of instructions is also typically included. The markings are optionally located on or attached to the containers. For example, when the letters, numbers, or other symbols forming the markings are affixed, molded, or etched into the container itself, the markings are located on the container; when the markings are also present in the reservoir or carrier containing the containers (e.g., as packaging inserts), the markings are attached to the containers. Additionally, the markings indicate that the contents are intended for a specific therapeutic application. Furthermore, the markings also indicate instructions for use of the contents (e.g., in the methods described herein). In some embodiments, the pharmaceutical composition is presented in a packaging or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The packaging contains, for example, metal or plastic foil, such as blister packs. Alternatively, the packaging or dispenser device may include instructions for administration. For patients, the packaging or dispenser may bear notices on the container in the form prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the drug form for human or veterinary administration. For example, this notice may be a label or approved product insert from the U.S. Food and Drug Administration (FDA) for prescription drug approval. In some embodiments, a composition containing the compounds provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled to indicate the condition to be treated.

[0659] method

[0660] This invention provides a method for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats), comprising contacting cells with an effective amount of a compound or salt of formula (I) or (II). The inhibition of the interaction between menin and one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) can be evaluated and confirmed by a variety of methods known in the art. Non-limiting embodiments include those demonstrating: (a) reducing the binding of menin to one or more proteins or protein fragments (e.g., MLL1, MLL2, MLL fusion proteins, MLL partial tandem repeats, or peptide fragments thereof); (b) reducing cell proliferation and / or cell survival; (c) increasing cell differentiation; (d) reducing the levels of downstream targets (e.g., Hoxa9, DLX2, and Meis1) of MLL1, MLL2, MLL fusion proteins, and / or MLL partial tandem repeats; and / or (e) reducing tumor volume and / or tumor growth rate. One or more of the above items can be determined using medicine boxes and commercially available analyses.

[0661] The present invention also provides methods for treating disease symptoms (including, but not limited to, symptoms involving menin, MLL, MLL1, MLL2 and / or MLL fusion proteins, such as cancer) using the compounds or pharmaceutical compositions of the present invention.

[0662] In some embodiments, a method of treating cancer is provided, the method comprising administering to an individual in need 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 a brain tumor. In some embodiments, the cancer is leukemia. In some embodiments, the cancer includes solid tumors.

[0663] In some embodiments, the present invention provides a method for treating a condition in an individual in need, wherein the method includes determining whether the individual has an MLL fusion protein and, if the individual is found to have an MLL fusion protein, administering to the individual a therapeutically effective dose of a compound or salt of formula (I) or (II).

[0664] The MLL fusion protein has also been identified in hematologic malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, some embodiments relate to administering a compound or salt of formula (I) or (II) to a patient requiring treatment for a hematologic malignancy. This malignancy includes, but is not limited to, leukemia and lymphoma. For example, the compound disclosed herein can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myeloid leukemia (CML), acute monocytic leukemia (AMoL), hairy cell leukemia, and / or other leukemias. In other embodiments, the compound can be used for lymphomas, such as Hodgkin's lymphoma or all subtypes of non-Hodgkin's lymphoma.

[0665] Whether a tumor or cancer includes an MLL fusion protein can be determined by: evaluating the nucleotide sequence encoding the MLL fusion protein, evaluating the amino acid sequence of the MLL fusion protein, or evaluating the properties of the putative MLL fusion protein.

[0666] Methods for detecting the nucleotide sequence of MLL fusion proteins 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) analysis, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, real-time PCR analysis, PCR sequencing, mutant allele-specific PCR amplification (MASA) analysis, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation analysis, hybridization analysis, TaqMan analysis, SNP genotyping analysis, high-resolution melting analysis, and microarray analysis. In some embodiments, for example, direct sequencing of specific regions (e.g., exon 2 and / or exon 3) in the MLL or fusion partner gene is used to identify MLL fusion proteins. This technique will identify all possible mutations in the sequenced region.

[0667] Methods for detecting MLL fusion proteins are known to those skilled in the art. These methods include (but are not limited to) detecting MLL fusion proteins using a specific binding agent (e.g., an antibody) for the fusion protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0668] Methods for determining whether a tumor or cancer includes an MLL fusion protein can utilize various samples. In some embodiments, the sample is obtained from an individual with a tumor or cancer. In some embodiments, the sample is obtained from an individual with cancer or 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 cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0669] This invention also relates to a method for treating hyperproliferative disorders in mammals, comprising administering to the mammal a therapeutically effective amount of a compound or salt of formula (I) or (II). In some embodiments, the method relates to treating cancers such as acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, and Burkitt's lymphoma. Lymphoma, carcinoid tumors, atypical teratoid tumors, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing's sarcoma. Sarcoma), extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of unknown primary origin, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma. Cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip cancer and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus carcinoma and nasal cavity carcinoma, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pulmonary blastoma, primary central nervous system cancer. Nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, unusual cancers in childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some implementations, the method relates to the treatment of non-cancerous hyperplastic conditions, such as benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hyperplasia (BPH)). In some cases, the method relates to the treatment of leukemia, hematologic malignancies, solid tumor cancers, prostate cancer (e.g., castration-resistant prostate cancer), breast cancer, Ewing's sarcoma, osteosarcoma, primary osteosarcoma, T-cell prelymphocytic leukemia, glioma, glioblastoma, liver cancer (e.g., hepatocellular carcinoma), or diabetes. In some cases, leukemia includes AML, ALL, mixed-lineage leukemia, or leukemia with partial tandem duplication of MLL.

[0670] In certain specific embodiments, the present invention relates to a method of treating lung cancer, the method comprising administering to an individual in need an effective amount of any of the above-described compounds (or pharmaceutical compositions comprising them). 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) glandular tumors, carcinoid tumors, and undifferentiated carcinomas.

[0671] Individuals who may be treated with the compounds of the present invention or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, stereoisomers, isotopes, hydrates, or derivatives thereof according to the methods of the present invention include, for example, individuals diagnosed with the following diseases: acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma. Lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, lower... Pharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary origin, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodyplasia / myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, nipple cancer. Neuroblastoma, paraganglioma, paranasal sinus carcinoma and nasal cavity carcinoma, parathyroid carcinoma, penile cancer, pharyngeal cancer, pleural pulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, unusual cancers in childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, virus-induced cancer, leukemia, hematologic malignancies, solid tumor cancers, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, osteosarcoma, primary osteosarcoma.T-cell prelymphoblastic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or diabetes. In some embodiments, individuals treated with the compounds of the present invention include those diagnosed with non-cancerous hyperplastic conditions (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hyperplasia (BPH)).

[0672] The present invention further provides a method for modulating the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) by contacting menin with an effective amount of a compound or salt of formula (I) or (II). Modulation may be the inhibition or activation of the activity of menin, one or more of their binding partners, and / or one or more downstream menin targets or proteins of their binding partners. In some embodiments, the present invention provides a method for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) by contacting menin with an effective amount of a compound or salt of formula (I) or (II). In some embodiments, the present invention provides a method for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) by contacting cells, tissues, or organs expressing menin, MLL1, MLL2, MLL fusion proteins, and / or MLL partial tandem repeats. In some embodiments, the present invention provides a method for inhibiting protein activity in an individual (including, but not limited to, rodents and mammals (e.g., humans)) by administering an effective amount of a compound or salt of formula (I) or (II). In some embodiments, the inhibition percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0673] In some embodiments, the present invention provides a method for inhibiting the interaction of menin in cells with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats), which is achieved by contacting the cells with an amount of the compound of the present invention sufficient to inhibit the interaction of menin in cells with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats). In some embodiments, the present invention provides a method for inhibiting the interaction of menin in tissues with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats), which is achieved by contacting the tissue with an amount of a compound or salt of formula (I) or (II) sufficient to inhibit the interaction of menin in tissues with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats). In some embodiments, the present invention provides a method for inhibiting the interaction of menin in an organism with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats), which is achieved by contacting the organism with an amount sufficient to inhibit the interaction of menin in the organism with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats). In some embodiments, the present invention provides a method for inhibiting the interaction of menin in an animal with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats), which is achieved by contacting the animal with an amount sufficient to inhibit the interaction of menin in the animal with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats). In some embodiments, the present invention provides a method for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) in mammals, which is achieved by contacting the mammal with an amount of the compound of the present invention sufficient to inhibit the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) in mammals. In some embodiments, the present invention provides a method for inhibiting the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) in humans, which is achieved by contacting the human with an amount of the compound of the present invention sufficient to inhibit the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats) in humans.The present invention provides a method for treating diseases in individuals requiring treatment mediated by the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins, or MLL partial tandem repeats).

[0674] The present invention also provides a method for treating conditions mediated by the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion proteins or MLL partial tandem repeats), which is achieved by administering a therapeutically effective amount of a compound or salt of formula (I) or (II) to an individual in need.

[0675] The present invention further provides a method for treating conditions mediated by chromosomal rearrangement on chromosome 11q23 in individuals in need, which is achieved by administering to the individual a therapeutically effective amount of a compound or salt of formula (I) or (II).

[0676] The present invention also provides a method for treating a disease or condition by administering an effective amount of a compound or salt of formula (I) or (II) to an individual suffering from such a disease or condition.

[0677] The present invention further provides a method for treating a disease or symptom by administering a compound or salt of formula (I) or (II) to an individual suffering from a disease or symptom, wherein the compound binds to menin and inhibits the interaction of menin with one or more proteins (e.g., MLL1, MLL2, MLL fusion protein or MLL partial tandem repeat).

[0678] The present invention further provides a method for stabilizing menin, comprising contacting menin with a compound or salt of formula (I) or (II). In some embodiments, the contacting step comprises contacting menin with a compound in an amount sufficient to stabilize menin. In some embodiments, the contacting step occurs in vivo. In some embodiments, the contacting step occurs in vitro. In some embodiments, the contacting step occurs in cells.

[0679] The present invention also provides a method for combination therapy, wherein an agent known to regulate other pathways or other components of the same pathway or even overlapping target enzyme groups is used in combination with a compound or salt of formula (I) or (II). In one aspect, the therapy comprises (but is not limited to) combining one or more compounds of the present invention with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects.

[0680] If desired, the compounds or pharmaceutical compositions of the present invention may be used in combination with Notch inhibitors and / or c-Myb inhibitors. If desired, the compounds or pharmaceutical compositions of the present invention may be used in combination with MLL-WDR5 inhibitors and / or Dot11 inhibitors.

[0681] Many chemotherapeutic agents are currently known in the industry and can be used in combination with the compounds of this invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, bioreaction modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0682] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules (e.g. (Imatinib Mesylate) (bortezomib), Casodex (bicalutamide) Gefitinib and Adriamycin, as well as numerous chemotherapeutic agents. 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; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and tris(hydroxymethyl)melamine; nitrogen mustard. Mustard, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamineoxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrourea, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine;Antibiotics, such as aclacinomycin, actinomycin, antramycin, azoserine, bleomycin, cactinomycin C, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, and mycophenolic acid. acid), nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5) -FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine;Androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenergics, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; aceglatone; aldophosphamide glycoside; and aminolevulinic acid. acid); amsacrine; bestrabucil; bisantrene; edatrexate; defosfamine; demecolcine; diaziquone; eflornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; rice Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK.RTM.; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid acid); triaziquone; 2,2′,2″-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa;Taxanes, such as paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also included are anti-hormonal agents, such as anti-estrogens, used as suitable chemotherapeutic cell modulators to regulate or inhibit hormonal effects on tumors, including (e.g.) tamoxifen (Nolvadex™), raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; nitrogen mustard chlorate; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). If desired, the compounds or pharmaceutical compositions of the present invention can be used in combination with the most frequently prescribed anticancer drugs, such as:

[0683] ABVD, AVICINE, Abagovomab, acridine carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiourea, Amonafide, anthrone, anti-CD22 immunotoxin, antitumor agents, antitumor herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW2992, Biricodar, Brostallicin, Bryostatin, Buthioninesulfoximine, CBV (chemotherapy), Calyculin, Cell cycle nonspecific antitumor agents, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Im... exon, imiquimod, indomethacin, iroflavone, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, 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, Triplatinum Tetranitrate, Tri(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126, or Zosuquidar.

[0684] This invention also relates to a method of using a compound or salt of formula (I) or (II) or the pharmaceutical composition provided herein in combination with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative disorders in mammals. Techniques for administering radiation therapy are known in the art and can be used in the combination therapies described herein. The administration of the compounds of this invention in this combination therapy can be determined as described herein.

[0685] Radiotherapy can be delivered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and permanent or temporary interstitial short-range radiotherapy. As used herein, the term "short-range radiotherapy" refers to radiotherapy delivered by spatially confined radioactive material inserted into or near a site of tumor or other proliferative tissue disease. This term is intended (but is not limited to) 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 Lu). Suitable radioactive sources used as cell modifiers in this invention include solids and liquids. By way of non-limiting embodiments, the radioactive source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 (as a solid source), I-125 (as a solid source), or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material may also be a fluid derived from any solution of the radionuclide (e.g., a solution of I-125 or I-131), or a slurry of a suitable fluid containing small particles of a solid radionuclide (e.g., Au-198, Y-90) may be used to generate the radioactive fluid. Furthermore, the radionuclide may be embodied in a gel or radioactive microspheres.

[0686] The compounds or pharmaceutical compositions of the present invention may be used in combination with a certain amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or autophagy inhibitors.

[0687] Anti-angiogenic agents (e.g., MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors) may be used in combination with the compounds of the present invention 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 CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.Examples of useful matrix metalloproteinase inhibitors are illustrated in WO96 / 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 / 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 WO 98 / 30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90 / 05719 (published May 31, 1990), WO 99 / 52910 (published October 21, 1999), WO 99 / 52889 (published October 21, 1999), WO The entire contents of the following patent applications are incorporated herein by reference: PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional 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 have little or no MMP-1 inhibitory activity. More preferably, they selectively inhibit MMP-2 and / or AMP-9 relative to 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 that can be used in this invention are AG-3340, RO32-3555, and RS 13-0830.

[0688] Autophagy inhibitors include (but are not limited to) chloroquine, 3-methyladenine, and hydroxychloroquine (Plaquenil). TM), bafilomycin A1, 5-amino-4-imidazolamide riboside (AICAR), okadaic acid, autophagy-inhibiting alginate toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels (e.g., adenosine, LY204002, N6-mercaptopurine riboside, and vincristine). Additionally, antisenses or siRNAs that inhibit protein expression, including (but not limited to) ATG5 (which is involved in autophagy), may be used.

[0689] In some embodiments, the compounds described herein are formulated or administered in conjunction with liquid or solid tissue barriers (also known as lubricants). Examples of tissue barriers include (but are not limited to) polysaccharides, polysaccharides, seprafilm, interceed, and hyaluronic acid.

[0690] In some embodiments, the pharmaceutical preparation administered in conjunction with the compounds described herein includes any drug suitable for inhalation delivery, such as analgesics like codeine, dihydromorphine, ergotamine, fentanyl, or morphine; angina preparations like diltiazem; antihistamines like cromoglycate, ketotifen, or nedocromil; anti-infectives like cephalosporins, penicillin, streptomycin, sulfonamides, tetracyclines, or pentamidine; antihistamines like methapyrilene; and anti-inflammatory agents like beclomethasone, flunisolide, budesonide, tipredane, or triamcinolone. Acetone or fluticasone; antitussives, such as noscapine; bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol. mol), salmeterol, terbutalin, isotharine, tulobuterol, (osinalin) or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridyl)ethoxy]hexyl]amino]methyl]benzyl alcohol; diuretics, such as amiloride; anticholinergics, such as ipratropium, atropine or oxitropium; hormones, such as cortisone, hydrocortisone or prednisolone;Xanthines, such as aminophylline, cholinetheophyllinate, lysine theophyllinate, or theophylline; and therapeutic proteins and peptides, such as insulin or glucagon. Those skilled in the art will understand that, where appropriate, pharmaceutical preparations are used in the form of salts (e.g., alkali metal or amine salts or acid addition salts), esters (e.g., low-carbon alkyl esters), or solvates (e.g., hydrates) to optimize the activity and / or stability of the preparation.

[0691] Other exemplary therapeutic agents that may be used in combination therapy include (but are not limited to) agents as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progesters, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogues; adrenocortical hormones, inhibitors of insulin synthesis and action, oral hypoglycemic agents and endocrine pancreas drugs, agents affecting calcification and bone renewal: calcium, phosphates, parathyroid hormones. Vitamin D, calcitonin, vitamins (e.g., water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K and E), growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting on the neuromuscular junction and / or autonomic ganglia; catecholamines, sympathomimetic drugs and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0692] Therapeutic agents may also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, serotonin (5-hydroxytryptamine), lipids generated by the biotransformation of selective hydrolysis products of membrane phospholipids, arachidic acid, prostaglandins, lectins, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesics and antipyretics, agents that inhibit the synthesis of prostaglandins and lectins, selective inhibitors that induce cyclooxygenase, selective inhibitors that induce cyclooxygenase-2, autosecodylins, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involving humoral and cellular immune responses, lipid-derived autosecodylins, arachidic acid, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthine, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0693] Other therapeutic agents covered in this article include diuretics, vasopressins, agents that affect kidney water retention, rennet, angiotensin, agents that can be used to treat myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, beta-adrenergic receptor antagonists, agents used to treat hypercholesterolemia, and agents used to treat dyslipidemia.

[0694] Other therapeutic agents covered include medications for controlling stomach acidity, medications for treating peptic ulcers, medications for treating gastroesophageal reflux disease, prokinetic agents, antiemetics, medications for irritable bowel syndrome, medications for diarrhea, medications for constipation, medications for inflammatory bowel disease, medications for biliary tract diseases, and medications for pancreatic diseases. Therapeutic agents for treating protozoan infections, medications for treating malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis, and / or leishmaniasis, and / or chemotherapy for helminthiasis are also included. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolone and agents for urinary tract infections, penicillins, cephalosporins and others, β-lactam antibiotics, agents including aminoglycosides, protein synthesis inhibitors, drugs used in chemotherapy for tuberculosis, mycobacterium avium complex disease and leprosy, antifungal agents, and antiviral agents (including nonretroviral and antiretroviral agents).

[0695] Examples of therapeutic antibodies that can be combined with the compounds of the present invention include (but are not limited to) anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies (e.g., alemtuzumab, bevacizumab, and gemtuzumab).

[0696] Furthermore, the methods described in this article cover therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressants, tolerogens, and immunostimulants. Additionally, therapeutic agents acting on the blood and blood-forming organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulants, thrombolytics, and antiplatelet drugs are also included.

[0697] For the treatment of renal cell carcinoma, the compounds of this invention can be combined with sorafenib and / or avastin. For the treatment of endometrial disorders, the compounds of this invention can be combined with doxorubicin, taxotere (paclitaxel), and / or cisplatin (carboplatin). For the treatment of ovarian cancer, the compounds of this invention can be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan, and / or tamoxifen. For the treatment of breast cancer, the compounds of this invention can be combined with taxotere (paclitaxel), gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901, avastin, herceptin, OSI-906, and / or OSI-930. For the treatment of lung cancer, the compounds of this invention can be combined with paclitaxel, gemcitabine, cisplatin, pemetrexed, tascifa, PD0325901 and / or antiseptic.

[0698] Other therapeutic agents that can be combined with the compounds of the present invention can be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," 10th edition (edited by Hardman, Limbird, and Gilman) or the Physician's Desk Reference, the entire contents of which are incorporated herein by reference.

[0699] Depending on the condition being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Therefore, in some embodiments, one or more of the compounds of the present invention are co-administered with other agents as described above. In combination therapy, the compounds described herein are administered simultaneously or separately with a second agent. This combination administration may include administe...

Claims

1. A compound of formula (IA), (I-A) Or its pharmaceutically acceptable salt, wherein: C is selected from piperidinyl and piperazineyl; L 2 is -CH2-; L 3 is -CH2CH(R 50 )-, and R 50 is methyl; R 1 C 1-3 Halogenated alkyl groups; R 2 Selected from hydrogen, halogens, -OR 52 -NHR 52 -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 group; R 3 It is hydrogen; Each R A and R B Independently selected from halogen, -CN, -OR 52 -N(R) 52 )2、-NR 53 R 54 C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group; Each R C Selected independently from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; m and p are each an independent integer from 0 to 3; n is an integer from 1 to 3; R 51 Selected from hydrogen and C 1-6 alkyl; R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl and C 2-20 Alkyne groups, each of which is optionally halogenated, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted; R 53 and R 54 It forms a heterocycle together with the nitrogen atom to which it is attached; and R 57 is -S(=O)2R 52 .

2. The compound of claim 1, wherein: R 2 Selected from halogens, -OR 52 -NHR 52 -CN,C 1-3 Alkyl, -CH2OR 52 -CH2N(R) 52 2. C 1-3 Haloalkyl, C 2-3 alkenyl and C 2-3 Alkyne group.

3. The compound of claim 1, wherein the compound is: Or its pharmaceutically acceptable salt.

4. A compound of formula (II-A), (II-A) in: C is selected from piperidinyl and piperazineyl; L 2 It is -CH2-; L 3 For optional use by R 56 Substituted C2 alkylene, and R 56 C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; R 1 C 1-3 Halogenated alkyl groups; R 2 It is -NHCH3; R 3 Selected from hydrogen and C 1-3 alkyl; Each R A and R B Each occurrence is independently selected from halogen, CN, -OR. 52 -N(R) 52 )2 and C 1-10 Alkyl; each R C Each occurrence is independently selected from -S(=O)2R 52 -S(=O)2N(R) 52 )2、-S(=O)2NR 53 R 54 and -NR 52 S(=O)2R 52 ; m and p are each an independent integer from 0 to 3; n is an integer from 1 to 4; R 51 Selected from hydrogen and C 1-6 alkyl; R 52 Each time it appears, it is independently selected from hydrogen; and C. 1-20 Alkyl, C 2-20 alkenyl and C 2-20 Alkyne groups, each of which is optionally halogenated, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbon rings or 3- to 6-membered heterocyclic rings are substituted; and R 53 and R 54 It forms a heterocycle together with the nitrogen atom to which it is attached.

5. The compound of claim 4, wherein L 3 -CH2CH(R) 56 )-, and R 56 It is a methyl group.

6. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-5 and a pharmaceutically acceptable carrier.

7. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating an individual’s disease or condition, wherein the disease or condition is selected from hematologic malignancies, solid tumors, and diabetes.

8. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating a disease or condition in an individual, wherein the disease or condition is selected from leukemia, prostate cancer, breast cancer, liver cancer, and brain tumors.

9. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating a disease or condition in an individual, wherein the disease or condition is a hematologic malignancy.

10. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating a disease or condition in an individual, wherein the disease or condition is leukemia.

11. The use as claimed in claim 10, wherein the leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), mixed lineage leukemia (MLL), or leukemia having partial tandem duplication of MLL.

12. The use as claimed in claim 10, wherein the leukemia is AML.

13. The use as described in claim 10, wherein the leukemia is ALL.

14. Method for preparing compound 2: （2） Including compounds 2-7: （2-7） Mixed with methanesulfonyl chloride in the presence of Et3N.

15. The method of claim 14, wherein compounds 2-7 are obtained by passing compounds 2-6. （2-6） Prepared by mixing with trifluoroacetic acid.

16. The method of claim 15, wherein compounds 2-6 are produced by passing compounds with the following structures With compounds 2-5 （2-5） It was prepared by mixing NaBH(OAc)3 and Et3N in the presence of NaBH(OAc)3 and Et3N.

17. The method of claim 16, wherein compounds 2-5 （2-5） By using compounds 2-4 （2-4） With 5-formyl-4-methyl-1H-indole-2-nitrile Prepared by mixing in the presence of Cs2CO3.

18. Compounds or their salts having the following structures: (2-5) or (2-4).

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