Substituted inhibitors of Menin-MLL and methods of using the same

Abstract

To provide compounds for inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins.SOLUTION: The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] <Cross-reference> This application claims the benefit of U.S. Provisional Patent Application No. 62 / 309,372, filed Mar. 16, 2016; U.S. Provisional Patent Application No. 62 / 334,369, filed May 10, 2016; U.S. Provisional Patent Application No. 62 / 431,389, filed Dec. 7, 2016; and U.S. Provisional Patent Application No. 62 / 446,640, filed Jan. 16, 2017, the disclosures of which are hereby incorporated by reference.

Background Art

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

[0003] The menin protein encoded by the multiple endocrine neoplasia (MEN) gene is a ubiquitously expressed nuclear protein involved in DNA processing and interactions with repair proteins, chromatin that modifies proteins, and numerous transcription factors (Agarwal, et al.; Horm Metab Res, 2005, 37(6): 369-374). The association of menin with the N-terminus of the MLL fusion protein is required for the observed tumorigenic activity of the MLL fusion protein. This association has been shown to constitutively upregulate the expression of the HOX and MEIS1 oncogenes, reducing the proliferation and differentiation of hematopoietic cells that leads to leukemia progression. Since menin has been shown to function as a common tumorigenic cofactor in MLL-related leukemia, the interaction between menin, the MLL fusion protein, and MLL represents a potential chemotherapy target.

[0004] The prognosis of patients (especially infants) with leukemia having a chromosomal translocation of the MLL gene is dismal, with a 5-year survival rate of less than 40% (Slany; Haematologica, 2009, 94(7): 984-993). New treatment strategies are urgently needed to treat these leukemias. Small molecule inhibitors that block the menin-MLL interaction are thus beneficial targets for the treatment of diseases related to the MLL fusion protein.

Summary of the Invention

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

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

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

[0008]

Chemical formula

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

[0010]

Chemical formula

[0011] In some embodiments, for the compound of formula (II), R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 alkyl, and C 1-3 haloalkyl, or two R C groups bonded to different atoms can combine to form a C 1-3 bridge.

[0012] For the compound of formula (I) or (II), C may be a 5- to 12-membered heterocycle, where the heterocycle contains at least one nitrogen atom. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is selected from piperidinyl and piperazinyl.

[0013] In some embodiments, for the compound of formula (I), C is

[0014]

Chemical formula

[0015] In some embodiments, for the compound of formula (II), C is

[0016] [Chemical] selected from, where R 57 is -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 ; and -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 and -NR 52 S(=O)2R 52 substituted with one or more substituents selected from C 1-10 alkyl is selected from. In some embodiments, R 57 is -S(=O)R 52 -S(=O)2R 52 -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 is selected from. In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3.

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

[0018] In some embodiments, for the compound of formula (I) or (II), H is a 5- to 12-membered heterocyclic ring optionally substituted with one or more R 50 ; A is a 3- to 12-membered heterocyclic ring; and B is a 3- to 12-membered heterocyclic ring.

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

[0020]

Chemical formula

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

[0022]

Chemical formula

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

[0024]

Chemical formula

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

[0026] For the 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 contains less than 10 atoms. In some embodiments, L 1 is -N(R 51 )-. In some embodiments, L 2 contains less than 10 atoms. In some embodiments, L 2 is C 50 alkylene optionally substituted with one or more R 1-4 . In some embodiments, L 2 is selected from -CH2-, -N(R 51 )-, -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)2-. In some embodiments, L 3 contains less than 20 atoms. In some embodiments, L 3 is C 50 alkylene optionally substituted with one or more R 1-6 . In some embodiments, L 3 is C2 alkylene substituted with at least one C 1-3 alkyl or C 1-3 haloalkyl and optionally further substituted with one or more R 50 . In some embodiments, L 3 is =O, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkyl(cyclopropyl), C 1-3 alkyl(NR 52 C(O)R 52 ), or -O(C 1-6is substituted with (alkyl). In some embodiments, L 3 is substituted with -CH3. In some embodiments, the compound of formula (I) or (II) is selected from Table 1.

[0027] For the compound of formula (I), L 3 is

[0028]

Chemical formula

[0029]

Chemical formula

[0030] In some embodiments, for the compound of formula (I) or (II), H is thienopyrimidinyl optionally substituted with one or more R 50 ; A is a 3- to 12-membered heterocyclic ring; B is a 6- to 12-membered bicyclic heterocyclic ring; m is an integer from 0 to 3; and n is an integer from 1 to 3.

[0031] In some embodiments, for the compound of formula (I): H is thienopyrimidinyl optionally substituted with one or more R 50 ; A is selected from piperidinylene and piperazinylene; B is indolylene; L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH2-; L3 is a single bond, -O-, -S-, -N(R 51 ), -N(R 51 ),CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 ), -C(O)N(R 51 ),C(O)-, -C(O)N(R 51 ),C(O)N(R 51 ), -N(R 51 ),C(O)-, -N(R 51 ),C(O)N(R 51 ), -N(R 51 ),C(O)O-, -OC(O)N(R 51 ), -C(NR 51 ), -N(R 51 ),C(NR 51 ), -C(NR 51 ),N(R 51 ), -N(R 51 ),C(NR 51 ),N(R 51 ), -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 ),S(O)2-, -S(O)2N(R 51 ), -N(R 51 ),S(O)-, -S(O)N(R 51 ), -N(R 51 ),S(O)2N(R 51 ), -N(R 51 ),S(O)N(R 51 ); alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 s, wherein two R 3 s bonded to the same or different atoms of L 50 may together optionally form a ring; R A , R B , and R C are each independently selected from R 50 at each occurrence, or two R A groups, two RB a radical, or two Rs C the radicals may optionally combine to form a ring; m is an integer from 0 to 3; n is an integer from 1 to 3, p is an integer from 0 to 6; R 57 is -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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 each is independently, -S(=O)R 52 -S(=O)2R 58 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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)NR53 R 54 、 -P(O)(OR 52 )2, and -P(O)(R 52 )2 are each substituted at each occurrence with one or more substituents selected from C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl ; and R 58 is hydrogen; and C 1-20 alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle.

[0032] In some embodiments, for the compound of formula (II): H is thienopyrimidinyl optionally substituted with one or more R 50 ; A is selected from piperidinylene and piperazinylene; B is indolylene; L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH2-; L 3 is C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is substituted with one or more R 56 and further optionally substituted with one or more R 50 ; R A , R B and R C are each independently selected from R 50 at each occurrence, or two R A groups bonded to the same atom or different atoms, two RB groups, or two Rs C groups may be joined together optionally to form a bridge or a ring; m is an integer from 0 to 3; n is an integer from 1 to 3, p is an integer from 0 to 6; R 56 is independently selected, each time it occurs, from -OR 59 =O, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, where the C in R 56 alkyl, C 1-10 alkenyl, and C 2-10 alkynyl are each independently halogen, -NO2, -CN, -OR 2-10 -SR, -N(R 59 )2, -NR 52 R, -S(=O)R 52 -S(=O)2R, -S(=O)2N(R 53 )2, -S(=O)2NR 54 R, -NR 52 S(=O)2R, -NR 52 S(=O)2N(R 52 )2, -NR 53 S(=O)2NR 54 R, -C(O)R 52 -C(O)OR, -OC(O)R 52 -OC(O)OR, -OC(O)N(R 52 )2, -OC(O)NR 52 R, -NR 52 C(O)R, -NR 53 C(O)OR, -NR 54 C(O)N(R 52 )2, -NR 52 C(O)NR 52 R, 52 52 53 54 52 52 52 52 52 52 52 53 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 ring, and optionally substituted at each occurrence with one or more substituents selected from 3- to 12-membered heterocycles; wherein, R 56 in the C 3-12 carbon ring and 3- to 12-membered heterocycle are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52)2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from; and further here, R 56 optionally forms a single bond to ring C; and R 59 is independently selected from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle each time they occur, each of which is halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or optionally substituted by a 3-6 membered heterocycle.

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

[0034] In some embodiments, for the compound of formula (I) or (II), H is

[0035]

Chemical formula

[0036]

Chemical formula

[0037]

Chemical formula

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

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

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

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

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

[0043] In certain embodiments, the present disclosure provides a kit comprising a pharmaceutical composition described herein and instructions for using the composition to treat a subject afflicted with a disease or disorder mediated by the interaction of menin with another protein.

[0044] <Incorporation by reference> All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

[0045] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention will be obtained from the following detailed description that illustrates exemplary embodiments in which the principles of the invention are utilized, and from the following appended drawings.

Figure 1

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Figure 10

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Figure 12

Figure 13

BEST MODE FOR CARRYING OUT THE INVENTION

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0047] The term "MLL fusion protein" refers to a protein having an N-terminal fragment of MLL that is fused to a partner protein. Non-limiting examples of partner proteins include those located at 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22, 9p13.3, 9p22 (MLLT3 / AF9), ABI1, ABI2, ACACA, ACTN4, AFF1 / AF4, AFF3 / LAF4, AFF4 / AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13, C2CD3, CASC5, CASP8AP2, CBL, CEP164, CEP170B, CREBBP, DCP1A, DCPS, EEFSEC / SELB, ELL, EPS15, 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). The MLL fusion protein may also be generated through the binding of a gene encoding the MLL protein and a gene encoding a partner protein that generates a fusion gene. The translation of this fusion gene may result in one or more polypeptides having functional properties derived from each of the original proteins.

[0048] The term "C x-y " or "C x -C y ", when used in combination with a chemical moiety such as alkyl, alkynyl, or alkenyl, means a group containing from 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 straight-chain and branched-chain alkyl groups having from x to y carbons in the chain. "C x-y alkenyl" and "Cx-y "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group each containing at least one double or triple bond. Unless specifically defined otherwise herein, C x-y alkyl, C x-y alkenyl, or C x-y alkynyl is optionally substituted by one or more substituents such as the substituents described herein.

[0049] "Carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. The carbocyclic ring can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. The rings of the bicyclic carbocyclic ring can each be selected from a saturated ring, an unsaturated ring, and an 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 typical embodiments, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings is included in the definition of the carbocyclic ring as long as the valences permit. Typical carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless specifically defined otherwise herein, the carbocyclic ring is optionally substituted by one or more substituents such as those described herein.

[0050] "Heterocyclic ring" refers to a saturated ring, unsaturated ring, or aromatic ring containing one or more heteroatoms. Typical heteroatoms include atoms of N, O, Si, P, B, and S. The heterocyclic ring can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each of the rings of the bicyclic heterocyclic ring can be selected from a saturated ring, unsaturated ring, and aromatic ring. The heterocyclic ring may be bonded to the remainder of the molecule through any atom of the heterocyclic ring, such as a carbon atom or nitrogen atom of the heterocyclic ring, as permitted by the valence. In some embodiments, the heterocyclic ring is heteroaryl. In some embodiments, the heterocyclic ring is heterocycloalkyl. In a typical embodiment, the heterocyclic ring (e.g., pyridyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene.

[0051] "Heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, where the heteroatoms can each 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, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. The heteroatoms in heteroaryl can optionally be oxidized. One or more nitrogen atoms, if present, can optionally be quaternized. Heteroaryl may be bonded to the remainder of the molecule through any atom of heteroaryl, such as a carbon atom or nitrogen atom of heteroaryl, as valence permits. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10 - hexahydrocyclooct[a]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8 - methano - 5,6,7,8 - tetrahydroquinazolinyl, naphthyridinyl, 1,6 - naphthyridinonyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a - octahydrobenzo[h]quinazolinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4 - d]pyrimidinyl, pyridinyl, pyrido[3,2 - d]pyrimidinyl, pyrido[3,4 - d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8 - tetrahydroquinazolinyl, 5,6,7,8 - tetrahydrobenzo[4,5]thieno[2,3 - d]pyrimidinyl, 6,7,8,9 - tetrahydro - 5H - cyclohepta[4,5]thieno[2,3 - d]pyrimidinyl, 5,6,7,8 - tetrahydropyrido[4,5 - c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3 - d]pyrimidinyl, thieno[3,2 - d]pyrimidinyl, thieno[2,3 - c]pyridinyl, and thiophenyl (i.e., thienyl). Unless specifically defined otherwise herein, the term "heteroaryl" means including heteroaryl as defined above, optionally substituted by one or more substituents such as those described herein.,

[0052] The compounds of the present disclosure also include crystalline and non - crystalline forms of those compounds, pharmaceutically acceptable salts of said compounds having the same type of activity, and active metabolites, for example, in addition to polymorphs, pseudopolymorphs, solvates, hydrates, non - solvated polymorphs (including anhydrates), stereopolymorphs, and non - crystalline forms of said compounds, combinations thereof are included.,

[0053] The compounds described in this specification exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same number of atoms but a different atomic mass or mass number than that found predominantly in nature. All isotopic variations of the compounds of the present disclosure are included within the scope of this disclosure, whether or not radioactive. For example, hydrogen has three naturally occurring isotopes represented by 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment of deuterium can provide certain therapeutic advantages such as increased in vivo half-life and / or exposure, or can provide compounds useful for investigating in vivo pathways of drug excretion and metabolism. Isotopically enriched compounds can be prepared by conventional techniques well known to those of ordinary skill in the art.

[0054] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are spatially arranged. Enantiomers are pairs of stereoisomers that are mirror images of each other and cannot be superimposed on each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to denote a racemic mixture where appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. The specific compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, and the asymmetric centers can be defined as (R)- or (S)- with respect to absolute stereochemistry. The chemical entities, pharmaceutical compositions, and methods of the present application are meant to include all possible stereoisomers thereof, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. The optical activity of a compound can be analyzed via appropriate methods including, but not limited to, chiral chromatography and polarimetry, and the degree of preponderance of one stereoisomer over the other isomers can be determined.

[0055] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the Z-form or the E-form (or, cis-form or trans-form). Further, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the chemical entities described herein are likewise intended to include all Z-, E-, and tautomeric forms.

[0056] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbon or heteroatoms of the structure. "Substitution" or "substituted with" is such that the substitution follows the allowed valences of the atoms being substituted and the substituents, and implies the tacit condition that a stable compound is brought about that does not spontaneously undergo deformations such as rearrangement, cyclization, elimination, etc. as a result of the substitution. As used herein, the term "substituted" is considered to include all acceptable substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Acceptable substituents can be one or more and the same or different for a suitable organic compound. For the purposes of this disclosure, a heteroatom such as nitrogen can be provided with a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (thioester, thioacetate, or thioformate, etc.), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, carbocycle, heterocycle, cycloalkyl, heterocycloalkyl, aromatic moiety and heteroaromatic moiety. In some embodiments, substituents can be any of the substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oxime (=N-OH), hydrazino (=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 -O-R c -C(O)N(R a ) 2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2); and including alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oximo(=N-OH), hydrazine(=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a ) 2、-R b -N(R a ) 2、-R b -C(O)R a 、-Rb -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) and is optionally substituted by; where R a is each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and R a is each, as valence permits, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), 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 -O-R c -C(O)N(R a )2、 -R b -N(R a )C(O)OR a 、 -R b -N(R a )C(O)R a 、 -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) and is optionally substituted; and wherein, R B is each independently a direct bond, or is selected from a straight or branched alkylene, alkenylene, or alkynylene chain, and R C is each a straight or branched alkylene, alkenylene, or alkynylene chain.

[0057] It is understood by those skilled in the art that, where appropriate, substituents may themselves be substituted. Unless specifically stated as "unsubstituted", references to chemical moieties in this specification are understood to include substituted variants. For example, references to a "heteroaryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0058] When substituents are specified by their conventional chemical formulas and written from left to right, these equally encompass chemically identical substituents resulting from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0059] The terms "salt" or "pharmaceutically acceptable salt" refer to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which the 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 the salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, (cyclic amines, basic ion exchange resins, etc., specifically including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from the salts of ammonium, potassium, sodium, calcium, and magnesium.

[0060] The terms "effective amount" or "therapeutically effective amount" refer to an amount of a compound described herein that is sufficient to affect the intended use, including but not limited to the treatment of a disease as defined below. A therapeutically effective amount will vary depending on the intended treatment use (in vivo), or the condition of the subject and the disease being treated, e.g., the body weight and age of the subject, the severity of the disease condition, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. This term also applies to the dose that induces a specific response in target cells, e.g., a decrease in platelet adhesion and / or cell migration. The specific dose will vary depending on the specific compound selected, the dosing regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system by which the compound is carried.

[0061] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including but not limited to therapeutic and / or prophylactic benefits. Therapeutic benefit means eradication or amelioration of the underlying disorder being treated. Additionally, a therapeutic benefit can be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be affected by the underlying disorder. In certain embodiments, with respect to prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even in the absence of a diagnosis of the disease.

[0062] "Therapeutic effect", as the term is used herein, encompasses therapeutic and / or prophylactic benefits as described above. Prophylactic effect includes delaying or preventing the onset of a disease or illness, delaying or preventing the development of symptoms of a disease or illness, slowing, halting, or reversing the progression of a disease or illness, or any combination thereof.

[0063] The terms "co-administered", "administered in combination with", and their grammatical equivalents encompass the administration of two or more agents to an animal, including a human, such that the agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0064] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit the biological functions (e.g., activity, expression, binding, protein - protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and / or MLL fusion protein). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but compounds that inhibit the biological activity of the target protein by interacting with other members of the signaling pathway of which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are related to tumor progression, growth, or expansion.

[0065] The term "agonist", as used herein, refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibition of the activity or expression of the target protein or otherwise. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. Preferred agonists herein specifically interact (e.g., bind) with the target, but compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other members of the signaling pathway of which the target polypeptide is a member are also specifically included within this definition.

[0066] "Signal transduction" is the process by which a stimulatory or inhibitory signal is transmitted to and within a cell to elicit an intracellular response. A modulator of a signaling pathway refers to a compound that regulates the activity of one or more cellular proteins mapped to the same specific signaling pathway. A modulator can increase (agonist) or suppress (antagonist) the activity of a signaling molecule.

[0067] "Anticancer agent", "antineoplastic agent", or "chemotherapeutic agent" refers to any agent useful for the treatment of tumor diseases. One type of anticancer agent includes chemotherapeutic agents. "Chemotherapy" means the administration of one or more chemotherapeutic agents and / or other agents to cancer patients by various methods including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of suppositories.

[0068] "Subject" refers to an animal, such as a mammal, for example, a human. The methods described herein may be useful for both human treatment and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human. "Mammal" includes both humans and non-domestic animals such as wild animals (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), as well as domestic animals such as experimental animals and pets.

[0069] "Prodrug" means a compound that can be converted, under physiological conditions or by solvolysis, into a bioactive compound described herein (e.g., a compound of formula (I) or (II)). Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject but is converted in vitro to an active compound, e.g., by hydrolysis. Prodrug compounds frequently have the advantage of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7 9, 21 24 (Elsevier, Amsterdam); Higuchi, T., et al., ”Pro drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, each of which is hereby incorporated by reference in its entirety). The term "prodrug" also means any covalently attached carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds are typically prepared by modifying a functional group present in the active compound in such a way that, upon conventional manipulation or in vivo, the modifying substance is cleaved to the parent active compound. A prodrug includes a compound wherein a hydroxy, amino, or mercapto group is attached to any group that cleaves to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, derivatives of acetate, formate, and benzoate of a hydroxy functional group, or derivatives of acetamide, formamide, and benzamide of an amine functional group in the active compound.

[0070] The term "in vivo" refers to an event occurring in the body of a subject.

[0071] The term "in vitro" refers to an event occurring outside the body of a subject. For example, an in vitro assay encompasses any assay performed outside the subject. An in vitro assay includes cell-based assays in which living or dead cells are utilized. An in vitro assay also includes cell-free assays in which intact cells are not utilized.

[0072] "Optional" or "optionally" means that the event or situation described hereinafter may or may not occur and that this description includes examples of the event or situation occurring and not occurring. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted and that this description includes both substituted aryl groups and aryl groups having no substitution.

[0073] "Pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent approved by the US Food and Drug Administration as acceptable for use in humans or domestic animals.

[0074] The present disclosure provides compounds for modulating the interaction of menin with proteins such as MLL1, MLL2, and MLL fusion oncoproteins. In certain embodiments, the present disclosure provides compounds and methods for inhibiting the interaction of menin with signaling molecules upstream or downstream thereof, including but not limited to MLL1, MLL2, and MLL fusion oncoproteins. The compounds of the present disclosure may be used in methods for treating a variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL fusion protein, and menin. In certain embodiments, the compounds of the present disclosure covalently bind to menin and inhibit the interaction between menin and MLL. In certain embodiments, the compounds of the present disclosure non-covalently interact with menin and inhibit the interaction between menin and MLL.

[0075] The compounds of the present disclosure may be used in methods for treating a variety of diseases associated with MLL1, MLL2, MLL fusion protein, and menin. In certain embodiments, the compounds of the present disclosure non-covalently interact with menin and inhibit the interaction between menin and MLL. In certain embodiments, the compounds of the present disclosure covalently bind to menin and inhibit the interaction between menin and MLL.

[0076] In some aspects, the present disclosure provides compounds or salts that selectively bind to the menin protein and / or modulate the interaction of menin with an MLL protein (e.g., MLL1, MLL2, or MLL fusion protein). In certain embodiments, the compound modulates the menin protein by binding to and / or interacting with one or more amino acids and / or one or more metal ions. Certain compounds may occupy the pockets of F9 and / or P13 of menin. The binding of the compounds disclosed herein may interfere with downstream signaling of menin or MLL (e.g., MLL1, MLL2, or MLL fusion protein).

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

[0078]

Chem.

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

[0080]

Chemical formula

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

[0082]

Chemical formula

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

[0084] [Chemical] In the formula: H is selected from a carbocyclic ring and a 5- to 12-membered heterocyclic ring, each of which is optionally substituted with one or more R 5-12 ; 50 and is optionally substituted with; A, B, and C are each independently selected from a carbocyclic ring and a 3- to 12-membered heterocyclic ring; 3-12 ; L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 ), -, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 ), -, -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 ), -, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 ), -, -N(R 51 )C(O)O-, -OC(O)N(R 51 ), -, -C(NR 51 ), -, -N(R 51 )C(NR 51 ), -, -C(NR 51 )N(R 51 ), -, -N(R 51 )C(NR 51 )N(R 51 ), -, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 ), -, -N(R 51 )S(O)-, -S(O)N(R 51 ), -, -N(R 51 )S(O)2N(R 51 ), -, -N(R 51 )S(O)N(R 51)-; selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 and where L 1 or L 2 two R 50 groups bonded to the same or different atoms of can together optionally form a ring; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and further optionally substituted with one or more R 50 ; R A , R B , and R C are each independently selected from R 50 at each occurrence, or two R A groups, two R B groups, or two R C groups bonded to the same or different atoms can together optionally form a bridge or a ring; m, n, and p are each independently an integer from 0 to 6, R 50 is independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52, -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 ), -P(O)(NR 52 )(R 52 , -NR 52 P(O)(R 52 ), -P(O)(NR 52 )(OR 52 ), -P(O)(NR 52 )2, =O, =S, =N(R 52 ); each independently, halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 ), -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 ), -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 ), -C(O)NR 53 R 54 , -P(O)(OR 52 ), -P(O)(R 52 ), -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 ), =O, =S, =N(R 52 ), C 3-12 carbon ring, and optionally substituted at each occurrence with one or more substituents selected from 3- to 12-membered heterocycles, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; and C 3-12 carbon ring and 3- to 12-membered heterocycle selected at each occurrence from wherein R 50 in C 3-12 carbon ring and 3- to 12-membered heterocycle are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R52 , -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, optionally substituted with one substituent selected from; R 51 is independently hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; Each independently, halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -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 3-12C optionally substituted at each occurrence with one or more substituents selected from a carbon ring and a heterocyclic ring having 3 to 12 members 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and C 3-12 a carbon ring and a heterocyclic ring having 3 to 12 members each selected at each occurrence, wherein R 51 the C in 3-12 the carbon ring and the heterocyclic ring having 3 to 12 members are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR52 )(R 52 )、 -P(O)(NR 52 )(R 52 )、 -NR 52 P(O)(R 52 )、 -P(O)(NR 52 )(OR 52 )、 -P(O)(NR 52 )2、 =O、 =S、 =N(R 52 )、 C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally substituted with one substituent selected from; R 52 is independently hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1 - 6 membered heteroalkyl, C 3-12 carbocycle, and 3 - 12 membered heterocycle, each selected at each occurrence, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3 - 6 membered heterocycle; R 53 and R 54 together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more R 50 ; R 56 is independently -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 R54 、 -C(O)R 52 、 -C(O)OR 52 、 -OC(O)R 52 、 -OC(O)OR 52 、 -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 )2, -C(O)NR 53 R 54 、 -P(O)(OR 52 )2, -P(O)(R 52 )2, -P(O)(OR 52 )(R 52 )、 -P(O)(NR 52 )(R 52 )、 -NR 52 P(O)(R 52 )、 -P(O)(NR 52 )(OR 52 )、 -P(O)(NR 52 )2, =O, =S, =N(R 52 )、 C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbon ring, and a 3- to 12-membered heterocyclic ring, each selected at the time of occurrence; Here, R 56 in the C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl are each independently 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, -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 is optionally substituted at each occurrence with one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring; wherein R 56 the carbon ring and the 3- to 12-membered heterocyclic ring in 3-12 are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R54 、 -S(=O)R 52 、 -S(=O)₂R 52 、 -S(=O)₂N(R 52 )₂、 -S(=O)₂NR 53 R 54 、 -NR 52 S(=O)₂R 52 、 -NR 52 S(=O)₂N(R 52 )₂、 -NR 52 S(=O)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, optionally substituted with one substituent selected therefrom; and further herein, R 56Optionally forms a single bond to ring C; and R 59 is independently selected from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle each time they occur, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle; Here, for the compound or salt of formula (II), when R 56 is -CH3, L 3 is not further substituted by -OH, -NH2, or -CN.

[0085] In some embodiments, for the compound of formula (I) or (II), H is a 5-12 membered heterocycle such as a 6-12 membered bicyclic heterocycle optionally substituted by one or more R 50 . In some embodiments, H contains one or more heteroatoms such as 1, 2, 3, 4, 5, or 6 ring heteroatoms. In some embodiments, H contains at least 1, 2, 3, 4, or 5 ring nitrogen atoms. In some embodiments, H is optionally substituted thienopyrimidinyl by one or more R 50 . In some embodiments, H is substituted by C 1-4 haloalkyl such as -CH2CF3. In some embodiments, H is substituted by one or more R 50 (e.g., by replacing the hydrogen connected to the ring atom by a single bond to R 50 ). H can be substituted by 0, 1, 2, 3, 4, 5, or 6 or more R 50 groups. H can be substituted by 1, 2, 3, 4, 5, or 6 R 50 groups such as H substituted by 1 or 2 R 50 groups. In some embodiments, H contains at least 1, 2, 3, 4, 5, or 6 R 50is substituted with a group. In some embodiments, H is substituted with up to 6, 5, 4, 3, 2, or 1 R 50 group.

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

[0087]

Chemical formula

[0088]

Chemical formula

[0089]

Chemical formula

[0090]

Chemical formula

[0091]

Chemical formula

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

[0093]

Chemical formula

[0094] In some embodiments, for the compounds of formula (I) or (II), L 1 contains less than 20 atoms, such as less than 10 atoms. In some embodiments, L 1 contains 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In some embodiments, L 1contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. In some embodiments, L 1 contains at least one heteroatom, for example L 1 contains at least one nitrogen. In some embodiments, L 1 is substituted with one or more R 50 . In some embodiments, L 1 is unsubstituted. In some embodiments, L 1 is selected from a single bond, -O-, -S-, -N(R 51 ), -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 ), -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 ), -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 ), -N(R 51 )S(O)2N(R 51 ), alkylene, alkenylene, heteroalkenylene, and heteroalkenylene. In some embodiments, L 1 is selected from a single bond, -O-, -S-, -N(R 51 ), -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 ), -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 ), -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 ), -N(R 51 )S(O)2N(R 51 ), C 1-6 alkylene, and C 2-6 alkenylene, where C 1-6 alkylene and C 2-6 alkenylene are each independently one or more R 50is optionally replaced. In some embodiments, L 1 is -N(R 51 )- such as -NH-. In some embodiments, L 1 is -O-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, C 1-4 alkylene, C 2-4 alkenylene, and C 1-4 heteroalkylene. In some embodiments, L 1 is -N(R 51 )- where R 51 is selected from hydrogen and alkyl.

[0095] In some embodiments, for the compounds of formula (I) or (II), A is a 3- to 12-membered heterocycle such as a 5- to 8-membered heterocycle. In some embodiments, A is a 6-membered monocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom. In some embodiments, A contains at least one ring nitrogen. In some embodiments, A is

[0096]

Chemical formula

[0097]

Chemical formula

[0098] In some embodiments, A is

[0099]

Chemical formula

[0100] In some embodiments, A is substituted with one or more RAs (e.g., by replacing the hydrogen connected to the ring atom by a single bond to RA). A can be substituted with 0, 1, 2, 3, 4, 5, or 6 or more R A groups. A can be substituted with 1 or 2 R A groups, such as A substituted with 1, 2, 3, 4, 5, or 6 R A groups. In some embodiments, A is substituted with at least 1, 2, 3, 4, 5, or 6 R A groups. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with m R A groups, 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.

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

[0102] In some embodiments, for a compound of formula (I) or (II), L 2 contains less than 20 atoms, such as less than 10 atoms. In some embodiments, L 2 contains less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. In some embodiments, L 2 contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. In some embodiments, L 2 contains at least one heteroatom, for example L 2 contains at least one nitrogen. In some embodiments, L 2 is C 50 alkylene, such as C 1-4 alkylene, optionally substituted with one or more R 1-10 . In some embodiments, L 2 is substituted with one or more R 50 . In some embodiments, L 2 is unsubstituted. In some embodiments, L 2is selected from a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkenylene, and heteroalkenylene. In some embodiments, L 2 is selected from a single bond, -O-, -S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, C 1-6 alkylene, and C 2-6 alkenylene, where C 1-6 alkylene and C 2-6 alkenylene are each independently optionally substituted with one or more R 50 . In some embodiments, L 2 is 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 heteroalkylene. In some embodiments, L2 is selected from -CH2-, -N(R 51 ), -N(R 51 )CH2-, -N(R 51 )C(O)-, and -N(R 51 )S(O)2-. In some embodiments, L 2 is -CH2-.

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

[0104]

Chemical formula

[0105]

Chemical formula

[0106]

Chemical formula

[0107] In some embodiments, B is

[0108]

Chemical formula

[0109] In some embodiments, B is

[0110]

Chemical formula

[0111]

Chemical formula

[0112] In some embodiments, B is one or more R Bis replaced (e.g., by replacing a hydrogen atom attached to a ring atom by a single bond to RB). B can be substituted with 0, 1, 2, 3, 4, 5, or 6 or more R B groups. B can be substituted with 1 or 2 R B groups such as B substituted with 1, 2, 3, 4, 5, or 6 R B groups. In some embodiments, B is substituted with at least 1, 2, 3, 4, 5, or 6 R B groups. In some embodiments, B is substituted with n R B groups, where n is an integer from 0 to 6. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is at least 1, 2, 3, 4, 5, or 6. In some embodiments, n is at most 6, 5, 4, 3, 2, or 1. In some embodiments, n is an integer from 1 to 3.

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

[0114] In some embodiments, for the compound of formula (II), L 3 contains less than 30 atoms, such as less than 20 atoms. In some embodiments, L 3 contains less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. In some embodiments, L 3 contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. In some embodiments, L 3 contains at least one heteroatom, for example L 3 contains at least one nitrogen. In some embodiments, L 3 is C 50 alkylene, such as C 1-4 alkylene, optionally substituted with one or more R 1-10 . In some embodiments, L 3 is substituted with one or more R 50 . In some embodiments, L 3 is unsubstituted. In some embodiments, L 3 is a single bond, -O-, -S-, -N(R 51 ), -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 ), -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 ), -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 ), -N(R51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkenylene, and heteroalkenylene. In some embodiments, L 3 is optionally substituted with one or more R 50 is C 1-6 alkylene, where R 50 is deuterium, C 1-4 alkyl, C 1-4 haloalkyl, and -OR 52 . In some embodiments, L 3 is -CH2CH(R 50 )- such as -CH2CH(CH3)-. In some embodiments, L 3 Two R 50 groups attached to the same or different atoms of L 3 optionally form a bridge or a ring such as a cyclopropyl ring. In some embodiments, L 50 is substituted with R 50 , where R 3 is deuterium, C 1-4 alkyl, C 1-4 haloalkyl, and -OR 52 . In some embodiments, L 3 is substituted with -CH3. In some embodiments, L 3 is substituted with at least one C 1-3 alkyl or C 1-3 haloalkyl and optionally further substituted with one or more R 50 is C2 alkylene. In some embodiments, L 3 is =O, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkyl(cyclopropyl), C 1-3 alkyl(NR 52 C(O)R 52 ), or -O(C 1-6 alkyl).

[0115] In some embodiments, for the compound of formula (I), L 3 is

[0116]

Chemical formula

[0117]

Chemical formula

[0118]

Chemical formula

[0119]

Chemical formula

[0120] In some embodiments, for a compound of formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 ; and L 3 is substituted with one or more R 50 , where L 3 is not -CH2CH(OH)-. In some embodiments, for a compound of formula (I), C is azetidinylene, piperidinylene, or piperazinylene; R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 ; and L 3 is substituted with C 1-4 alkyl or C 1-4 haloalkyl.

[0121] In some embodiments, for a compound of formula (I), L 3 is selected from

[0122]

Chemical formula

[0123]

Chemical formula

[0124] In some embodiments, for a compound of formula (II), L 3 contains less than 30 atoms, such as less than 20 atoms. In some embodiments, L 3 contains less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 atoms. In some embodiments, L 3contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 atoms. In some embodiments, L 3 is substituted with one or more R 56 and is optionally substituted with one or more additional R 50 to form a C 1-4 alkylene such as C 1-10 alkylene. In some embodiments, L 3 is substituted with one or more R 50 In some embodiments, L 3 is substituted with R 56 In some embodiments, L 3 is selected from alkylene and alkenylene. In some embodiments, L 3 is substituted with one or more R 56 to form a C 1-6 alkylene, where R 56 is selected from deuterium, C 1-4 alkyl, C 1-4 haloalkyl, and -OR 59 In some embodiments, L 3 is substituted with R 56 to form a C 1-4 alkylene, where R 56 forms a single bond to ring C. In some embodiments, L 3 is -CH2CH(R 56 )- such as -CH2CH(CH3)-. In some embodiments, two R 3 groups bonded to the same or different atoms of L 56 optionally form a bridge or a ring such as a cyclopropyl ring. In some embodiments, L 3 is substituted with R 56 where R 56 forms a single bond to ring C. In some embodiments, L 3 is substituted with one or more groups selected from C 1-4 alkyl, C 1-4 haloalkyl, and -OR 59 In some embodiments, L 3 is substituted with -CH3. In some embodiments, L3 is C alkylene substituted with -CH3 and further optionally substituted with R 50 wherein R is not -OH, -NH2, or -CN. In some embodiments, L 1-4 is C2 alkylene substituted with at least one C 50 alkyl or C 3 haloalkyl and optionally further substituted with one or more R 1-3 . In some embodiments, L 1-3 is substituted with =O, C 50 alkyl, C 3 haloalkyl, C 1-6 alkyl(cyclopropyl), C 1-6 alkyl(NR 1-3 C(O)R 1-3 ), or -O(C 52 alkyl). 52 ) 1-6

[0125] In some embodiments, for the compound of formula (II), L 3 is selected from

[0126]

Chemical formula

[0127]

Chemical formula

[0128]

Chemical formula

[0129]

Chemical formula

[0130]

Chemical formula

[0131]

Chemical formula

[0132] In some embodiments, with respect to the compound 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 a 5- to 7-membered monocyclic heterocycle, an 8- to 10-membered fused bicyclic heterocycle, and a 7- to 12-membered spirocyclic heterocycle. In some embodiments, the heterocycle contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is

[0133]

Chem.

[0134]

Chem.

[0135]

Chem.

[0136]

Chem.

[0137]

Chem.

[0138] In some embodiments, for the compounds of formula (I), C is

[0139]

Chemical formula

[0140] In some embodiments, for the compounds of formula (I), R 57 is -S(=O)2R 58 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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 selected from, each of which is -S(=O)2R 58 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 -NR 52 S(=O)2R 52 -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54, -C(O)NH(C 1-6 alkyl), -C(O)NR 53 R 54 is independently substituted at each occurrence with one or more substituents selected from. In some embodiments, R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , and -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, and -NR 52 S(=O)2NR 53 R 54 selected from C 1-6 alkyl substituted with one or more substituents selected from. In some embodiments, R 57 is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, and -NR 52 S(=O)2R 52 selected from. In some embodiments, R 57 is selected from -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -NHS(=O)2CH3, and -S(=O)2NHCH3.

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

[0142] In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 alkyl, and C 1-3 haloalkyl, or two R C groups attached to different atoms may together form a C 1-3 bridge. In some embodiments, R C is C 1-3 alkyl such as -CH3, and C 1-3is selected from haloalkyl.

[0143] In some embodiments, for the compound of formula (II), C is C 3-12 selected from 3- to 12-membered heterocycles such as carbocycles and 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 contains at least one nitrogen atom, such as one or two nitrogen atoms. In some embodiments, C contains at least one ring nitrogen. In some embodiments, C is

[0144]

Chemical formula

[0145]

Chemical formula

[0146]

Chemical formula

[0147]

Chemical formula

[0148]

Chemical formula

[0149] In some embodiments, for the compound of formula (II), C is,

[0150]

Chemical formula

[0151] In some embodiments, for the compound of formula (I) or (II), R C is, halogen, -OR 52, -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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 C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl selected from, each of which is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -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 is optionally substituted independently at each occurrence with one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring; where R C the carbon ring and the 3- to 12-membered heterocyclic ring in each contain halogen, -NO2, -CN, -OR 3-12 、 -SR 52 、 -N(R 52 )2、 -NR 52 R 53 、 -S(=O)R 54 、 -S(=O)2R 52 、 -S(=O)2N(R 52 )2、 -S(=O)2NR 52 R 53 、 -NR 54 、 -NR 52 S(=O)2R 52 、 -NR 52 、 -NR 52 S(=O)2N(R 52 )2、 -S(=O)2NR53 R 54 、 -C(O)R 52 、 -C(O)OR 52 、 -OC(O)R 52 、 -OC(O)OR 52 、 -OC(O)N(R 52 )2、 -OC(O)NR 53 R 54 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2、 -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 )2、 -C(O)NR 53 R 54 、 -P(O)(OR 52 )2、 -P(O)(R 52 )2、 =O、 =、 S、 =N(R 52 )、 C 1-6 alkyl、 C 1-6 haloalkyl、 C 2-6 alkenyl、 and C 2-6 alkynyl, and is independently optionally substituted with one or more substituents selected from

[0152] In some embodiments, R C is -N(R 52 )2、 -NR 53 R 54 、 -NR 52 S(=O)2R 52 、 -C(O)R 52 、 -C(O)OR 52 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2、 -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 )2、 and -C(O)NR 53 R 54is selected from. In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , C 1-6 alkyl, and -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 substituted C 1-6 alkyl selected from.

[0153] In some embodiments, C is

[0154]

Chemical formula

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

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

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

[0158] In some embodiments, for the compounds of formula (II), L 1 contains fewer than 10 atoms, L 2 contains fewer than 10 atoms, and L 3 contains fewer than 20 atoms. In some embodiments, L 1 , L 2 and L 3 each contain at least one atom, such as at least 2 atoms. In some embodiments, L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 ), -N(R 51) CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene, independently selected, L 3 is substituted with one or more R 56 and optionally further substituted with one or more R 50 and is selected from C 1-10 alkylene and C 2-10 alkenylene. In some embodiments, L 1 and L 2 are each 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 is substituted with one or more R 56 and optionally further substituted with one or more R 50 and is selected from C 1-10 alkylene and C 2-10 alkenylene. In some embodiments, L 1 is -O-, S-, -N(R 51 )-, -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 51 )-, -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 )-, -S(O)2-, -S(O)-, -N(R 51 )S(O)2-, -S(O)2N(R 51 )-, -N(R 51 )S(O)2N(R 51 )-, alkylene, alkenylene, heteroalkylene, and heteroalkenylene; L2 is C alkylene optionally substituted with one or more R 50 ; L 1-4 is C alkylene substituted with one or more R 3 and optionally further substituted with one or more R 56 ; in some embodiments, L 50 and L 1-4 are each independently selected from -O-, -S-, -N(R 1 ); C alkylene and 1-4 membered heteroalkylene, each of which is optionally substituted with one or more R 2 ; L 51 is C alkylene substituted with one or more R 1-4 and optionally further substituted with one or more R 50 ; in some embodiments, L 3 is -NH, L 56 is -CH2-, and L 50 is C alkylene substituted with one or more R 1-4 and optionally further substituted with one or more R 1 ; 2 ; 3 in certain embodiments, with respect to the compound of formula (I): 56 ; H is a 5-12 membered bicyclic heterocycle optionally substituted with one or more R 50 ; 1-4 ; A, B and C are each independently selected from 3-12 membered heterocycles;

[0159] ; L ; L 50 ; and L are each independently a single bond, -O-, -S, -N(R ), -N(R 1 ), -N(R 2 )CH2-, -C(O), -C(O)O, -OC(O), -OC(O)O, -C(O)N(R 3 ), -C(O)N(R 51 ), -C(O)N(R 51 )C(O)-, -C(O)N(R 51 ), -C(O)N(R 51 )C(O)N(R 51 ), -N(R 51 ), -N(R 51)C(O), -N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O)O, -OC(O)N(R 51 ), -C(NR 51 ), -N(R 51 )C(NR 51 ), -C(NR 51 )N(R 51 ), -N(R 51 )C(NR 51 )N(R 51 ), -S(O)2, -OS(O), -S(O)O-, -S(O), -OS(O)2, -S(O)2O, -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O), -S(O)N(R 51 ), -N(R 51 )S(O)2N(R 51 )-, -N(R 51 )S(O)N(R 51 ); independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 and where two R 1 , L 2 or L 3 groups attached to the same or different atoms of any one of can optionally form a ring together; 50 ; R A , R B and R C are each independently selected from R 50 each time they occur, or two R A groups, two R B groups, or two R C groups attached to the same or different atoms can optionally form a ring together; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R 50 is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ); each independently being halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -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 An optionally substituted C selected independently at each occurrence by one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring, 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; and C 3-12 selected independently at each occurrence from a carbon ring and a 3- to 12-membered heterocyclic ring; wherein R 50 the C in 3-12 the carbon ring and the 3- to 12-membered heterocyclic ring are each halogen, -NO2, -CN, -OR 52 、 -SR 52 、 -N(R 52 )2、 -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R 52 、 -S(=O)2N(R 52 )2、 -S(=O)2NR53 R 54 、 -NR 52 S(=O)2R 52 、 -、NR 52 S(=O)2N(R 52 )2、 -NR 52 S(=O)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, and is independently optionally substituted with one or more substituents selected from; R 51 is hydrogen, -C(O)R 52 、 -C(O)OR 52 、 -C(O)N(R 52 )2、 -C(O)NR 53 R 54 ; each is halogen, -NO2, -CN, -OR 52 、 -SR 52 、 -N(R 52 )2、 -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R52 ,-S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 ,-NR 52 S(=O)2R 52 ,-NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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 ring and one or more substituents independently selected from 3- to 12-membered heterocycles, optionally substituted each time of occurrence, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and C 3-12 carbon ring and 3- to 12-membered heterocycles independently selected each time of occurrence; wherein R 51 the C in 3-12 the carbon ring and 3- to 12-membered heterocycles are each 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, are each independently optionally substituted with one or more substituents selected from; R 52 is hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12A carbon ring and a 3- to 12-membered heterocyclic ring, each independently selected at each occurrence, each of which is halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Optionally substituted by a carbon ring or a 3- to 6-membered heterocyclic ring; R 53 And R 54 Together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted with one or more R 50 ; R 57 Is -S(=O)R 52 、-S(=O)2R 58 、-S(=O)2N(R 52 )2、-S(=O)2NR 53 R 54 、-NR 52 S(=O)2R 52 、-NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)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 C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is -S(=O)R 52 、-S(=O)2R 58 、-S(=O)2N(R 52 )2、-S(=O)2NR 53 R 54 、-NR 52 S(=O)2R 52 、-NR 52 S(=O)2N(R 52 )2、-NR52 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, each occurrence independently substituted with one or more substituents selected from; and R 58 is hydrogen; and C 1-20 alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle, wherein for the compound or salt of formula (I), C is azetidinylene, piperidinylene or piperazinylene, and R 57 is -S(=O)2R 58 、 -S(=O)2N(R 52 )2、 or -NR 52 S(=O)2R 52 when: p is an integer from 1 to 6; and / or L 3 is substituted with one or more R 50 where L 3 is not -CH2CH(OH)-.

[0160] In certain embodiments, for the compound of formula (II): H is a 5-12 membered bicyclic heterocycle optionally substituted with one or more R 50 ; A, B and C are each independently selected from 3-12 membered heterocycles; L 1 and L 2 are each independently a single bond, -O-, -S-, -N(R 51 ), -N(R 51 )CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 51 ), -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O)-, -N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O)O-, -OC(O)N(R 51 ), -C(NR 51 ), -N(R 51 )C(NR 51 ), -C(NR 51 )N(R 51 ), -N(R 51 )C(NR 51 )N(R 51 ), -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 51 )S(O)2-, -S(O)2N(R 51 ), -N(R 51 )S(O)-, -S(O)N(R 51 ), -N(R 51 )S(O)2N(R 51 ), -N(R 51 )S(O)N(R 51 ); independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 s, where two R 1 s or two R 2 s attached to the same or different atoms of L 50 may together optionally form a ring; L 3 is C 1-6 alkylene, C 2-6 alkenylene, and C 2-6Selected from alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ; R A , R B and R C are each independently selected from R 50 each time they occur, or two R A groups, two R B groups or two R C groups attached to the same or different atoms can together optionally form a bridge or a ring; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R 50 is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR52 C(O)NR 53 R 54 、-C(O)N(R 52 )2、-C(O)NR 53 R 54 、-P(O)(OR 52 )2、-P(O)(R 52 )2、=O、=S、=N(R 52 ); each independently being halogen, -NO2, -CN, -OR 52 、-SR 52 、-N(R 52 )2、-NR 53 R 54 、-S(=O)R 52 、-S(=O)2R 52 、-S(=O)2N(R 52 )2、-S(=O)2NR 53 R 54 、-NR 52 S(=O)2R 52 、-NR 52 S(=O)2N(R 52 )2、-NR 52 S(=O)2NR 53 R 54 、-C(O)R 52 、-C(O)OR 52 、-OC(O)R 52 、-OC(O)OR 52 、-OC(O)N(R 52 )2、-OC(O)NR 53 R 54 、-NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、-NR 52 C(O)N(R 52 )2、-NR 52 C(O)NR 53 R 54 、-C(O)N(R 52 )2、-C(O)NR 53 R 54 、-P(O)(OR 52 )2、-P(O)(R 52 )2、 =O、=S、=N(R 52 )、C 3-12C, optionally substituted independently at each occurrence by one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; and C 3-12 a carbon ring and a 3- to 12-membered heterocyclic ring, each independently selected at each occurrence; where R 50 the C in 3-12 the carbon ring and the 3- to 12-membered heterocyclic ring are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -,, NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R52 )、C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and is optionally independently substituted with one or more substituents selected from; R 51 is hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; each of which is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR52 ) 2, -P(O)(R 52 ) 2, =O, =S, =N(R 52 ), C 3-12 carbon ring and one or more substituents selected from 3- to 12-membered heterocyclic rings, optionally substituted independently at each occurrence, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and C 3-12 carbon ring and 3- to 12-membered heterocyclic rings, each independently selected at each occurrence; where R 51 the C in 3-12 carbon ring and 3- to 12-membered heterocyclic rings are each, 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, and is independently optionally substituted with one or more substituents selected from; R 52 is hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each independently selected at each occurrence, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle; R 53 and R 54 together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more R 50 ; R 56 is -OR 59 、 =O、 C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, each independently selected at each occurrence, where C 56 in R 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl are each independently halogen, -NO2, -CN, -OR 59 、 -SR 52 、 -N(R 52 )2、 -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R 52 、 -S(=O)2N(R 52 )2、 -S(=O)2NR 53 R 54 、 -NR52 S(=O)2R 52 、 -NR 52 S(=O)2N(R 52 )2、 -NR 52 S(=O)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 optionally substituted, each time it occurs, independently, with one or more substituents selected from a carbon ring and a 3 - 12 membered heterocyclic ring; wherein R 56 the C in 3-12 the carbon ring and the 3 - 12 membered heterocyclic ring are each independently halogen, -NO2, -CN, -OR 52 、 -SR 52 、 -N(R 52 )2、 -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R 52 、 -S(=O)2N(R 52 )2、 -S(=O)2NR 53 R 54 、 -NR 52 S(=O)2R 52 、 -NR 52 S(=O)2N(R 52 )2、 -NR 52 S(=O)2NR53 R 54 、 -C(O)R 52 、 -C(O)OR 52 、 -OC(O)R 52 、 -OC(O)OR 52 、 -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 are each independently optionally substituted with one or more substituents selected therefrom; and further, where R 56 optionally forms a single bond to ring C; and R 59 is C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each independently selected at each occurrence, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle, here, with respect to the compound or salt of formula (II), when R 56 is -CH3, L 3 is not further substituted with -OH, -NH2, or -CN.

[0161] In certain embodiments, for the compounds of formula (I): H is thienopyrimidinyl optionally substituted with one or more R 50 ; A is selected from piperidinylene and piperazinylene; B is indolylene; L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH2-; L 3 is a single bond, -O-, -S, -N(R 51 ), -N(R 51 )CH2-, -C(O), -C(O)O, -OC(O), -OC(O)O, -C(O)N(R 51 ), -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O), -N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O)O, -OC(O)N(R 51 ), -C(NR 51 ), -N(R 51 )C(NR 51 ), -C(NR 51 )N(R 51 ), -N(R 51 )C(NR 51 )N(R 51 ), -S(O)2, -OS(O), -S(O)O-, -S(O), -OS(O)2, -S(O)2O, -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O), -S(O)N(R 51 ), -N(R 51 )S(O)2N(R 51 ), -N(R 51 )S(O)N(R 51); independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 and where two R 3 groups bonded to the same or different atoms of L 50 can optionally form a ring together; R A , R B and R C are each independently selected from R 50 each time they occur, or two R A groups, two R B groups or two R C groups bonded to the same or different atoms can optionally form a ring together; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R 57 is -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 C 1-10 alkyl, C 2-10 alkenyl, and C 2-10Selected from alkynyl, each of which is -S(=O)R 52 , -S(=O)2R 58 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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 is independently substituted at each occurrence with one or more substituents selected from; and R 58 is hydrogen; and C 1-20 alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle, wherein for the compound or salt of formula (I), when C is azetidinylene, piperidinylene or piperazinylene and R 57 is -S(=O)2R 58 , -S(=O)2N(R 52 )2, or -NR 52 S(=O)2R 52 then: p is an integer from 1 to 6; and / or L 3 is one or more R 50is replaced, where L 3 is not -CH2CH(OH)-.

[0162] In certain embodiments, for the compounds of formula (I): H is thienopyrimidinyl optionally substituted with one or more R 50 ; A is selected from piperidinylene and piperazinylene; B is indolylene; L 1 and L 2 are each independently selected from -O-, -S-, -NH-, and -CH2-; L 3 is C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ; R A , R B and R C are each independently selected from R 50 at each occurrence, or two R A groups, two R B groups or two R C groups attached to the same atom or different atoms can together optionally form a bridge or a ring; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R 56 is -OR 59 , =O, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl each independently selected at each occurrence, where the C 56 in R 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl is halogen, -NO2, -CN, -OR59 、 -SR 52 、 -N(R 52 )2, -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R 52 、 -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 、 -NR 52 S(=O)2R 52 、 -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)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 optionally substituted independently at each occurrence with one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring; where R 56 the C 3-12 in the carbon ring and the 3- to 12-membered heterocyclic ring are each 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, independently and optionally substituted with one or more substituents selected from; and further, where R 56 optionally forms a single bond to ring C; and R 59 is C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12A carbon ring and a 3- to 12-membered heterocyclic ring, each independently selected at each occurrence, each of which is halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Optionally substituted by a carbon ring or a 3- to 6-membered heterocyclic ring, Here, for the compound or salt of formula (II), R 56 When it is -CH3, L 3 is not further substituted by -OH, -NH2, or -CN.

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

[0164]

Chemical formula

[0165]

Chemical formula

[0166]

Chemical formula

[0167]

Chemical formula

[0168]

Chemical formula

[0169]

Chemical formula

[0170]

Chemical formula

[0171]

Chemical formula

[0172]

Chemical formula

[0173] In some embodiments, C is

[0174]

Chemical Formula

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

[0176]

Chemical formula

[0177]

Chemical formula

[0178]

Chemical formula

[0179]

Chemical formula

[0180]

Chemical formula

[0181]

Chemical formula

[0182]

Chemical formula

[0183]

Chemical formula

[0184]

Chemical formula

[0185]

Chemical Structure

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

[0187]

Chemical formula

[0188]

Chem.

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

[0190]

Chemical formula

[0191]

Chemical formula

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

[0193]

Chemical formula

[0194]

Chemical formula

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

[0196] [ka] piperidinyl and piperazinyl, such as, where R 57 is hydrogen and R 50 In some embodiments, C is selected from:

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

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

[0199]

Chemical formula

[0200]

Chemical formula

[0201] [Chemical formula] selected from. In some embodiments, R C is -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C 1-3 alkyl, and C 1-3 haloalkyl, or two R C groups bonded to different atoms can together form a C 1-3 bridge. In some embodiments, R C is C 1-3 alkyl and C 1-3 selected from haloalkyl. In some embodiments, p is selected from the integers 0 to 4, such as p is selected from the integers 0 to 2. In some embodiments, p is 0. In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52 S(=O)2R 52 , -C(O)R 52 , -C(O)OR 52 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, and -C(O)NR 53 R 54 selected from. In some embodiments, R C is -N(R 52 )2, -NR 53 R 54 , -NR 52S(=O)2R 52 、 -C(O)R 52 、 -C(O)OR 52 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2、 -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 )2、 -C(O)NR 53 R 54 、 C 1-6 alkyl, and -N(R 52 )2、 -NR 53 R 54 、 -NR 52 S(=O)2R 52 、 -C(O)R 52 、 -C(O)OR 52 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2、 -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 )2、 and -C(O)NR 53 R 54 substituted C 1-6 is selected from alkyl.

[0202] In some embodiments, C is

[0203]

Chemical formula

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

[0205]

Chemical formula

[0206]

Chem.

[0207]

Chemical formula

[0208]

Chemical formula

[0209]

Chemical formula

[0210]

Chem.

[0211]

Chem.

[0212]

Chem.

[0213]

Chemical formula

[0214] In some embodiments, C is

[0215]

Chemical formula

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

[0217]

Chem.

[0218]

Chem.

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

[0220]

Chemical formula

[0221]

Chemical formula

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

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

[0224] In certain embodiments, the compounds of formula (I) or (II) are preferably used as non-racemic mixtures, where one enantiomer is present in excess over its corresponding enantiomer. Typically, such mixtures contain 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 with an enantiomeric excess of at least 96%, which means that the compound has less than 2% of the corresponding enantiomer. In some embodiments, the compound is provided with a diastereomeric excess of at least 96%, which means that the compound has less than 2% of the corresponding diastereomer.

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

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

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

[0228] [Chemical formula] wherein H is C 5-12Selected from a carbon ring and a 5- to 12-membered heterocyclic ring, each of which is optionally substituted with one or more R 50 ; A is selected from a single bond, C 3-12 Selected from a carbon ring and a 3- to 12-membered heterocyclic ring; B is selected from C 3-12 Selected from a carbon ring and a 3- to 12-membered heterocyclic ring; C is a 3- to 12-membered heterocyclic ring; L 1 、L 2 and L 3 are each independently selected from a single bond, -O-, -S, -N(R 51 ), -N(R 51 )CH2-, -C(O), -C(O)O, -OC(O), -OC(O)O, -C(O)N(R 51 ), -C(O)N(R 51 )C(O)-, -C(O)N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O), -N(R 51 )C(O)N(R 51 ), -N(R 51 )C(O)O, -OC(O)N(R 51 ), -C(NR 51 ), -N(R 51 )C(NR 51 ), -C(NR 51 )N(R 51 ), -N(R 51 )C(NR 51 )N(R 51 ), -S(O)2, -OS(O), -S(O)O-, -S(O), -OS(O)2, -S(O)2O, -N(R 51 )S(O)2, -S(O)2N(R 51 ), -N(R 51 )S(O), -S(O)N(R 51 ), -N(R 51 )S(O)2N(R 51 ), -N(R 51 )S(O)N(R 51 ); independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50 is optionally replaced, where L 1 , L 2 or L 3 and two R groups attached to any one same or different atom of 50 can optionally form a bridge or a ring together; R A , R B and R C are each independently selected from R 50 at each occurrence, or two R groups, two R A groups or two R B groups attached to the same or different atoms can optionally form a bridge or a ring together; C m, n and p are each independently an integer from 0 to 6; R 50 is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R​52 ) 2, -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 ) 2, -C(O)NR 53 R 54 、 -P(O)(OR 52 ) 2, -P(O)(R 52 ) 2, =O, =S, =N(R 52 ) is independently selected at each occurrence; each of which is halogen, -NO2, -CN, -OR 52 、 -SR 52 、 -N(R 52 ) 2, -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R 52 、 -S(=O)2N(R 52 ) 2, -S(=O)2NR 53 R 54 、 -NR 52 S(=O)2R 52 、 -NR 52 S(=O)2N(R 52 ) 2, -NR 52 S(=O)2NR 53 R 54 、 -C(O)R 52 、 -C(O)OR 52 、 -OC(O)R 52 、 -OC(O)OR 52 、 -OC(O)N(R 52 ) 2, -OC(O)NR 53 R 54 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 ) 2, -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 ) 2, -C(O)NR 53 R 54 、 -P(O)(OR 52 ) 2, -P(O)(R 52 ) 2, =O, =S, =N(R 52 )、 C3-12 A C optionally and independently at each occurrence substituted with one or more substituents selected from a carbocyclic ring and a 3- to 12-membered heterocyclic ring 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; and C 3-12 a carbocyclic ring and a 3- to 12-membered heterocyclic ring, each independently selected at each occurrence; wherein R 50 the C in 3-12 the carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -, NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52)2, =O, =S, =N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 optionally and independently substituted with one or more substituents selected from alkynyl; R 51 is hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; each of which is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54, -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12 optionally substituted, independently at each occurrence, with one or more substituents selected from a carbocyclic ring and a 3- to 12-membered heterocyclic ring, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and C 3-12 a carbocyclic ring and a 3- to 12-membered heterocyclic ring, each independently selected at each occurrence; wherein R 51 the C 3-12 in the carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -, NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR53 R 54 、 -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 )、 C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and is independently optionally substituted with one or more substituents selected from; R 52 is hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each independently selected at each occurrence, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle; R 53 and R 54 together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more R 50 ; R 57 is 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 C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl selected therefrom, each of which is -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 R54 ,-P(O)(OR 52 )2,-P(O)(R 52 )2,=S,and=N(R 52 )are each independently selected at each occurrence;and R 58 is hydrogen;and C 1-20 alkyl,C 3-20 alkenyl,C 2-20 alkynyl,1-6 membered heteroalkyl,C 3-12 carbocycle,and 3-12 membered heterocycle,each of which is optionally substituted by halogen,-CN,-NO2,-NH2,-NHCH3,-NHCH2CH3,=O,-OH,-OCH3,-OCH2CH3,C 3-12 carbocycle,or 3-6 membered heterocycle.

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

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

[0231]

Chemical formula

[0232] [Chemical formula] is. In some embodiments, L 3 is

[0233] [Chemical formula] is. In some embodiments, C is

[0234] [Chemical formula] selected from. In some embodiments, L 3 is

[0235] [Chemical formula] selected from, and C is

[0236] [Chemical formula] selected from.

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

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

[0239] [Chemical formula] wherein: H is selected from carbocyclic rings and 5- to 12-membered heterocyclic rings, each of which is optionally substituted with one or more R 5-12 ; 50 ; A, B, and C are each independently selected from carbocyclic rings and 3- to 12-membered heterocyclic rings; 3-12 ; L1 and L 2 each represents a single bond, -O-, -S-, -N(R 51 ), -N(R 51 ), -N(R 51 ), -C(O)N(R 51 ), -C(O)N(R 51 ), -C(O)N(R 51 ), -N(R 51 ), -N(R 51 ), -N(R 51 ), -N(R 51 ), -OC(O)N(R 51 ), -C(NR 51 ), -N(R 51 ), -C(NR 51 ), -C(NR 51 ), -N(R 51 ), -N(R 51 ), -N(R 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)2N(R 51 ), -N(R 51 ), -S(O)N(R 51 ), -N(R 51 ), -N(R 51 ), -N(R 51 ), -N(R 51 ); independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 s, where two R 1 s or L 2 s attached to the same or different atoms of L 50 can optionally form a ring together; L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 s and optionally further substituted with one or more R 50is replaced by; R A 、R B and R C are each independently selected at each occurrence from R 50 or two R A groups, two R B groups or two R C groups may optionally form a bridge or a ring together; m, n and p are each independently an integer from 0 to 6; R 50 is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR52 ) 2, -P(O)(R 52 ) 2, =O, =S, =N(R 52 ) are independently selected at each occurrence; each being independently optionally substituted at each occurrence with 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 optionally substituted at each occurrence independently with one or more substituents selected from carbocyclic rings, and 3- to 12-membered heterocyclic rings, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; and C 3-12 a carbon ring and a 3- to 12-membered heterocyclic ring, each independently selected at each occurrence; wherein R 50 the C in 3-12 the carbon ring and the 3- to 12-membered heterocyclic ring are each independently halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 )、C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6optionally and independently substituted with one or more substituents selected from alkynyl; R 51 is hydrogen, -C(O)R 52 , -C(O)OR 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 ; each of which is halogen, -NO2, -CN, -OR 52 , -SR 52 , -N(R 52 )2, -NR 53 R 54 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , -NR 52 S(=O)2N(R 52 )2, -NR 52 S(=O)2NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -OC(O)OR 52 , -OC(O)N(R 52 )2, -OC(O)NR 53 R 54 , -NR 52 C(O)R 52 , -NR 52 C(O)OR 52 , -NR 52 C(O)N(R 52 )2, -NR 52 C(O)NR 53 R 54 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 ), C 3-12C, optionally substituted at each occurrence independently with one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and C 3-12 a carbon ring and a 3- to 12-membered heterocyclic ring, each selected independently at each occurrence; wherein R 51 the C in 3-12 the carbon ring and the 3- to 12-membered heterocyclic ring are each 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(R52 )), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, and is independently optionally substituted with one or more substituents selected from; R 52 is hydrogen; and C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 1-6 membered heteroalkyl, C 3-12 Carbocycle, and 3-12 membered heterocycle, each independently selected at each occurrence, each of which is halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 Carbocycle, or 3-6 membered heterocycle, optionally substituted; R 53 and R 54 together with the nitrogen atom to which they are attached, form a heterocycle optionally substituted with one or more R 50 ; R 56 is -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 52C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2、 -NR 52 C(O)NR 53 R 54 、 -C(O)N(R 52 )2、 -C(O)NR 53 R 54 、 -P(O)(OR 52 )2、 -P(O)(R 52 )2、 =O、 =S、 =N(R 52 )、 C 1-10 alkyl、 C 2-10 alkenyl、 C 2-10 alkynyl、 C 3-12 each independently selected from a carbon ring and a 3- to 12-membered heterocyclic ring at each occurrence, where R 56 the C in 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are each, independently, 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 optionally and independently at each occurrence, substituted with one or more substituents selected from a carbon ring and a 3- to 12-membered heterocyclic ring; where R 56 the C 3-12 in the carbon ring and the 3- to 12-membered heterocyclic ring are each independently halogen, -NO2, -CN, -OR 52 、 -SR 52 、 -N(R 52 )2、 -NR 53 R 54 、 -S(=O)R 52 、 -S(=O)2R 52 、 -S(=O)2N(R 52 )2、 -S(=O)2NR 53 R 54 、 -NR 52 S(=O)2R 52 、 -NR 52 S(=O)2N(R 52 )2、 -NR 52 S(=O)2NR 53 R 54 、 -C(O)R 52 、 -C(O)OR 52 、 -OC(O)R 52 、 -OC(O)OR 52 、 -OC(O)N(R 52 )2、 -OC(O)NR 53 R 54 、 -NR 52 C(O)R 52 、 -NR 52 C(O)OR 52 、 -NR 52 C(O)N(R 52 )2、 -NR 52 C(O)NR53 R 54 、 -C(O)N(R 52 )2, -C(O)NR 53 R 54 、 -P(O)(OR 52 )2, -P(O)(R 52 )2, =O, =S, =N(R 52 )、 C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and is independently optionally substituted with one or more substituents selected from; and further, where R 56 optionally forms a single bond to ring C; and R 59 is C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1-6 membered heteroalkyl, C 3-12 carbocycle, and 3-12 membered heterocycle, each independently selected at each occurrence, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C 3-12 carbocycle, or 3-6 membered heterocycle.

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

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

[0242]

Chemical formula

[0243]

Chemical formula

[0244]

Chemical formula

[0245]

Chemical formula

[0246]

Chemical formula

[0247]

Chemical formula

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

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

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

[0251] In some embodiments, for a compound of formula (I) or (II), R A 、R B and R C One or more of them, when present, contain a moiety that covalently reacts with one or more residues on menin. In some embodiments, R A 、R B and R C One or more of them, when present, contain a moiety that covalently reacts with one or more isoforms of menin, such as isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO:2), isoform 3 (SEQ ID NO:3) of menin. In certain embodiments, R A 、R B and R C One or more of them, when present, contain a moiety that covalently reacts with menin, where the menin protein shares at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO:2) or isoform 3 (SEQ ID NO:3).

[0252] In some embodiments, for a compound of formula (I) or (II), R A , R B and R C , when one or more of them are present, contain an electrophilic group that is susceptible to the influence of a nucleophilic attack from a residue on menin. Suitable electrophilic moieties known to those skilled in the art that bind to a nucleophilic residue, for example, electrophilic moieties known to bind to a cysteine residue, are contemplated herein. In some embodiments, one or more of R A , R B and R C , when present, contain a moiety other than an electrophile, where the moiety can bind to or react covalently with a residue on menin. In some embodiments, a compound or salt of formula (I) or (II) can (a) covalently bind to menin and (b) inhibit the interaction between menin and MLL.

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

[0254] In some embodiments, for a compound of formula (I) or (II), R C is a moiety comprising an α,β-unsaturated carbonyl; an α,β-unsaturated sulfonyl; an epoxide; an aldehyde; a sulfonyl fluoride; a halomethylcarbonyl, a dihalomethylcarbonyl, or a trihalomethylcarbonyl.

[0255] In some embodiments, for a compound of formula (I) or (II), R C is

[0256] [Chemical formula] selected from; wherein, L 5 is a single bond; and C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is optionally independently substituted with one or more R 32 ; R 22 and R 23 are each, hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, and -CN; each being halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR20 ) 2, -P(O)(R 20 ) 2, -OP(O)(OR 20 ) 2, -CN, C 3-10 A carbon ring and one or more substituents selected from 3- to 10-membered heterocyclic rings, optionally substituted independently at each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl; and C 3-10 A carbon ring and a 3- to 10-membered heterocyclic ring, independently selected; where R 22 and R 23 of C 3-10 The carbon ring and the 3- to 10-membered heterocyclic ring are each halogen, -OR 20 , -SR 20 , -N(R 20 ) 2, -N(R 20 ) C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 ) 2, -N(R 20 ) S(O)2R 20 , -NO2, =O, =S, =N(R 20 )), -P(O)(OR 20 ) 2, P(O)(R 20 ) 2, -OP(O)(OR 20 ) 2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, optionally substituted independently with one or more substituents selected from; or R 22 and R 23 together with the carbon atom to which they are attached form a carbon ring; R 24 is hydrogen, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2, -OC(O)R 20 , -S(O)2R20 and -S(O)2N(R 20 )2; each independently optionally substituted, at each occurrence, with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 3-10 alkyl, C 1-6 alkenyl, and C 2-6 alkynyl; and 2-6 C C 3-10 carbon ring and 3- to 10-membered heterocyclic ring, selected from; wherein the C 24 carbon ring and 3- to 10-membered heterocyclic ring of R 3-10 are each independently optionally substituted, at each occurrence, with one or more substituents selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, P(O)(R20 ) 2, -OP(O)(OR 20 ) 2, -CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, independently and optionally substituted with one or more substituents selected from; R 20 is independently selected from R 52 each time it occurs; and R 32 is independently selected from R 50 each time it occurs.

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

[0258] In some embodiments, R 23 is hydrogen; each of which is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 )), -P(O)(OR 20 )2, -P(O)(R 20)2, -OP(O)(OR 20 )2, -CN, C 3-10 carbon ring, and optionally substituted independently at each occurrence with one or more substituents selected from 3- to 10-membered heterocyclic rings, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and C 3-10 selected from carbon rings and 3- to 10-membered heterocyclic rings; wherein C 3-10 carbon rings and 3- to 10-membered heterocyclic rings are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally substituted independently with one or more substituents selected therefrom.

[0259] In some embodiments, R 23 is hydrogen; halogen, -OR 20 , -SR 20 , -N(R 20 )2, =O, =S, =N(R 20 ), and -CN, optionally substituted with one or more substituents selected therefrom, C 1-6 alkyl; and halogen, -OR 20 , -SR20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 )、-P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents selected from C3- and 3- to 10-membered heterocycles.

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

[0261] In some embodiments, R 22 is hydrogen and -CN; each of which is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20) 2, -N(R 20 ) S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 3-10 alkyl, C 1-6 alkenyl, and C 2-6 alkynyl; and 2-6 is optionally independently substituted at each occurrence with one or more substituents selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, C C 3-10 selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring; where C 3-10 the carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently optionally substituted with a halogen, -OR 20 , -SR 20 , -N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -OC(O)R 20 , -S(O)2R 20 , -S(O)2N(R 20 )2, -N(R 20 )S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -P(O)(OR 20 )2, -P(O)(R 20 )2, -OP(O)(OR 20 )2, -CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl. In some embodiments, R

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

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

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

[0265] In some embodiments, R 21 is

[0266]

Chemical formula

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

[0268] The chemical substances described in this specification can be synthesized according to one or more exemplary schemes of this specification and / or techniques known in the art. The substances used in this specification are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, and they are utilized for illustrative purposes. Although various steps are described and depicted in Scheme 1 and Examples 1-5, in some cases, the steps can be carried out in an order different from the order shown in Scheme 1 and Examples 1-6. Various modifications can be made to these synthetic reaction schemes, as suggested to those skilled in the art who refer to the present disclosure included in this application. The reference numerals or R groups in each scheme do not necessarily correspond to the reference numerals or R groups in the claims or other schemes or tables of this specification.

[0269] Unless otherwise specified, the reactions described in this specification generally occur at atmospheric pressure within a temperature range of -10°C to 200°C. Further, unless otherwise specified, the reaction times and conditions are intended to be approximate reaction times and conditions. For example, the reaction occurs at approximately atmospheric pressure within a temperature range of about -10°C to about 110°C over a period of about 1 hour to about 24 hours; the remaining reactions are carried out overnight for an average of about 16 hours.

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

[0271]

Chemical formula

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

[0273]

Table 1-1

[0274]

Table 1-2

[0275]

Table 1-3

[0276]

Table 1-4

[0277]

Table 1-5

[0278]

Table 1-6

[0279]

Table 1-7

[0280]

Table 1-8

[0281]

Table 1-9

[0282]

Table 1-10

[0283]

Table 1-11

[0284]

Table 1-12

[0285]

Table 1-13

[0286]

Table 1-14

[0287]

Table 1-15

[0288]

Table 1-16

[0289]

Table 1-17

[0290]

Table 1-18

[0291]

Table 1-19

[0292]

Table 1-20

[0293]

Table 1-21

[0294]

Table 1-22

[0295]

Table 1-23

[0296]

Table 1-24

[0297]

Table 1-25

[0298]

Table 1-26

[0299]

Table 1-27

[0300]

Table 1-28

[0301]

Table 1-29

[0302]

Table 1-30

[0303]

Table 1-31

[0304]

Table 1-32

[0305]

Table 1-33

[0306]

Table 1-34

[0307]

Table 1-35

[0308]

Table 1-36

[0309]

Table 1-37

[0310]

Table 1-38

[0311]

Table 1-39

[0312]

Table 1-40

[0313]

Table 1-41

[0314]

Table 1-42

[0315]

Table 1-43

[0316]

Table 1-44

[0317]

Table 1-45

[0318]

Table 1-46

[0319]

Table 1-47

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

[0321]

Table 2-1

[0322]

Table 2-2

[0323]

Table 2-3

[0324]

Table 2-4

[0325]

Table 2-5

[0326]

Table 2-6

[0327] Pharmaceutical composition

[0328] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human or a non-human mammal. When administered to an animal such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound or salt of formula (I) or (II) and a pharmaceutically acceptable carrier.

[0329] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for infusion. In still more embodiments, the pharmaceutical composition comprises a compound as disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described hereinbelow.

[0330] Suitable routes of administration include, but are not limited to, oral administration, intravenous administration, rectal administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, transmucosal administration, transdermal administration, intravaginal administration, otic administration, nasal administration, and topical administration. Further, by way of example only, parenteral delivery includes not only intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal infusions, but also intramuscular, subcutaneous, intravenous, and intramedullary injections.

[0331] In certain embodiments, the composition of the compound or salt of formula (I) or (II) is often administered locally rather than systemically, for example, via direct injection of the compound into an organ, as a depot formulation or a sustained release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Further, in other embodiments, the compound or salt of formula (I) or (II) is delivered in a targeted drug delivery system, for example, in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target and are selectively taken up by the organ. Further, in still other embodiments, the composition is provided in the form of an immediate release formulation, a sustained release formulation, or an intermediate release formulation. In still other embodiments, the composition is administered locally.

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

[0333] In some embodiments, the compound or salt of formula (I) or (II) is administered in a single dose. Typically, such administration is by injection (e.g., intravenous injection) to rapidly introduce the agent. However, other routes may be used as needed. In some embodiments, a single dose of the compound or salt of formula (I) or (II) is used in the treatment of acute diseases.

[0334] In some embodiments, the compound or salt of formula (I) is administered in multiple doses. In some embodiments, the dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, the dosing is approximately once a month, once a week, once every two weeks, or once every other day. In another embodiment, the compound or salt of formula (I) or (II) and another agent are both administered from about once a day to about six times a day. In another embodiment, the administration of the compound or salt of formula (I) or (II) and another agent continues for less than about 7 days. In yet another embodiment, the administration continues for about 6 days or more, about 10 days or more, about 14 days or more, about 28 days or more, about 2 months or more, about 6 months or more, or 1 year or more. In some cases, continuous dosing is achieved and maintained as needed.

[0335] Administration of a compound or salt of formula (I) or (II) may continue, if necessary. In some embodiments, the compounds of the disclosure are administered for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 7 days or more, 14 days or more, or 28 days or more. In some embodiments, the compounds of the disclosure are administered for 28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day or less, or for a portion thereof. In some embodiments, a compound or salt of formula (I) or (II) is administered continuously and chronically (e.g., for the treatment of chronic effects).

[0336] In some embodiments, a compound or salt of formula (I) or (II) is administered at various dosages. It is known in the art that, due to variability among patients in the pharmacokinetics of a compound, individualization of the dosing regimen is necessary for optimal treatment. Dosing for a compound or salt of formula (I) or (II) may be found by routine experimentation in light of the present disclosure.

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

[0338] Pharmaceutical compositions are provided herein that contain a compound or salt of formula (I) or (II) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the compounds or salts described herein are administered as a pharmaceutical composition that combines a compound of formula (I) or (II) with other active ingredients, such as in combination therapy. All combinations of active ingredients described in the following combination therapy section and throughout this specification are included herein. In certain embodiments, the pharmaceutical composition contains one or more compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

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

[0340] In one embodiment, the compound or salt of formula (I) or (II) is formulated as an aqueous solution. In certain embodiments, the aqueous solution is selected from physiologically compatible buffers such as, but not limited to, Hank's solution, Ringer's solution, or physiological saline. In other embodiments, the compound or salt of formula (I) or (II) is formulated for transmucosal administration. In certain embodiments, the transmucosal formulation contains a penetration enhancer appropriate for the barrier to be penetrated. In yet another embodiment where the compound or salt of formula (I) or (II) is formulated for other parenteral injections, the appropriate formulation contains an aqueous or non-aqueous solution. In certain embodiments, such solutions contain physiologically compatible buffers and / or excipients.

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

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

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

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

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

[0346] In yet another embodiment, the compound or salt of formula (I) or (II) is administered locally. The compound or salt of formula (I) or (II) may be formulated into various locally administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, sedatives, creams, or ointments. Such pharmaceutical compositions may optionally contain solubilizing agents, stabilizers, isotonicity enhancers, buffers, and preservatives.

[0347] In still other embodiments, the compound or salt of formula (I) or (II) is formulated for transdermal administration. Transdermal formulations may utilize transdermal delivery devices and transdermal patches and may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or adhesive. In various embodiments, such patches are constructed for continuous, pulsed, or on-demand delivery of the pharmaceutical. In additional embodiments, transdermal delivery of the compound or salt of formula (I) or (II) is achieved by, for example, iontophoresis patches. In one embodiment, the transdermal patch provides controlled delivery of the compound or salt of formula (I) or (II). In certain embodiments, the rate of absorption is slowed by using a rate-limiting membrane or by trapping the compound in a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase the degree of absorption. The absorption enhancer or carrier includes a pharmaceutically acceptable absorbent solvent that aids passage through the skin. For example, in one embodiment, the transdermal device is in the form of a dressing that includes a backing member, a reservoir containing the compound or salt of formula (I) or (II) optionally with a carrier, a rate control barrier optionally for delivering the compound to the skin of the host at a predetermined rate controlled over a long period of time, and means for securing the device to the skin.

[0348] In other embodiments, the compound or salt of formula (I) or (II) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. The pharmaceutical composition of the compound or salt of formula (I) or (II) is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, other suitable gases). In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges, such as those used in inhalers or injectors, for example, are formulated to contain a powder mixture of the compound or salt of formula (I) or (II) and a suitable powder base such as lactose or starch.

[0349] In yet other embodiments, the compound or salt of formula (I) may be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, including conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone (PEG). In the suppository form of the composition, low melting waxes such as mixtures of fatty acid glycerides, optionally combined with cocoa butter, melt first.

[0350] In certain embodiments, the pharmaceutical composition may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation. Suitable formulations depend on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients may also be appropriately used. The pharmaceutical composition containing the compound or salt of formula (I) or (II) is produced by conventional methods such as, for example, conventional mixing, dissolving, granulating, sugar coating, gelating, emulsifying, encapsulating, entrapping, or compression processes.

[0351] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and a compound or salt of formula (I) or (II), often referred to herein as the active agent or active ingredient. The active ingredient may be in the free acid or free base form, or in a pharmaceutically acceptable salt form. Further, the compound or salt of formula (I) or (II) may be in the non-solvated or solvated form, together with a pharmaceutically acceptable solvent such as water or ethanol. In addition, the pharmaceutical composition optionally contains other drugs or pharmaceuticals, carriers, preservatives, stabilizers, adjuvants such as wetting agents or emulsifiers, solubilizing agents, salts for adjusting osmotic pressure, buffers, and / or other pharmaceutically valuable substances.

[0352] The method for preparing a composition containing a compound or salt of formula (I) or (II) includes the step of formulating a compound having one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound or salt of formula (I) or (II). Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical composition of the compound or salt of formula (I) or (II) include solutions or suspensions, forms suitable for solutions or suspensions in a liquid before use, or solid forms as emulsions. These compositions may also optionally contain trace amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers.

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

[0354] In one embodiment, the aqueous suspension comprises one or more polymers as suspending agents. The polymers include water-soluble polymers such as cellulose polymers, for example hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Particular pharmaceutical compositions described herein include mucoadhesive polymers selected, for example, from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

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

[0356] The pharmaceutical composition optionally contains one or more pH regulators 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 tris(hydroxymethyl)aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0357] In addition, the useful composition optionally contains one or more salts in amounts necessary to bring the weight molar osmotic concentration of the composition within an acceptable range. Such salts include cations of sodium, potassium, or ammonium, and anions of chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

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

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

[0360] The pharmaceutical composition may optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium bisulfite.

[0361] In certain embodiments, the aqueous suspension composition is packaged in a non-resealable container for single-dose use. Alternatively, a resealable container for multiple-dose use is employed, in which case it is typical to include a preservative in the composition.

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

[0363] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% - about 2% w / v glycerol, (b) about 0.1% - about 1% w / v methionine, (c) about 0.1% - about 2% w / v monothioglycerol, (d) about 1 mM - about 10 mM EDTA, (e) about 0.01% - about 2% w / v ascorbic acid, (f) 0.003% - about 0.02% w / v polysorbate 80, (g) 0.001% - 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 such as magnesium and zinc; or (n) combinations thereof.

[0364] In some embodiments, the concentration of a compound or salt of formula (I) or (II) provided in a pharmaceutical composition 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%, 0.09%, 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% w / w, w / v, or v / v.

[0365] In some embodiments, the concentration of the compound or salt of formula (I) or (II) provided in the pharmaceutical composition is 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% w / w, w / v, or v / v.

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

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

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

[0369] 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, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

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

[0371] For use in the therapeutic uses described herein, kits and products are also provided herein. In some embodiments, such kits include a carrier, package, or container partitioned to receive one or more containers such as vials, tubes, etc., each of the containers containing one of the separate elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

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

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

[0374] Method

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

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

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

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

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

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

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

[0382] Methods for detecting MLL fusion proteins are known to those of skill in the art. These methods include, but are not limited to, detection of MLL fusion proteins using a binding agent specific for the fusion protein (e.g., an antibody), protein electrophoresis and Western blotting, and direct peptide sequencing.

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

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

[0385] In certain embodiments, the disclosure relates to a method for the treatment of lung cancer, the method comprising administering to a subject in need thereof any of an effective amount of the above compound (or a pharmaceutical composition comprising the same). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), e.g., adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenoma, carcinoid tumor, and undifferentiated carcinoma.

[0386] Subjects treatable by a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, stereoisomer, isotope-substituted form, hydrate, or derivative of a compound according to the method of the present disclosure include, for example, subjects diagnosed with having: acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid rhabdoid tumor, germinoma, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS) of the extrahepatic bile duct, germinoma, CNS cancer, endometrial cancer, epithelioma, esophageal cancer, neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet tumor, pancreatic endocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck of unknown primary, midline ductal carcinoma, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal cavity and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach,gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, choriocarcinoma, abnormal cancers in childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, virus-induced cancer, leukemia, hematological malignancies, solid tumor cancer, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing sarcoma, osteosarcoma, primary osteosarcoma, T cell prolymphocytic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or diabetes. In some embodiments, the subject treated by the compounds of the present disclosure includes a subject diagnosed with the treatment of non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).,

[0387] The present disclosure further provides a method of modulating the interaction of menin with one or more proteins (such as MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) by contacting menin with an effective amount of a compound or salt of formula (I) or (II). The modulation can inhibit or activate the protein activity of menin, one or more of its binding partners, and / or one or more downstream targets of menin, or one or more of its binding partners. In some embodiments, the present disclosure provides a method of inhibiting the interaction of menin with one or more proteins (such as MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) by contacting menin with an effective amount of a compound or salt of formula (I) or (II). In some embodiments, the present disclosure provides a method of inhibiting the interaction of menin with one or more proteins (such as MLL1, MLL2, MLL fusion proteins, or partial tandem duplications of MLL) by contacting cells or tissues or organs that express menin, MLL1, MLL2, MLL fusion proteins, and / or partial tandem duplications of MLL. In some embodiments, the present disclosure provides a method of inhibiting the protein activity of a subject by administering to the subject an effective amount of a compound or salt of formula (I) or (II), where the subject includes, but is not limited to, rodents and mammals (such as humans). In some embodiments, the modulation rate is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the inhibition rate is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

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

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

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

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

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

[0393] The present disclosure further provides a method for stabilizing menin, the method comprising the step of 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 is performed in vivo. In some embodiments, the contacting step is performed in vitro. In some embodiments, the contacting step is performed in cells.

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

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

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

[0397] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as numerous chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include the following: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenethiophosphoramide, triethylenephosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide (cholophosphamide), estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide (trofosfamide), uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysin (aclacinomysin), actinomycin, authramycin (authramycin), azaserine, bleomycin, cactinomycin, calicheamicin, carabicin (carabicin), calminomycin, caldophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin (esorubicin), idarubicin, marcellomycin (marcellomycin), mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin (potfiromycin), promycin, quelamycin (quelamycin), rodorubicin (rodorubicin), streptozocin, streptozocin, tubercidin, ubenimex, dinostatin,Antibiotics such as 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, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine, etc., androgens such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demeclocycline; diacron; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichloroethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes such as paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts of any of the above.Acids or derivatives. Further suitable chemotherapeutic cytomodulators include antihormonal agents that act to regulate or inhibit the hormonal action on tumors, such as: for example, tamoxifen (NolvadexTM), raloxifene, aromatase that inhibits 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and antiestrogens including toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO). If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with commonly prescribed anti-cancer agents such as: Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 antiserum, anti-malignant tumor agent, anti-tumor herbal medicine, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), caliculin,Cell cycle non-specific anti-cancer drugs, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, feruginol, folotyn, phosphoestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, ilofibrate, ranidazole, larotaxel, lenalidomide, lukansone, rutotecan, mafosfamide, mitozolomide, nahoxidine, nedaplatin, olaparib, ortataxel, PAC-1, popo, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, talidazole, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.,

[0398] The present disclosure further relates to methods for using a compound or salt of formula (I) or (II), or a pharmaceutical composition provided herein, in combination with radiation therapy to inhibit abnormal cell growth in a mammal or to treat a proliferative disorder. Techniques for administering radiation therapy are known in the art and these techniques can be used in the combination therapies described herein. Administration of the compounds of the present disclosure in such combination therapies can be determined as described herein.

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

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

[0401] Angiogenesis inhibitors such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. Angiogenesis inhibitors include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib.Examples of useful matrix metalloproteinase inhibitors are described below and are incorporated herein by reference in their entirety: WO 96 / 33172 (published October 24, 1996), WO 96 / 27583 (published March 7, 1996), EP 97304971.1 (filed July 8, 1997), EP 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 98 / 30566 (published July 16, 1998), EP 606,046 (published July 13, 1994), EP 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 99 / 29667 (published June 17, 1999), PCT / IB98 / 01113 (filed July 21, 1998), EP 99302232.1 (filed March 25, 1999), GB 9912961.1 (filed June 3, 1999), Taiwan Patent Application No. 60 / 148,464 (filed August 12, 1999), US Patent No. 5,863,949 (issued January 26, 1999), US Patent No. 5,861,510 (issued January 19, 1999), and EP 780,386 (published June 25, 1997). Preferred MMP-2 and MMP-9 inhibitors have little or no activity against MMP-1. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 relative to other matrix-metalloproteinases (e.g., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0402] Autophagy inhibitors include, but are not limited to: chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, algal toxins that inhibit autophagy and inhibit type 2A or type 1 protein phosphatases, analogs of cAMP, and drugs such as adenosine, LY204002, N6-mercaptopurine riboside, vincristine that increase cAMP levels. In addition, antisense or siRNA that inhibits the expression of proteins including, but not limited to, ATG5 (related to autophagy) may further be used.

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

[0404] In some embodiments, the agent administered in combination with the compounds described herein comprises a suitable drug that is effectively delivered by an inhalant, such as, for example: analgesics such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; formulations for angina such as diltiazem; anti-allergic substances such as cromoglycic acid, ketotifen, or nedocromil; drugs for infectious diseases such as cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; antihistamines such as metapyrilene; anti-inflammatory agents such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone); antitussives such as noscapine; bronchodilators such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzene methanol; diuretics such as amiloride; anticholinergic agents such as ipratropium, atropine, or oxitropium; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophyllinate, or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. Where appropriate, it will be apparent to those skilled in the art that the agent may be used in the form of a salt (e.g., as an alkali metal or amine salt, or as an acid addition salt), or as an ester (e.g., a lower alkyl group ester), or as a solvate compound (e.g., a hydrate) in order to optimize the activity and / or stability of the agent.

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

[0406] The therapeutic agent may further include agents for pain and inflammation such as: histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by in vivo changes in the products of selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory drugs, antipyretics, drugs that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate the interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium antagonists, membrane stabilizers and leukotriene inhibitors.

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

[0408] Other therapeutic agents contemplated include: drugs used for the control of gastric juice acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary tract disease, agents used for pancreatic disease. Therapeutic agents used for the treatment of protozoal diseases, drugs used for the treatment of malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis, and / or leishmaniasis, and / or drugs used in the chemotherapy of helminthiasis. Other therapeutic agents include: antibacterial agents, sulfonamides, trimethoprim-sulfamethoxazole combinations, quinolones, agents for urinary tract infections, penicillins, cephalosporins, and other β-lactam antibiotics, agents containing aminoglycosides, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, Mycobacterium avium complex disease and Hansen's disease, antifungal agents, antiviral agents including non-retroviral drugs and anti-retroviral drugs.

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

[0410] Furthermore, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressants, tollergens, and immunostimulants, are contemplated by the methods of this specification. In addition, therapeutic agents acting on blood and hematopoietic organs, antianemic agents, growth factors, minerals, and vitamins, anticoagulants, thrombolytics, and antiplatelet agents.

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

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

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

[0414] The following examples are given for the purpose of illustrating various embodiments of the present disclosure and are not intended to limit the present disclosure in any way. The examples represent presently preferred embodiments and are typical of the methods and compositions described herein, but are not intended to limit the scope of the present disclosure. Those skilled in the art will envision modifications thereto and other uses within the spirit of the disclosure as defined by the claims.

Example

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

[0416]

Chem.

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

[0418] Process B: Preparation of Compound 59-3: To a solution of 59-2 (905 mg, 2.85 mmol) in MeOH (20 mL), (Boc)2O (1.24 g, 5.71 mmol) and Pd / C catalyst were added. The reaction mixture was stirred at room temperature for 8 h under H2. TLC indicated that the reaction was complete. The reaction was filtered and concentrated. The residue was purified by silica gel colu...

Claims

1. A process for preparing a compound of formula (II-A), wherein 【Chemical 1】 wherein, L ２ is -CH ２ -, and L ３ is -CH ２ CH(CH ３ ), the process comprises coupling a Compound 1 having the following structure [Chemical Formula 2] and a Compound 2 having the following structure [Chemical Formula 3] through a reductive amination reaction, wherein C is selected from piperidinyl and piperazinyl, R １ is a C １－３ haloalkyl, and R ２ is selected from halogen, -OR ５２ , -N(R ５２ ), ２ , -CN, C １－３ alkyl, C １－３ alkyl-OR ５２ , C １－３ alkyl-N(R ５２ ), ２ , C １－３ haloalkyl, C ２－３ alkenyl, and C ２－３ alkynyl, R ３ is selected from hydrogen, halogen, -OH, -N(R ５２ ), -CN, -C(O)OR ２ , -CN, -C(O)OR ５２ , C １－３ alkyl, and C １－３ haloalkyl, R Ａ and R Ｂ are each independently halogen, -CN, -OR ５２ , -N(R ５２ ), -NR ２ R ５３ , -C(O)R ５４ , -C(O)OR ５２ , -OC(O)R ５２ , -NR ５２ C(O)R ５２ , -C(O)N(R ５２ ), -C(O)NR ５２ R ２ , C ５３ alkyl, C ５４ alkenyl, and C １－１０ alkynyl, or =O formed by two R ２－１０ groups bonded to the same carbon atom combining together, where R ２－１０ B is a substituent of indole, Ａ and are each selected at each occurrence from the above, R Ｃ is selected at each occurrence from R ５０ or two R groups bonded to the same or different atoms can optionally combine to form a bridge or a ring Ｃ and m and p are each independently an integer from 0 to 6, n is an integer from 1 to 4, R ５０ is independently halogen, -NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ), -NR ２ R ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), -S(=O) ２ NR ２ R ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), -NR ２ S(=O) ５２ NR ２ R ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), -OC(O)NR ２ R ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), -NR ２ C(O)NR ５２ R ５３ R ５４ , -C(O)N(R ５２ ), -C(O)NR ２ R ５３ R ５４ , -P(O)(OR ５２ ), -P(O)(R ２ ), -P(O)(R ５２ ), -P(O)(R ２ , selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocyclic ring and 3- to 12-membered heterocyclic ring at each occurrence, or Two Rs bonded to the same carbon ５０ groups combine to form =O, =S, or =N(R ５２ ) and are joined together Here, each of C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is halogen, -NO ２ 、 -CN, -OR ５２ 、 -SR ５２ 、 -N(R ５２ ) ２ 、 -NR ５３ R ５４ 、 -S(=O)R ５２ 、 -S(=O) ２ R ５２ 、 -S(=O) ２ N(R ５２ ) ２ 、 -S(=O) ２ NR ５３ R ５４ 、 -NR ５２ S(=O) ２ R ５２ 、 -NR ５２ S(=O) ２ N(R ５２ ) ２ 、 -NR ５２ S(=O) ２ NR ５３ R ５４ 、 -C(O)R ５２ 、 -C(O)OR ５２ 、 -OC(O)R ５２ 、 -OC(O)OR ５２ 、 -OC(O)N(R ５２ ) ２ 、 -OC(O)NR ５３ R ５４ 、 -NR ５２ C(O)R ５２ 、 -NR ５２ C(O)OR ５２ 、 -NR ５２ C(O)N(R ５２ ) ２ 、 -NR ５２ C(O)NR ５３ R ５４ 、 -C(O)N(R ５２ ) ２ 、 -C(O)NR ５３ R ５４ 、 -P(O)(OR ５２ ) ２ 、 -P(O)(R ５２ ) ２ 、 =O, =S, =N(R ５２ )、 C ３－１２ optionally substituted at each occurrence with one or more substituents selected from carbon rings and 3- to 12-membered heterocyclic rings, Here, R ５０ In C ３－１２ The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently halogen, -NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ), ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), ２ , -S(=O) ２ NR ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), ２ , -NR ５２ S(=O) ２ NR ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), ２ , -OC(O)NR ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), ２ , -NR ５２ C(O)NR ５３ R ５４ , -C(O)N(R ５２ ), ２ , -C(O)NR ５３ R ５４ , -P(O)(OR ５２ ), ２ , -P(O)(R ５２ ), ２ , =O, =S, =N(R ５２ ), C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ optionally substituted with one or more substituents selected from alkynyl, R ５１ is independently selected at each occurrence from hydrogen and C １－６ alkyl, R ５２ is independently selected, at each occurrence, from hydrogen, and C １－２０ alkyl, C ２－２０ alkenyl, C ２－２０ alkynyl, C １－６ heteroalkyl, C ３－１２ carbocyclic, and 3- to 12-membered heterocyclic, each of which is optionally substituted by halogen, -CN, -NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ carbocyclic, or 3- to 6-membered heterocyclic, and R ５３ and R ５４ form a heterocyclic ring together with the nitrogen atom to which they are attached, process.

2. Compound 2 having the following structure 【Chemical 4】 is prepared through the reaction in the following Compound 3 【Chemical Formula 5】 and Compound 4 【Chemical Formula 6】 The process according to claim 1, characterized in that.

3. R Ｃ is -C(O)R ５２ 、 -S(=O)R ５２ 、 -S(=O) ２ R ５２ 、 -S(=O) ２ N(R ５２ ) ２ 、 -S(=O) ２ NR ５３ R ５４ 、 -NR ５２ S(=O) ２ R ５２ 、 C １－３ alkyl, and C １－３ haloalkyl, or two R Ｃ groups bonded to the same carbon are joined together to form =O, or two R Ｃ groups bonded to different atoms are joined together to form a C １－３ bridge, the process according to claim 1 or 2, characterized in that.

4. C is from the following structures i to iv [Chemical Formula 7] selected from Here, R ５７ is -S(=O)R ５２ -S(=O) ２ R ５２ -S(=O) ２ -S(=O) ５２ N(R ２ -S(=O) ２ NR ５３ R ５４ -NR ５２ S(=O) ２ R ５２ and C １－１０ alkyl, where C １－１０ alkyl is -S(=O)R ５２ -S(=O) ２ R ５２ -S(=O) ２ N(R ５２ ), ２ -S(=O) ２ NR ５３ R ５４ and -NR ５２ S(=O) ２ R ５２ substituted with one or more substituents selected from, and characterized in that the process according to any one of claims 1 to 3

5. m is 0 and n is an integer from 1 to 3. The process according to any one of claims 1 to 4, characterized in that.

6. Compound 2 having a structure of 【Chemical 8】 is the following Compound 5 【Chemical Formula 9】 The process according to any one of claims 1 to 3, characterized in that.

7. Compound 4 having a structure of 【Chemical Formula 10】 is the following Compound 6 【Chemical 11】 The process according to any one of claims 2 to 3, characterized in that.

8. The following 【Chemical Formula 12】 or 【Chemical 13】 A compound having the structure of, or a salt thereof, wherein wherein C is piperazinyl, R Ｂ is each independently 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 , C １－１０ alkyl, C ２－１０ alkenyl, and C ２－１０ alkynyl, each selected at each occurrence, where R B is a substituent of indole, R Ｃ is selected at each occurrence from R ５０ or two R groups bonded to the same or different atoms may be joined together optionally to form a bridge or a ring Ｃ and p is an integer from 0 to 6, n is an integer from 1 to 4, R ５０ is independently halogen, -NO ２ , -CN, -SR ５２ , -N(R ５２ ), -NR ２ R ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N(R ５２ ), -S(=O) ２ NR ２ R ５３ R ５４ , -NR ５２ S(=O) ２ R ５２ , -NR ５２ S(=O) ２ N(R ５２ ), -NR ２ S(=O) ５２ NR ２ R ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ), -OC(O)NR ２ R ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ), -NR ２ C(O)NR ５２ R ５３ R ５４ , -C(O)N(R ５２ ), -C(O)NR ２ R ５３ R ５４ , -P(O)(OR ５２ ), -P(O)(R ２ , -P(O)(R ５２ ), -P(O)(R ２ , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocyclic ring and 3- to 12-membered heterocyclic ring, each selected at the time of generation, or Two Rs ５０ groups combine to form =O, =S, or =N(R ５２ ) Here, each of C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl is halogen, -NO ２ 、-CN, -OR ５２ 、-SR ５２ 、-N(R ５２ ) ２ 、-NR ５３ R ５４ 、-S(=O)R ５２ 、-S(=O) ２ R ５２ 、-S(=O) ２ N(R ５２ ) ２ 、-S(=O) ２ NR ５３ R ５４ 、-NR ５２ S(=O) ２ R ５２ 、-NR ５２ S(=O) ２ N(R ５２ ) ２ 、-NR ５２ S(=O) ２ NR ５３ R ５４ 、-C(O)R ５２ 、-C(O)OR ５２ 、-OC(O)R ５２ 、-OC(O)OR ５２ 、-OC(O)N(R ５２ ) ２ 、-OC(O)NR ５３ R ５４ 、-NR ５２ C(O)R ５２ 、-NR ５２ C(O)OR ５２ 、-NR ５２ C(O)N(R ５２ ) ２ 、-NR ５２ C(O)NR ５３ R ５４ 、-C(O)N(R ５２ ) ２ 、-C(O)NR ５３ R ５４ 、-P(O)(OR ５２ ) ２ 、-P(O)(R ５２ ) ２ 、=O, =S, =N(R ５２ )、C ３－１２ optionally substituted at each occurrence with one or more substituents selected from a carbon ring and a heterocyclic ring having 3 to 12 members, Here, R ５０ C in ３－１２ The carbocycle and the 3- to 12-membered heterocycle each independently represent a halogen, —NO ２ , -CN, -OR ５２ , -SR ５２ , -N(R ５２ ) ２ , -NR ５３ R ５４ , -S(=O)R ５２ , -S(=O) ２ R ５２ , -S(=O) ２ N (R ５２ ) ２ , -S(=O) ２ N.R. ５３ R ５４ , -NR ５２ S (=O) ２ R ５２ , -NR ５２ S (=O) ２ N (R ５２ ) ２ , -NR ５２ S (=O) ２ N.R. ５３ R ５４ , -C(O)R ５２ , -C(O)OR ５２ , -OC(O)R ５２ , -OC(O)OR ５２ , -OC(O)N(R ５２ ) ２ , -OC(O)NR ５３ R ５４ , -NR ５２ C(O)R ５２ , -NR ５２ C(O)OR ５２ , -NR ５２ C(O)N(R ５２ ) ２ , -NR ５２ C(O)NR ５３ R ５４ , -C(O)N(R ５２ ) ２ , -C(O)NR ５３ R ５４ , -P(O)(OR ５２ ) ２ , -P(O)(R ５２ ) ２ , =O, =S, =N(R ５２ ), C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ optionally substituted with one or more substituents selected from alkynyl, R ５２ is independently selected at each occurrence from hydrogen, and methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, C ２－２０ alkenyl, C ２－２０ alkynyl, C １－６ heteroalkyl, C ３－１２ carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO ２ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , =O, -OH, -OCH ３ , -OCH ２ CH ３ , C ３－１２ carbocycle, or 3- to 6-membered heterocycle, and R ５３ and R ５４ form a heterocyclic ring together with the nitrogen atom to which they are attached, or a salt thereof.

9. Compound 2 having a structure of 【Chemical 13】 is the following Compound 5, 【Chemical 14】 or Compound 4 having a structure of 【Chemical Formula 15】 is the following Compound 6, 【Chemical 16】 The compound according to claim 8, or a salt thereof.

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