BR112017026085B1 - METHODS AND COMPOSITIONS FOR INHIBITING THE INTERACTION OF MENIN WITH MLL PROTEINS - Google Patents

Abstract

METHODS AND COMPOSITIONS FOR INHIBITING THE INTERACTION OF MENIN WITH MLL PROTEINS. The present report provides compositions and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL fusion oncoproteins. The compositions and methods of use are useful for treating leukemia, solid cancers, diabetes and other diseases dependent on the activity of MLL1, MLL2, MLL fusion proteins and/or menin.

Description

CROSS REFERENCE

[0001] This application claims the benefit of US provisional application No. 62/171,108, filed on June 4, 2015, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The mixed lineage leukemia protein (MLL) is a histone methyltransferase critical for the epigenetic regulation of gene transcription. Many acute leukemias, including acute myoblastic 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 in chromosome 11, band q23 (11q23). MLL chimeric fusion proteins contain approximately 1400 amino acids from the N terminus of MLL, but are fused to one of approximately 80 partner proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). MLL fusion proteins lack the original C-terminal histone methyltransferase activity of MLL and have the ability to regulate the transcription of numerous oncogenes, including HOX and MEIS1, resulting in increased cell proliferation and ultimately reduced cell differentiation. analysis leading to leukemogenesis.

[0003] The menin protein, which is encoded by the Multiple Endocrine Neoplasia gene, is a ubiquitously expressed nuclear protein that is involved in interactions with DNA processing and repair proteins, chromatin modifiers and numerous transcription factors (Agarwal, et al.; Horm Metab Res, 2005, 37(6): 369-374). The association of menin with the N terminus of MLL fusion proteins is necessary for the observed oncogenic activity of MLL fusion proteins. This association has been shown to constitutively upregulate the expression of HOX and MEIS1 oncogenes and hinder the proliferation and differentiation of hematopoietic cells leading to the development of leukemia. Since menin has been shown to function as a general oncogenic cofactor in MLL-related leukemias, the interaction between menin and MLL-MLL fusion proteins represents a potential chemotherapeutic target.

[0004] Patients, especially children, with leukemias harboring chromosomal translocations of the MLL gene have a dismal prognosis, with a five-year survival rate of less than 40% (Slany; Haematologica, 2009, 94(7): 984993). A new strategy for the treatment of these leukemias is urgently needed. Small molecule inhibitors that block the menin-MLL interaction are therefore valuable targets for the treatment of diseases involving MLL fusion proteins.

SUMMARY OF THE INVENTION

[0005] The present report refers to a need in the art to provide compositions and methods for inhibiting menin protein-protein interaction with MLL1, MLL2 and MLL fusion oncoproteins. The compositions and methods herein may be useful for treating diseases dependent on the activity of MLL1, MLL2, MLL fusion proteins, and/or menin, such as leukemia, solid cancers, and diabetes. In certain embodiments, a compound of the report noncovalently interacts with menin and inhibits the interaction of menin with MLL. In certain embodiments, a compound of the report covalently binds menin and inhibits the interaction of menin with MLL.

[0006] In some embodiments of a compound provided herein, the compound binds non-covalently or covalently to any one or more isoforms of menin, for example, isoform 1 (SEQ ID NO: 1), isoform 2 ( SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, the menin protein shares 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more identity. sequence 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 report provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: each of X1 and X2 is independently CR2 or N; each of X3 and X4 is independently C or N; each of Y1 and Y2 is independently CR3, N, NR4, O or S; provided that when X1 is CR2, X2 is CR2 or N, X3 is C, X4 is C, and one of Y1 and Y2 is S, the other of Y1 or Y2 is N; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylene - carbonyl; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III, and B-IV; where B is connected on any ring atom to L2; ; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 each of R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from among H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, 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; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkyl-amino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroaryl-amino and heteroarylalkylamino, where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or ring.

[0008] In some embodiments of a compound of Formula I, the compound has the structure of Formula IA:

[0009] In some embodiments of a compound of Formula I or Formula I-A, X3 is C and X4 is C. In some embodiments of a compound of Formula I or Formula I-A, X1 is CR2.

[0010] In some embodiments of a compound of Formula I or Formula I-A, R2 in X1 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl or haloalkyl. In some embodiments of a compound of Formula I or Formula I-A, R2 in X1 is amino. In some embodiments of a compound of Formula I or Formula I-A, R2 in X1 is alkyl, such as C1-C3 alkyl or methyl. In some embodiments of a compound of Formula I or Formula I-A, Y2 is CR3 and R3 in Y2 is selected from H, halo, amino, carboxyl, and alkyl. In some embodiments of a compound of Formula I or Formula IA, Y2 is CR3 and R3 in Y2 is selected from F, amino, carboxyl and methyl.

[0011] In another aspect, the present report provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X2 is CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; L3 is a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; L2 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a 3-7 membered saturated ring, or a 37 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III, and B-IV; where B is connected on any ring atom to L2; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 each of R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, 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; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino , cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylamino arylalkylamino , where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or a ring; and R14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl , heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, or heteroarylalkylamino.

[0012] In some embodiments of a compound of Formula II, the compound has the structure of Formula II-A:

[0013] In some embodiments of a compound of Formula II or Formula II-A, R14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl, such as halo, hydroxyl, amino, cyano , C1-C4 amido, C1-C4 alkyl, C1-C4 heteroalkyl or C1-C4 haloalkyl. In some embodiments of a compound of Formula II or Formula II-A, L3 is carbonyl, O, S or -NR5-.

[0014] In some embodiments of a compound of Formula II or Formula II-A, R14 is amino. In some embodiments of a compound of Formula II or Formula II-A, R14 is alkyl, such as C1-C3 alkyl or methyl. In some embodiments of a compound of Formula II or Formula II-A, X6 is CR3 and R3 in X6 is selected from H, halo, amino, carboxyl, and alkyl. In some embodiments of a compound of Formula II or Formula II-A, X6 is CR3 and R3 in X6 is selected from F, amino, carboxyl and methyl.

[0015] In yet another aspect, the present report provides a compound of Formula III: Or a pharmaceutically acceptable salt thereof, where: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; p is an integer from 1 to 9; (i) at least one RA is present on a carbon at position 2, 4 or 6 of the piperidine ring; (ii) at least one RA is present on each of the carbons in the 3 or 5 position of the piperidine ring, provided that when one RA is present on one of the carbons in the 3 or 5 position and at least one RA is present on the other carbons at position 3 or 5, an RA on the carbon at position 3 and an RA on the carbon at position 5 do not together form a bridge; or (iii) two RA are present on one of the carbons in position 3 or 5 of the piperidine ring, provided that when one RA is present on one of the carbons in position 3 or 5 and at least one RA is present on the other carbons in position 3 or 5, an RA on the carbon at position 3 and an RA on the carbon at position 5 do not together form a bridge; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl ; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkyl-amino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroaryl-amino , and heteroarylalkylamino, where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or ring.

[0016] In some embodiments of a compound of Formula III, RA is, at each occurrence, independently selected from H, halo, oxo, alkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl and cycloalkylalkyl.

[0017] In another aspect, the present report provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; p is an integer from 0 to 9; each of L1 and L2 is independently the bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl ; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; provided that for B-II when Z1 is CR7 or N, Z2 is CR7 or N, Z6 is NR9, Z7 is CR8 and Z8 is CR8, then Z5 is N; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino , cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylamino arylalkylamino , where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring; and provided that the compound of Formula IV is not any of the compounds IV-27, IV-28, IV-29, IV-30, IV-31 and IV-32 listed in Table 4d.

[0018] In some embodiments of a compound of Formula IV, B comprises a heteroatom ring. In some embodiments of a compound of Formula IV, B comprises an N-atom ring. In some embodiments of a compound of Formula IV, B comprises two heteroatom rings. In some embodiments of a compound of Formula IV, B comprises two rings with N atoms.

[0019] In yet another aspect, the present report provides a compound of Formula or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; L3 is a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl; L2 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a saturated 3-7 membered ring, or an unsaturated 3-7 membered ring, provided that when L3 is -NR5-, A is not a piperidine ring which is attached at the carbon at position 4 of the piperidine ring to L3 and connected at the N atom of the piperidine ring to L2; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 AB each of R, R, R, R, R, R, R, R, R, R, R, R, R, R, R and R is , at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino, where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring.

[0020] In some embodiments of a compound of Formula V, L3 is carbonyl, O or -NR5-. In some embodiments of a compound of Formula V, L2 is -NR5- or C1 alkylene. In some embodiments of a compound of Formula V, A is A-4, A-7, A-8, A-9, A-10, A-16, A-17, A-18, or A-57.

[0021] In another aspect, the present report provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; L1 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; L4 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl, provided that L4 is not a C1 alkylene; A is a bond, a saturated 3-7 membered ring or an unsaturated 3-7 membered ring, provided that when L1 is -NR5-, A is not a piperidine ring which is connected to the carbon at position 4 of the piperidine ring a L1 is connected to the N atom of the piperidine ring to L4; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L4; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 AB each of R, R, R, R, R, R, R, R, R, R, R, R, R, R, R and R is , at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino , cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or a ring; and provided that the compound of Formula VI is not the compound VI-43 listed in Table 4f.

[0022] In some embodiments of a compound of Formula VI, L1 is a bond. In some embodiments of a compound of Formula VI, L4 is -NR6CH2-, -NR6C(=O)- or -NR6SO2-. In some embodiments of a compound of Formula VI, RA is, at each occurrence, independently selected from H, cycloalkyl, aryl and heteroaryl. In some embodiments of a compound of Formula VI, A is A-7, A-8, A-9 or A-10.

[0023] In some embodiments of a compound of Formula VI, when L1 is a bond, L4 is -NR5-, R5 is H, and m is 0, A is not a piperidine ring that is connected to the carbon at position 4 of the piperidine ring to L4 and connected at the N atom of the piperidine ring to H-III. In some embodiments of a compound of Formula VI, the compound of Formula VI is not the compound VI-44 listed in Table 4f.

[0024] In another aspect, the present report provides a compound of Formula IX: or a pharmaceutically acceptable salt thereof, wherein: H-III is ; X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; A is a bond, a 3-7 membered saturated ring, or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; L1 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to –C(R16R16a)–; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; 9 10 11 10 11 12 13 each of Z, Z, and Z is independently CR, CR R, NR, O, or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; each of R16 and R16a is independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino; or R16 and R16a together with the carbon atom to which they are attached, together form an optionally substituted C3-10 carbocycle or an optionally substituted 3-10 membered heterocycle; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino, wherein two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring; provided that when one of X5 and X6 is CR3, the other of X5 or of the piperidine ring to -CR16R16a-, B is B-II, Z1 and Z2 are CR7, Z5 is C, Z6 is N, and Z7 and Z8 are CR8, Z6 is not substituted with an RB comprising a functional group that react in covalently forms with one or more of the menin residues.

[0025] In some embodiments of a compound of Formula IX, the compound has the structure of Formula IX-A:

[0026] In some embodiments of a compound of Formula IX or IX-A, the compound does not comprise a functional group that reacts covalently with one or more of the menin residues.

[0027] In another aspect, the present report provides a compound of Formula X: R n (X); or a pharmaceutically acceptable salt thereof, wherein: ; each of X1, X2 and X7 is independently CR2 or N; each of X3 and X4 is independently C or N; each of X5 and X6 is independently CR3, N, NR4, O or S; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3, and Z4 is independently CR7, N, or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 each of R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, 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; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino, where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring.

[0028] X7 X . In some embodiments of a compound of Formula In some embodiments of a compound of Formula X, R2 in X1 is amino. In some embodiments of a compound of Formula X, R2 in X1 is alkyl, such as C1-C3 alkyl or methyl. In some embodiments of a compound of Formula X, X6 is CR3 and R3 in X6 is selected from H, halo, amino, carboxyl and alkyl. In some embodiments of a compound of Formula X, X6 is CR3 and R3 in X6 is selected from F, amino, carboxyl and methyl.

[0029] In some embodiments of a compound provided herein, A, when present, is cycloalkyl, heterocyclic ring, aryl or heteroaryl. In some embodiments of a compound provided herein, A, when present, has one of the following structures: any one of CH or NH can be substituted with a bond to L1, L2, L3, L4 or RA. In some embodiments of a compound provided herein, A, when present, is a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 6-membered aryl, 5-membered heteroaryl, or 5-membered heteroaryl. 6 members.

[0030] In some embodiments of a compound provided here, L1, when present, is -NR5-.

[0031] In some embodiments of a compound provided here, L2, when present, is -CH2-, NR5, -NR6CH2-, -NR6C(=O)- or -NR6SO2-. In some embodiments of a compound provided herein, L2, when present, is C1-C4 alkylene.

[0032] In some embodiments of a compound provided here, X2, when present, is N. In some embodiments of a compound provided here, X2, when present, is CR2.

[0033] In some embodiments of a compound provided here, X6, when present, is CR3.

[0034] In some embodiments of a compound provided here, R3 in X6 is selected from H, halo, amino, carboxyl, and alkyl. In some embodiments of a compound provided herein, R3 in X6 is selected from F, amino, carboxyl and methyl.

[0035] In some embodiments of a compound provided here, X5, when present, is S.

[0036] In some embodiments of a compound provided here, R1, when present, is a haloalkyl. In some embodiments of a compound provided herein, R1, when present, is -CH2CF3 or -CH2CHF2.

[0037] In some embodiments of a compound provided here, m, when present, is 0. In some embodiments of a compound provided here, m, when present, is 1, 2 or 3.

[0038] In some embodiments of a compound provided here, p, when present, is 0. In some embodiments of a compound provided here, p, when present, is 1, 2 or 3.

[0039] In some embodiments of a compound provided herein, RA, when present, is, at each occurrence, independently selected from H, halo, oxo, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocyclylalkyl and cycloalkylalkyl.

[0040] In some embodiments of a compound provided here, n is 0. In some embodiments of a compound provided here, n is 1 or 2.

[0041] In some embodiments of a compound provided here, R15, when present, is H.

[0042] In some embodiments of a compound provided herein, R15 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl or haloalkyl. In some embodiments of a compound provided herein, R15 is amino. In some embodiments of a compound provided herein, R15 is alkyl. In some embodiments of a compound provided herein, R15 is C1-C3 alkyl. In some embodiments of a compound provided herein, R15 is methyl.

[0043] In some embodiments of a compound provided here, R5, when present, is H or alkyl.

[0044] In some embodiments of a compound provided herein, each R7, when present, is independently H, halo, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy.

[0045] In some embodiments of a compound provided herein, each R8, when present, is independently H, C1-C4 alkyl or cyano.

[0046] In some embodiments of a compound provided herein, each R9, when present, is independently H, C1-C4 alkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl. In some embodiments of a compound provided herein, each R9, when present, is independently H, C1-C4 alkyl or

[0047] In some embodiments of a compound provided here, B, when present, is BI. In some embodiments, BI is connected to L2, when present, or L4, when present, on a ring carbon. In some embodiments, BI is connected to L2, when present, or L4, when present, at a selected position of

[0048] In some embodiments of a compound provided here, B, when present, is B-II. In some embodiments, B-II is connected to L2, when present, or L4, when present, on a ring carbon. In some embodiments, B-II is connected to L2, when present, or L4, when present, at a selected position from t

[0049] In some embodiments of a compound provided here, B, when present, is B-III. In some embodiments, B-III is connected to L2, when present, or L4, when present, on a ring carbon. In some embodiments, B-III is connected to L2, when present, or L4, when present, at a selected position of

[0050] In some embodiments of a compound provided here, B, when present, is BIV. In some embodiments, B-IV is connected to L2, when present, or L4, when present, on a ring carbon. In some embodiments, B-IV is connected to L2, when present, or L4, when present, at a selected position of

[0051] In some embodiments of a compound provided herein comprising B-II, Z1 and Z2 are CR7; Z5 is C; Z6 is NR9; and Z7 and Z8 are CR8. In some embodiments of a compound provided herein comprising B-II, Z1 is CCH3; Z2 and Z8 are CH; Z5 is C; Z6 is NR9; and Z7 is CCN.

[0052] In some embodiments of a compound provided herein, the compound does not comprise a functional group that reacts covalently with one or more of the menin residues.

[0053] In some embodiments of a compound provided here, the compound is capable of (a) non-covalently binding to menin and (b) inhibiting the interaction of menin and MLL.

[0054] In some embodiments of a compound provided herein, one or more of R1, R2, R3, R4 5 6 7 8 9 10 11 12 13 14 15 16 16a A B , R , R , R , R , R , R , R, R, R, R, R, R, R, R and R, when present, comprise a functional group that reacts covalently with one or more of the menin residues. In some embodiments of a compound provided herein, the functional group reacts covalently with one or more cysteine residues in menin. In some embodiments of a compound provided herein, the functional group reacts covalently with a cysteine in menin at position 329 relative to SEQ ID NO: 2 when optimally aligned at position 334 relative to SEQ ID NO: 1 when optimally aligned.

[0055] In some embodiments of a compound provided here, the compound is capable of (a) covalently binding to menin and (b) inhibiting the interaction of menin and MLL.

[0056] In some embodiments of a compound provided herein, the compound comprises an RB selected from: where: G is selected from a bond, alkylene, heteroalkylene, C3-12 carbocycle, 3- to 12-membered heterocycle, and combinations thereof, where G is optionally substituted with one or more R32 groups; V is absent or selected from a C3-12 carbocycle, and 3- to 12-membered heterocycle; where V is optionally replaced with one or more R32 groups; each of R21 and R32 is, at each occurrence, independently selected from: H, halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20, -C(O)R20 , -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S (O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(0)(R20)2, -OP(O)(OR20)2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, - S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O )(R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 3- to 10-membered carbocycle and heterocycle; where two R32 on the same carbon atom can together form a 3- to 10-membered C3-10 carbocycle or heterocycle; wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R32 is independently optionally substituted with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N(R20)C(O) R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S(O)2N(R20) 2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP (O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; R20 in each occurrence is independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR30, -SR30, -N(R30)2, -N (R30)C(O)R30, -C(O)R30, -C(O)OR30, -C(O)N(R30)2, -OC(O)R30, -S(O)2R30, -S (O)2N(R30)2, -N(R30)S(O)2R30, -NO2, -P(O)(OR30)2, -P(O)(R30)2, -OP(O)(OR30 )2, e -CN; and 3 to 10 membered heterocycle and C3-10 carbocycle; and R30 in each occurrence is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0057] In some embodiments of a compound provided here, R21 comprises a functional group that reacts covalently with one or more of the menin residues. In some embodiments of a compound provided herein, the functional group reacts covalently with one or more cysteine residues in menin. In some embodiments of a compound provided herein, the functional group reacts covalently with a cysteine in menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned.

[0058] In some embodiments of a compound provided herein, R21 is a radical comprising an alpha, beta unsaturated carbonyl; an alpha, beta unsaturated sulfonyl; an epoxide; an aldehyde; sulfonyl fluoride; a halomethylcarbonyl; a dihalomethylcarbonyl; or a trihalomethylcarbonyl.

[0059] In some embodiments of a compound provided here, R21 is selected from: where: L5 is selected from a link; and C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is independently optionally substituted with one or more R32 groups; R22 and R23 are selected from hydrogen, halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C (O)N(R20)2, -OC(O)R20, -S(O)2R20, - S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O , =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2 and -CN; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, - C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 carbocycle and 3-10 membered heterocycle, wherein each C3-10 carbocycle and 3-10 membered heterocycle of R22 and R23 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, - N(R20)2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20 )2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; or R22 and R23, together with the carbon atoms to which they are attached, form a carbocyclic ring; R24 is selected from: hydrogen, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, and -S( O)2N(R20)2; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 carbocycle and 3-10 membered heterocycle, wherein each C3-10 carbocycle and 3-10 membered heterocycle of R24 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N( R20)2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S( O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2 , -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0060] In some embodiments of a compound provided here, L5 is a bond. In some embodiments of a compound provided herein, L5 is optionally substituted C1-6 alkylene. In some embodiments of a compound provided herein, L5 is selected from methylene, ethylene or propylene. In some embodiments of a compound provided herein, L5 is substituted with one or more substituents selected from halogen, -NO2, =O, =S, -OR20, -SR20 and -N(R20)2.

[0061] In some embodiments of a compound provided here, R23 is selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, - N(R20)C(O)R20, -C(O)R20, -C(O)OR20, - C(O)N(R20)2, -OC(O)R20, -S(O)2R20, - S(O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O )(R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 3- to 10-membered carbocycle and heterocycle, wherein each C3-10 3- to 10-membered carbocycle and heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20) 2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O) 2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0062] In some embodiments of a compound provided here, R23 is selected from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =O, =S, =N(R20) and -CN; and 3- to 10-membered heterocycle optionally substituted with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20, -C(O)R20, - C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O )2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN , C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0063] In some embodiments of a compound provided herein, R23 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =O, = S, =N(R20), and -CN.

[0064] In some embodiments of a compound provided here, R22 is selected from: hydrogen and -CN; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 3- to 10-membered carbocycle and heterocycle, wherein each C3-10 3- to 10-membered carbocycle and heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20) 2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O) 2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0065] In some embodiments of a compound provided here, R22 is selected from hydrogen; -CN; and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20 and -N(R20)2.

[0066] In some embodiments of a compound provided herein, R22 and R23, together with the carbon atoms to which they are attached, form a 5-, 6- or 7-membered carbocyclic ring.

[0067] In some embodiments of a compound provided herein, R24 is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, = O and -CN.

[0068] In some embodiments of a compound provided here, R21 is selected from:

[0069] In some embodiments of a compound provided here, R21 is a radical with 5 to 50 atoms.

[0070] In some embodiments of a compound provided here, R21 is a radical with 5 to 40 atoms.

[0071] In some embodiments, V is selected from a 3-8 membered saturated ring, 3-8 membered unsaturated ring, 4-10 membered fused bicyclic ring and 5-11 membered spiro bicyclic ring. V may be optionally replaced with one or more R32 groups, such as with 1, 2, 3, 4 or 5 R32 groups. In some embodiments, V is a 3-7 membered saturated ring, such as a 3-7 membered cycloalkyl or 3-7 membered aromatic or non-aromatic heterocycle. In some embodiments, V is a 3-7 membered unsaturated ring, such as a 6-membered aryl, 5-6 membered heteroaryl, or 3-7 membered cycloalkenyl.

[0072] In some embodiments of a compound provided herein, V is selected from a 3-8 membered saturated ring optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is a 3-, 4-, 5-, 6-, or 7-membered saturated carbocycle, any one of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from: is optionally substituted with one or more R32 groups.

[0073] In some embodiments of a compound provided herein, V is a 4, 5, 6, 7 or 8 membered saturated heterocycle, any one of which is optionally substituted with one or more R32 groups selected from azetidine, oxetane, piperidine, tetrahydrofuran, thiolane, imidazolidine, morpholine, thiomorpholine, azepane and homopiperazine, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from: homopiperazine, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from: any of which is optionally substituted with one or more R32 groups.

[0074] In some embodiments of a compound provided here, V is a bicyclic heterocycle, optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from any of which is optionally substituted with one or more R32 groups.

[0075] In certain embodiments, V is a 4-10 membered fused bicyclic ring, such as an 8-10 membered fused bicyclic ring. In certain embodiments, the fused bicyclic ring includes one or more heteroatoms such as one or more atoms selected from N, O and S. In certain embodiments, the fused bicyclic ring includes two heteroatoms such as two nitrogen atoms. Each of the rings of the fused bicyclic ring can be saturated or unsaturated. In particular embodiments, both rings of the fused bicyclic ring are saturated. Non-limiting examples of V comprising a fused bicyclic ring include

[0076] In some embodiments, V is a 5-11 membered spiro bicyclic ring, such as a 7-11 membered spiro bicyclic ring. In certain embodiments, the fused bicyclic ring includes one or more heteroatoms such as one or more atoms selected from N, O and S. In particular embodiments, the fused bicyclic ring includes two heteroatoms such as two nitrogen atoms. Non-limiting examples of V comprising a spiro bicyclic ring include

[0077] In some embodiments of a compound provided herein, V is selected from an unsaturated aromatic or heteroaromatic ring, either of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline, cinoline, phthalazine, furan, dihydrofuran, thiophene, dihydrothiophene, imidazole , imidazoline, oxazole, oxazoline, pyrrole, dihydropyrrole, thiazole, dihydrothiazole, pyrazole, dihydropyrazole, isoxazole, dihydroisoxazole, isothiazole, dihydroisothiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole and benzothiazole, any one of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is phenyl, optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is a heteroaromatic ring optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from pyridine, pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline, cinoline, phthalazine, furan, thiophene, imidazole, oxazole, pyrrole, thiazole , pyrazole, isoxazole, isothiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole and benzothiazole, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, V is selected from where any of which is optionally substituted with one or more R32 groups.

[0078] In some embodiments of a compound provided here, V is absent.

[0079] In some embodiments of a compound provided here, G is a bond.

[0080] In some embodiments of a compound provided herein, G is alkylene optionally substituted with one or more R32 groups.

[0081] In some embodiments of a compound provided herein, G is selected from methylene, ethylene, propylene and butylene, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound provided herein, G is selected from: where any of which is optionally substituted with one or more R32 groups.

[0082] In some embodiments of a compound provided herein, G is a heteroalkylene optionally substituted with one or more R32 groups.

[0083] In some embodiments of a compound provided herein, G is a 3- to 10-membered C3-10 carbocycle or heterocycle, any of which is optionally substituted with one or more R32 groups.

[0084] In some embodiments of a compound provided herein, G is a C3-10 saturated carbocycle or saturated 3- to 10-membered heterocycle, any of which is optionally substituted with one or more R32 groups.

[0085] In some embodiments of a compound provided herein, G is selected from: where any of which is optionally substituted with one or more R32 groups.

[0086] In some embodiments, the compound is selected from Table 4a, Table 4b, Table 4c, Table 4d, Table 4e or Table 4f. In some cases, the compound is not any of the compounds selected from IV-27 listed in Table 4d, IV-28 listed in Table 4d, IV-29 listed in Table 4d, IV-30 listed in Table 4d, IV-31 listed in Table 4d, IV-32 listed in Table 4d, VI-43 listed in Table 4f, and VI-44 listed in Table 4f.

[0087] In another aspect, the present report provides a pharmaceutical composition comprising a compound described herein 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.

[0088] In yet another aspect, the present report provides a method of inhibiting the interaction of menin and one or more of MLL1, MLL2, an MLL fusion protein and a Partial Tandem Duplication of MLL, comprising the count of menin with an effective amount of a compound described herein.

[0089] In another aspect, the present report provides a method of inhibiting the menin-MLL interaction, comprising counting the menin with an effective amount of a compound described herein, wherein the inhibition of the interaction is evidenced by a reduction in the expression of an MLL fusion protein target gene, such as HOXA9, DLX2 or MEIS1.

[0090] In another aspect, the present report provides a method of stabilizing menin, comprising contacting menin with a compound described here. In some embodiments, the contacting step comprises contacting the menin with an amount of the compound sufficient to stabilize the menin. In some embodiments, the contact step occurs in a cell.

[0091] In some embodiments of a method described here, the contacting step comprises contacting a cell expressing menin. In some embodiments of a method described herein, the method comprises administering a second therapeutic agent to the cell. In some embodiments of a method described herein, the contacting step occurs in vivo. In some embodiments of a method described herein, the contact step occurs in vitro.

[0092] In another aspect, the present report provides a method of treating a disease or condition associated with MLL fusion proteins, comprising administering to an individual in need of such treatment an effective amount of a compound described herein.

[0093] In yet another aspect, the present report provides a method of treating a disease or condition in an individual, comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition of a compound described herein.

[0094] In some embodiments of a method described herein, the disease or condition comprises leukemia, hematological malignancies, solid tumor, prostate cancer, breast cancer, liver cancer, brain tumor or diabetes. In some embodiments, the leukemia comprises AML, ALL, Mixed Lineage Leukemia or leukemias with Partial Tandem Duplications of MLL.

[0095] In another aspect, the present report provides a method of treating a disorder mediated by chromosomal rearrangement on chromosome 11q23 in an individual in need of such treatment, the method comprising: administering to the individual a therapeutically effective amount of a described compound here.

[0096] In yet another aspect, the present report provides a method of treating a disorder mediated by an interaction between menin and another protein, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound described herein. .

[0097] In some embodiments of a method described herein, the individual is a human.

[0098] In another aspect, the present report provides a kit comprising a pharmaceutical composition described herein and instructions for using the composition to treat an individual suffering from a disease or condition mediated by an interaction between menin and another protein.

[0099] The new characteristics of the invention are presented with particularity in the attached claims. A better understanding of the features and advantages of the present invention will be obtained with reference to the following detailed description which presents illustrative embodiments in which the principles of the invention are utilized.

INCORPORATION BY REFERENCE

[0100] All publications, patents and patent applications mentioned in this report are incorporated herein by reference as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0101] FIG. 1 is an amino acid sequence from human menin, isoform 1 (SEQ ID NO: 1).

[0102] FIG. 2 is an amino acid sequence from human menin, isoform 2 (SEQ ID NO: 2).

[0103] FIG. 3 is an amino acid sequence from human menin, isoform 3 (SEQ ID NO: 3).

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0104] Unless defined differently, all technical and scientific terms used herein have the same meaning commonly understood by a person skilled in the art to which this invention belongs.

[0105] “MLL fusion protein” refers to a protein with an N-terminal fragment of MLL fused to a partner protein. Non-limiting examples of a partner protein include 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22, 9p13.3, 9p22 (MLLT3/AF9), ABI1, ABI2, ACACA, ACTN4, AF1p, AFF1/ AF4, AFF3/LAF4, AFF4/AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13, C2CD3, CASC5, CASP8AP2, CBL, CBP, 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). MLL fusion proteins can be created by joining a gene coding for an MLL protein and a gene coding for a partner protein creating a fusion gene. Translation of this fusion gene can result in a single polypeptide or multiple peptides with functional properties derived from each of the original proteins.

[0106] “Amino” refers to the radical -NH2.

[0107] “Carbonyl” refers to a radical of Formula -C(=O)-.

[0108] “Carboxy” or “carboxyl” refers to the radical -CO2H.

[0109] “Cyan” refers to the radical -CN.

[0110] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0111] “Imino” refers to the radical =NH. Unless otherwise specifically indicated in this report, an imino group is optionally substituted.

[0112] “Nitro” refers to the radical -NO2.

[0113] “Oxo” refers to the radical =O.

[0114] “Thioxo” refers to the radical =S.

[0115] “Acyl” refers to the group -C(=O)Ra, where Ra is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon), heteroalkyl and heterocyclylalkyl. Unless otherwise specifically indicated in the report, an acyl group is optionally substituted.

[0116] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), containing from one to twelve carbon atoms (C1-C12 alkyl), preferably one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), and which is bonded to the remainder of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexinyl and the like. Alkyl includes alkenyls (one or more carbon-carbon double bonds) and alkynyls (one or more carbon-carbon triple bonds). Unless otherwise specifically indicated in the report, an alkyl group is optionally substituted.

[0117] “Alkoxy” refers to a radical of Formula -ORa where Ra is an alkyl group as defined herein containing from one to twelve carbon atoms. Unless otherwise specifically indicated in the report, an alkoxy group is optionally substituted.

[0118] “Alkylamino” refers to a radical of Formula -NHRa or -NRaRb where Ra and Rb are each independently an alkyl group as defined herein containing from one to twelve carbon atoms. Unless otherwise specifically indicated in the report, an alkylamino group is optionally substituted.

[0119] “Alkylaminoalkyl” refers to an alkyl radical comprising at least one alkylamino substituent. The alkylamino substituent can be on a tertiary, secondary or primary carbon. Unless otherwise specifically indicated in the report, an alkylaminoalkyl group is optionally substituted.

[0120] “Amide” or “starch” refers to a radical with Formula -C(=O)NRaRb or -NRaC(=O) Rb, wherein Ra and Rb are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon), heteroalkyl and heterocyclylalkyl, each of which may itself be optionally substituted. In some embodiments, it is a C1-C4 starch or amide group, which includes the starch carbonyl in the total number of carbons in the group. The amide RaRb of -NRaRb may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. Unless otherwise specifically indicated in the report, an amide group is optionally substituted.

[0121] “Aminoalkyl” refers to an alkyl radical comprising at least one amino substituent. The amino substituent can be on a tertiary, secondary or primary carbon. Unless otherwise specifically indicated in the report, an aminoalkyl group is optionally substituted.

[0122] “Aminocarbonyl” refers to an amido radical of Formula -C(=O)NRaRb, where Ra and Rb are each independently H or alkyl. Unless otherwise specifically indicated in the report, an aminocarbonyl group is optionally substituted.

[0123] “Aryl” refers to a hydrocarbon ring system radical comprising 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical is a fused monocyclic, bicyclic, tricyclic or tetracyclic ring system that may include fused or bridged ring systems. Aryl radicals include, but are not limited to, cenatrilene, cenaphthylene, acephenantrilene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and triphenylene. Unless otherwise specifically indicated in the report, the term “aryl” or the prefix “ar” (as in “aralkyl”) includes aryl groups that are optionally substituted.

[0124] “Aralkyl” refers to a radical of Formula -Rb-Rc where Rb is an alkylene chain as defined herein and Rc is one or more aryl radicals as defined herein, for example, benzyl, diphenylmethyl and the like. . Unless otherwise specifically indicated in the report, an aralkyl group is optionally substituted.

[0125] “Aralkylamino” refers to an aralkyl-NRa- radical, where Ra is H or alkyl. Unless otherwise specifically indicated in the report, an aralkylamino is optionally substituted.

[0126] “Aralkyloxy” refers to an aralkyl-O- radical. Unless otherwise specifically indicated in the report, an aralkyloxy is optionally substituted.

[0127] “Arylamino” refers to a -NRa-aryl radical, where Ra is H or alkyl. Unless otherwise specifically indicated in the report, an arylamino is optionally substituted.

[0128] “Aryloxy” refers to an -O-aryl radical. Unless otherwise specifically indicated in the report, an aryloxy is optionally substituted.

[0129] “Bicycloalkyl" refers to a radical with two cycloalkyl radicals, which contains one or more atoms in common. If the cycloalkyl radicals have exactly one atom in common they are said to be "spiro". Examples include, but are not limited to, limit to, spiro[2,2]pentane, spiro[5,5]undecane, spiro[4,5]decane, spiro[3,6]decane and the like. If cycloalkyl radicals have exactly two adjacent atoms in common they are said to be as being "fused." Examples include, but are not limited to, bicyclo[3,1,0]hexyl, perhydronaphthyl, and the like. If cycloalkyl radicals have more than two atoms in common they are said to be "bridged." Examples include, but are not limited to, tricyclo[3,3,1,1]decyl (“adamantyl”), bicyclo[1,1,1]pentyl, bicyclo[2,2,1]heptyl (“norbornyl”), bicyclo[2,2,2]octyl and the like. Unless otherwise specifically indicated in the report, a bicycloalkyl is optionally substituted.

[0130] “Carboxyalkyl” refers to a radical of Formula -Rb-Rc where Rb is an alkylene chain as defined here and Rc is a carboxy group as defined here. Unless otherwise specifically indicated in the report, the carboxyalkyl group is optionally substituted.

[0131] “Cyanoalkyl” refers to a radical of Formula -Rb-Rc where Rb is an alkylene chain as defined and Rc is a cyano group as defined herein. Unless otherwise specifically indicated in the report, a cyanoalkyl group is optionally substituted.

[0132] “Cycloalkyl” or “carbocyclic ring” refers to a non-aromatic monocyclic or polycyclic hydrocarbide radical, which may include fused, spiro or bridged ring systems, containing from three to fifteen carbon atoms, preferably containing from three to ten carbon atoms, and which is saturated or unsaturated and linked to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2,2,1]heptanyl and the like. A “cycloalkenyl” is a cycloalkyl comprising one or more carbon-carbon double bonds within the ring, such as cyclopentenyl and cyclohexenyl. Unless otherwise specifically specified in the report, a cycloalkyl group is optionally substituted.

[0133] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each ring atom is a carbon atom. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, for example, phenyl, can be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane or cyclohexene. Any combination of saturated, unsaturated, or aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl and naphthyl. Unless otherwise specifically indicated in the report, a carbocycle is optionally substituted by one or more substituents such as those described herein.

[0134] “Cycloalkylalkyl” refers to a radical of Formula -RbRd where Rb is an alkylene chain as defined here and Rd is a cycloalkyl radical as defined here. Unless otherwise specifically indicated in the report, a cycloalkylalkyl group is optionally substituted.

[0135] “Cycloalkylalkylamino” refers to a cycloalkylalkyl-NRa- radical, where Ra is H or alkyl and where the cycloalkylalkyl radical is linked through a carbon atom to nitrogen, where nitrogen functions as a ligand to fix the radical to the rest of the molecule. Unless otherwise specifically indicated in the report, a cycloalkylalkylamino is optionally substituted.

[0136] “Cycloalkylalkyloxy” refers to an -O-cycloalkylalkyl radical, where the cycloalkylalkyl radical is linked through a carbon atom to oxygen, where the oxygen functions as a ligand to attach the radical to the rest of the molecule. Unless otherwise specifically indicated in the report, a cycloalkylalkyloxy is optionally substituted.

[0137] “Cycloalkylamino” refers to a -NRa-cycloalkyl radical, where Ra is H or alkyl. Unless otherwise specifically indicated in the report, a cycloalkylamino is optionally substituted.

[0138] “Cycloalkyloxy” refers to an -O-cycloalkyl radical. Unless otherwise specifically indicated in the report, a cycloalkyloxy is optionally substituted.

[0139] “Halo” or “halogen” refers to fluorine, chlorine, bromine or iodine.

[0140] “Haloalkyl” refers to an alkyl group, as defined herein, that is substituted by one or more halogen atoms, as defined herein, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, -CH2CF3, - CH2CHF2, -CH2CH2F, -CHFCF3, - CHFCHF2, -CHFCH2F, -CHFCH3, -CF2CF3, -CF2CHF2, -CF2CH2F, -CF2CH3, - CH2CF2CH3, -CH2CHFCH3, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like . Unless otherwise specifically indicated in the report, a haloalkyl group is optionally substituted.

[0141] As used herein, the term "heteroatom" or "ring heteroatom" includes any element other than carbon or hydrogen. Preferred heteroatoms are oxygen (O), nitrogen (N), sulfur (S) and phosphorus (P).

[0142] “Heteroalkyl”, itself or in combination with another term, means, unless otherwise specified, a straight or branched chain monocyclic or polycyclic radical, which may include fused or bridged ring systems; or any combination thereof, comprising at least one carbon atom and at least one heteroatom, such as O, N, P, Si and S, wherein one or more heteroatoms can be oxidized. The heteroatom(s) may be positioned within the alkyl radical, for example, -CH2-O-CH2-; at a point of connectivity with the rest of the molecule, for example, -SO2CH(CH3)CH2-; or a combination thereof, for example, -NH2CH2CH2SO2CH2-. Unless otherwise specifically indicated in the report, a heteroalkyl group is optionally substituted.

[0143] “Heteroaryl” refers to a radical with a 5- to 14-membered ring system comprising one to thirteen carbon atoms; from one to six heteroatoms such as nitrogen, oxygen and sulfur; and one or multiple rings where at least one ring is aromatic. For the purposes of this invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems and one or more of the heteroatoms may be oxidized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinolinyl, dibenzofuranil, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl , indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranil, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl , 1-phenyl -1H-pyrrolyl, phenazinyl, phenothiazinyl, fenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazol il, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl). Unless otherwise specifically indicated in the report, a heteroaryl group is optionally substituted.

[0144] “Heteroarylalkyl” refers to a radical of Formula -RbRf where Rb is an alkylene chain as defined here and Rf is a heteroaryl group as defined here. Unless otherwise specifically indicated in the report, a heteroarylalkyl group is optionally substituted.

[0145] “Heteroarylalkylamino” refers to a heteroarylalkyl-NRa- radical, where Ra is H or alkyl. Unless otherwise specifically indicated in the report, a heteroarylalkylamino is optionally substituted.

[0146] “Heteroarylalkyloxy” refers to a heteroarylalkyl-O- radical. Unless otherwise specifically indicated in the report, a heteroarylalkyloxy is optionally substituted.

[0147] “Heteroarylamino” refers to a -NRa-heteroaryl radical, where Ra is H or alkyl. Unless otherwise specifically indicated in the report, a heteroarylamino is optionally substituted.

[0148] “Heteroaryloxy” refers to an -O-heteroaryl radical. Unless otherwise specifically indicated in the report, a heteroaryloxy is optionally substituted.

[0149] “Heterobicycloalkyl” refers to a bicycloalkyl structure in which at least one carbon atom of the ring is replaced with a heteroatom such as oxygen, nitrogen and sulfur. Unless otherwise specifically indicated in the report, a heterobicycloalkyl is optionally substituted.

[0150] “Heterocyclyl” or “heterocyclic ring” refers to a 3- to 18-membered non-aromatic ring consisting of two to twelve carbon atoms and one to six heteroatoms such as nitrogen, oxygen and sulfur. Unless otherwise specifically indicated in the report, the heterocyclyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; the heteroatoms may be optionally oxidized; and the heterocyclyl can be saturated or unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithyanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrh olidinyl , oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1.1-dioxo-thiomorpholinyl. Unless otherwise specifically indicated in the report, a heterocyclyl group is optionally substituted.

[0151] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6 to 12-membered bicyclic rings, and 6 to 12-membered bridge rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. The heterocycle can be linked to the rest of the molecule through any atom of the heterocycle, as long as the valence allows, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle, for example, pyridyl, can be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane or cyclohexene.

[0152] “Heterocyclylalkyl” or “heterocycloalkyl” refers to a radical of Formula -RbRe where Rb is an alkylene chain as defined here and Re is a heterocyclyl radical as defined here, and if the heterocyclyl is a nitrogen-containing heterocyclyl , the heterocyclyl is optionally linked to the alkyl radical on the nitrogen atom. Unless otherwise specifically indicated in the report, a heterocyclylalkyl group is optionally substituted.

[0153] “Heterocyclylalkylamino” refers to a heterocyclylalkyl-NRa- radical, where Ra is H or alkyl and where the heterocyclylalkyl radical is linked through a carbon atom to nitrogen, where the nitrogen functions as a ligand to fix the radical to the rest of the molecule. Unless otherwise specifically indicated in the report, a heterocyclylalkylamino is optionally substituted.

[0154] “Heterocyclylalkyloxy” refers to an -O-heterocycloalkyl radical, in which the heterocyclylalkyl radical is linked through a carbon atom to oxygen, where the oxygen functions as a ligand to attach the radical to the rest of the molecule. Unless otherwise specifically indicated in the report, a heterocyclylalkyloxy is optionally substituted.

[0155] “Heterocyclylamino” refers to a -NRa-heterocyclyl radical, where Ra is H or alkyl and where the heterocyclyl radical is linked through a carbon atom to nitrogen, where nitrogen functions as a ligand to fix the radical to the rest of the molecule. Unless otherwise specifically indicated in the report, a heterocyclylamino is optionally substituted.

[0156] “Heterocyclyloxy” refers to an -O-heterocyclyl radical, where the heterocyclyl radical is linked through a carbon atom to oxygen, where the oxygen functions as a ligand to attach the radical to the rest of the molecule. Unless otherwise specifically indicated in the report, a heterocyclyloxy is optionally substituted.

[0157] “Hydroxyalkyl” refers to an alkyl group comprising at least one hydroxyl substituent. The -OH substituent can be on a primary, secondary, or tertiary carbon. Unless otherwise specifically indicated in the report, a hydroxylalkyl group is optionally substituted.

[0158] “N-heteroaryl” refers to a heteroaryl radical as defined here containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the remainder of the molecule is through a nitrogen atom in the heteroaryl ring. Unless otherwise specifically indicated in the report, an N-heteroaryl group is optionally substituted.

[0159] “N-heterocyclyl” refers to a heterocyclyl radical as defined here containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the remainder of the molecule is through a nitrogen atom in the heterocyclyl ring. Unless otherwise specifically indicated in the report, an N-heterocyclyl group is optionally substituted.

[0160] “Thioalkyl” refers to a radical of Formula -SRa where Ra is an alkyl radical as defined herein containing from one to twelve carbon atoms. Unless otherwise specifically indicated in the report, a thioalkyl group is optionally substituted.

[0161] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain that links two groups in a molecule, which may be saturated or unsaturated (i.e., containing one or more double bonds and/or or triples), and contains from one to twelve carbon atoms, preferably from one to eight carbon atoms (C1-C8 alkylene) or from one to six carbon atoms (C1-C6 alkylene), for example methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propylene, n-butylene and the like. The alkylene chain is linked to the rest of the molecule through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule can be through a carbon, for example methylene, or any two carbons in the chain, for example -CH2CH(CH3)CH2CH2-. Unless otherwise specifically indicated in the report, an alkylene chain is optionally substituted.

[0162] “Alkylenecarbonyl” refers to a radical of Formula -C(=O)Ra-, where Ra is an alkylene chain as defined here. Unless otherwise specifically indicated in the report, an alkylenecarbonyl is optionally substituted.

[0163] “Alkenylene” is an unsaturated alkylene, as defined here, that comprises one or more carbon-carbon double bonds. Unless otherwise specifically indicated in the report, an alkenylene is optionally substituted.

[0164] “Alkenylenecarbonyl” refers to an unsaturated alkylenecarbonyl, as defined herein, that comprises one or more carbon-carbon double bonds. Unless otherwise specifically indicated in the report, an alkenylenecarbonyl is optionally substituted.

[0165] “Arylene” refers to a divalent aryl group that links one part of the molecule to another part of the molecule. Unless specifically indicated otherwise, an arylene is optionally substituted.

[0166] “Heteroalkylene” refers to an alkylene group comprising at least one heteroatom (e.g., N, O or S). In some embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene comprises at least one carbon-heteroatom-carbon bond). In other embodiments, the heteroatom is at one terminus of the alkylene and joins the alkylene to the remainder of the molecule (e.g., M1-H-A-M2, where M1 and M2 are parts of one molecule, H is a heteroatom, and A is an alkylene). . A heteroalkylene can have both internal and terminal heteroatoms, for example, -OCH2CH2OCH2CH2O-. Unless otherwise specifically indicated in the report, heteroalkylene is optionally substituted.

[0167] “Heteroalkylenecarbonyl” refers to a radical of Formula -C(=O)Ra-, where Ra is a heteroalkylene chain as defined here. Unless otherwise specifically indicated in the report, a heteroalkylenecarbonyl is optionally substituted.

[0168] “Heteroarylene” refers to a divalent heteroaryl group that links one part of the molecule to another part of the molecule. Unless specifically indicated otherwise, a heteroarylene is optionally substituted.

[0169] “Heteroarylenecarbonyl” refers to a radical of Formula -C(=O)Ra-, where Ra is a heteroarylene as defined here. Unless specifically indicated otherwise, a heteroarylenecarbonyl is optionally substituted.

[0170] “Heterocyclylalkylene” refers to a divalent heterocyclyl group that links one part of the molecule to another part of the molecule. Unless specifically indicated otherwise, a heterocycloalkylene is optionally substituted.

[0171] “Heterocyclylalkylenecarbonyl” refers to a radical of Formula -C(=O)Ra-, where Ra is a heterocycloalkylene as defined here. Unless specifically indicated otherwise, a heterocycloalkylenecarbonyl is optionally substituted. The term "substituted" used herein means any of the above groups (e.g., amino, carboxy, hydroxyl, imino, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, amido, aminoalkyl, aminocarbonyl, aryl, aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkyl quilamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene and/or heterocyclylalkylenecarbonyl), wherein at least one hydrogen atom is substituted by a bond to a non-hydrogen atom such as, but not limited to: a halogen atom such as F, Cl, Br and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, thiourea groups, sulfone groups such as alkyl sulfone groups, sulfonyl groups such as sulfonamide groups and sulfonylalkyl groups such as sulfonylmethane and sulfoxide groups such as alkyl sulfoxide groups; a nitrogen atom in groups such as amino, amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, urea and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; a phosphorus atom in groups such as dialkylphosphine oxide groups, phosphine oxide groups, phosphine groups, phosphate groups, phosphonate groups, phosphinate groups; and other heteroatoms in several other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher order bond (e.g., a double or triple bond) to a carbon atom or a heteroatom such as oxygen in oxo, carbonyl, carboxyl and ester groups; and nitrogen in groups such as imines, oximes, hydrazones and nitriles. “Substituted” includes any of the above groups in which one or more hydrogen atoms are substituted with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O) NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, -SO2NRgRh, -C(=O)Rg, -C(=O)ORg, -C (=O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh, where Rg and Rh are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl , N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, carbonyl, carboxy, cyano, hydroxyl, imino, nitro, oxo, thioxo, acyl, alkyl, alkoxy, alkylamino , alkylaminoalkyl, starch, aminoalkyl, aminocarbonyl, aryl, aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl , heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene , heteroalkylene, heteroalkylenecarbonyl , heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene, heterocyclylalkylenecarbonyl, trimethylsilanyl, dialkylphosoxide O)OR , -C(O)N(R)2, -N(R)C(O)OR , -N(R ) C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), -PO(Ra)2, or -PO (ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. In addition, each of the above substituents is optionally substituted with one or more of the above substituents.

[0172] The term “effective amount” or “therapeutically effective amount” refers to the amount of a compound described herein that is sufficient to achieve the intended application, including, but not limited to, the treatment of disease, as defined below . The therapeutically effective amount may vary depending on the application of the intended treatment (in vivo), or on the individual and the condition of the disease being treated, e.g., the weight and age of the individual, the severity of the disease, the manner of administration, and so on. which can be readily determined by a person skilled in the art. The term also applies to a dose that will induce a particular response in target cells, for example, reduced platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosage regimen to be followed, whether it is administered in combination with other compounds, time of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0173] As used herein, “treatment” or “treating” refers to an approach to obtaining beneficial or desired results with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit we mean eradication or improvement of the disorder in question being treated. Also, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the disorder in question such that an improvement is observed in the individual, even though the individual may still be afflicted by the disorder in question. In certain embodiments, for prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual exhibiting one or more of the physiological symptoms of a disease, even though a diagnosis of that disease may not yet have been established. been carried out.

[0174] A “therapeutic effect”, as the term is used here, encompasses a therapeutic benefit and/or a prophylactic benefit, as described above. A prophylactic effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the establishment of symptoms of a disease or condition, reducing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0175] The terms “co-administration,” “administered in combination with” and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal, including humans, such that both agents and/or or its metabolites are present in the individual 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.

[0176] “Pharmaceutically acceptable salt” includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable basic addition salts.

[0177] “Pharmaceutically acceptable acid addition salt” refers to those salts that maintain the effectiveness and biological properties of free bases, which are not biologically or otherwise desirable, and which are formed from inorganic salts such as , but not limited to, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid , alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, acid cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, acid 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1 acid, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like.

[0178] “Pharmaceutically acceptable basic addition salt” refers to those salts that maintain the effectiveness and properties of free acids, which are not biologically or otherwise desirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the salts of sodium, potassium, lithium ammonium, calcium magnesium, iron, zinc, copper, manganese, aluminum and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzatine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0179] The terms “antagonist” and “inhibitor” are used interchangeably here, and refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and/or an MLL fusion protein). Likewise, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. Although the preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included in this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth or dissemination of a tumor.

[0180] The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, either by inhibiting the activity or expression of the target protein. Likewise, the term “agonist” is defined in the context of the biological role of the target polypeptide. Although the preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included in this definition.

[0181] As used herein, “agent” or “biologically active agent” refers to a biological, pharmaceutical or chemical compound. Non-limiting examples include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin and a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for selection, such as plant or animal extracts and the like.

[0182] “Signal transduction” is a process during which stimulus or inhibitory signals are transmitted to and within a cell to produce an intracellular response. A modulator of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator can increase (agonist) or suppress (antagonist) the activity of a signaling molecule.

[0183] An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in treating a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a patient with cancer by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal or inhalation or in the form of a suppository.

[0184] The term “cell proliferation” refers to a phenomenon whereby the number of cells is changed as a result of division. This term encompasses cell growth whereby cell morphology is altered (e.g., increased in size) consistent with a sign of proliferation.

[0185] “Individual” refers to an animal, such as a mammal, for example a human. The methods described here may be useful in both human therapeutic and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0186] “Mammal” includes humans and both domestic animals such as laboratory animals and companion animals (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wild animals and the like.

[0187] “Prodrug” indicates a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described here (for example, the compound of Formula I-VI). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to an individual, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (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 Vehices in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press) each of which is incorporated herein in its entirety by reference. The term “prodrug” also includes any covalently linked carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds in which a hydroxy, amino or mercapto group is attached to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy or acetamide functional group, formamide and benzamide of an amino functional group in the active compound, and the like.

[0188] The term “in vivo” refers to an event that occurs in an individual's body.

[0189] The term “in vitro” refers to an event that occurs outside an individual's body. For example, an in vitro assay encompasses any assay performed outside of an individual. In vitro assays encompass cell-based assays in which living or dead cells are employed. In vitro assays also encompass a cell-free assay in which intact cells are not used.

[0190] In certain embodiments, the compounds described here are isotopically labeled. Isotopically labeled compounds (for example, an isotopologue) may have one or more atoms replaced by an atom having a different atomic mass or mass number. Non-limiting examples of isotopes that can be incorporated into the described compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 13 15 15 17 18 31 32 35 18 36 123 125 N, N, O, O, O, P, P, S, F, Cl, I and I, respectively. Certain isotopically labeled compounds, for example, those incorporating a radioactive isotope, are useful in studies of tissue distribution of drugs and/or substrates. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and easy means of detection. These radioactively labeled compounds may be useful in determining or measuring the effectiveness of compounds, by characterizing, for example, the site or mode of action, or binding affinity, the pharmacologically important site of action. Substitution with heavier isotopes such as deuterium, i.e., 2H, may allow certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and are thus preferred in some circumstances. Replacement with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies to examine receptor occupancy on the substrate. Isotopically labeled compounds in general can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in Preparations and Examples, as set forth below, using an appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0191] “Optional” or “optionally” means that the subsequently described circumstantial event may or may not occur, and that the description includes cases in which the event or circumstance occurs and cases in which it does not occur. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and unsubstituted aryl groups.

[0192] “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation, any adjuvant, vehicle, excipient, fluidizer, sweetening agent, diluent, preservative, colorant, flavor amplifier, surfactant, wetting agent, dispersing agent, suspending agent , stabilizer, isotonic agent, solvent, or emulsifier approved by the United States Food and Drug Administration as acceptable for use in humans or domestic animals.

[0193] The compounds of the invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus produce enantiomers, diastereomers and other stereoisometric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S) - or as (D)- or (L)- for amino acids. The present invention includes all such possible isomers, as well as their racemic and optically pure forms. A “stereoisomer” refers to a compound made of the same atoms linked by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are not capable of being superimposed in mirror images of each other. Optically active isomers (+) and (-), (R)- and (S)- or (D)- and (L)- can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques , for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis of an optically suitable precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0194] A “tautomer” refers to a proton exchange of one atom of a molecule for another atom of the same molecule. The present invention includes tautomers of any of the compounds and all tautomeric forms are included.

compounds

[0195] The present report provides compounds for modulating the interaction of menin with proteins such as MLL1, MLL2 and MLL fusion oncoproteins. In certain embodiments, the report provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including, but not limited to, MLL1, MLL2 and MLL fusion oncoproteins. The compounds of the report can be used in methods for treating a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL fusion proteins, and menin. In certain embodiments, a compound of the report covalently binds to menin and inhibits the interaction of menin with MLL. In certain embodiments, a compound of the report noncovalently interacts with menin and inhibits the interaction of menin with MLL.

[0196] The compounds of the report can be used in methods for treating a wide variety of diseases associated with MLL1, MLL2, MLL fusion proteins, and menin. In certain embodiments, a compound of the report noncovalently interacts with menin and inhibits the interaction of menin with MLL. In certain embodiments, a compound of the report covalently binds to menin and inhibits the interaction of menin with MLL.

[0197] In one aspect, the invention provides compounds that are capable of selectively binding to the menin protein and/or modulating the interaction of menin with an MLL protein (e.g., MLL1, MLL2, MLL fusion protein). In some embodiments, the compounds modulate the menin protein by binding to or interacting with one or more amino acids and/or one or more metal ions. Some compounds may occupy the F9 and/or P13 pocket in menin. Binding of these compounds can disrupt signaling downstream of menin or MLL (non-limiting examples include MLL1, MLL2, and MLL fusion proteins).

[0198] In some embodiments, there is provided here a compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof.

[0199] In other embodiments, a compound having the structure of Formula II is provided here: or a pharmaceutically acceptable salt thereof.

[0200] In still other embodiments, a compound having the structure of Formula III is provided here: or a pharmaceutically acceptable salt thereof.

[0201] In still further embodiments, a compound having the structure of Formula IV is provided here: or a pharmaceutically acceptable salt thereof.

[0202] In other embodiments, a compound having the structure of Formula V is provided here: or a pharmaceutically acceptable salt thereof.

[0203] In still other embodiments, a compound having the structure of Formula VI is provided here: or a pharmaceutically acceptable salt thereof.

[0204] In other embodiments, a compound having the structure of Formula IX is provided here: or a pharmaceutically acceptable salt thereof.

[0205] In other embodiments, a compound having the structure of Formula X is provided here: or a pharmaceutically acceptable salt thereof. HI Ring

[0206] In a compound of Formula I, H-I has the structure: In some cases, each of X1 and X2 is independently CR2 or N. In some cases, each of X3 and X4 is independently C or N. In some cases, each of Y1 and Y2 is independently CR3, N, NR4, O or S. In some cases, H-I does not contain three or more adjacent N atoms in the ring. In some cases, when X1 is CR2, X2 is CR2 or N, X3 is C, X4 is C, and one of Y1 and Y2 is S, then the other of Y1 or Y2 is N. In some cases, each of Y1 and Y2 is independently N, NR4, O or S. In some cases, at least one of Y1 and Y2 is independently N, NR4, O or S. In some cases, H-I is selected from one of the structures listed in Table 1a. In some cases, H-I is not one or more of the structures listed in Table 1a.

[0207] In a compound of Formula I, HI may contain one or more heteroatoms. In some cases, HI contains 0, 1, 2, 3, 4, 5 or 6 ring heteroatoms. In some cases, HI contains at least 1, 2, 3, 4, 5, or 6 ring heteroatoms. In some cases, HI contains up to 1, 2, 3, 4, 5 or 6 heteroatoms in the ring. In some cases, HI contains 0, 1, 2, 3, 4 or 5 N atoms in the ring. In some cases, HI contains at least 1, 2, 3, 4, or 5 N atoms in the ring. In some cases, HI contains up to 1, 2, 3, 4 or 5 N atoms in the ring. In some cases, HI contains 0 or 1 O atoms in the ring. In some cases, HI contains at least 1 O atom in the ring. In some cases, HI contains up to 1 O atom in the ring. In some cases, HI contains 0 or 1 S atoms in the ring. In some cases, HI contains at least 1 S atom in the ring. In some cases, HI contains up to 1 S atom in the ring. In some cases, HI contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the ring. In some cases, HI contains at least 2, 3, 4, 5, 6, 7, or 8 carbon atoms in the ring. In some cases, HI contains up to 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the ring. Table 1a: Non-limiting examples of HI structures

[0208] In a compound of Formula II, H-II has the structure: In some cases, X2 is CR2 or N. In some cases, each of X5 and X6 is independently CR3, N, NR4, O, or S. In some cases, each of X5 and X6 is independently N, NR4, O, or S. In some cases, at least one of X5 and X6 is independently N, NR4, O, or S. In some cases, H-II is selected from one of the structures listed in Table 1b. In some cases, H-II is not one or more of the structures listed in Table 1b.

[0209] In a compound of Formula II, H-II may contain one or more heteroatoms. In some cases, H-II contains 0, 1, 2, 3 or 4 ring heteroatoms. In some cases, H-II contains at least 1, 2, 3 or 4 ring heteroatoms. In some cases, H-II contains up to 1, 2, 3 or 4 ring heteroatoms. In some cases, H-II contains 0, 1, 2, 3 or 4 N atoms in the ring. In some cases, H-II contains at least 1, 2, 3, or 4 N atoms in the ring. In some cases, H-II contains up to 1, 2, 3 or 4 N atoms in the ring. In some cases, H-II contains 0 or 1 O atom in the ring. In some cases, H-II contains at least 1 O atom in the ring. In some cases, H-II contains up to 1 O atom in the ring. In some cases, H-II contains 0 or 1 S atom in the ring. In some cases, H-II contains at least 1 S atom in the ring. In some cases, H-II contains up to 1 S atom in the ring. In some cases, H-II contains 5, 6, 7, or 8 carbon atoms in the ring. In some cases, H-II contains at least 5, 6, 7, or 8 carbon atoms in the ring. In some cases, H-II contains up to 5, 6, 7 or 8 carbon atoms in the ring. Table 1b: Non-limiting examples of H-II structures H-III Ring

[0210] In a compound of any of Formulas III, IV, V, VI, and IX, H-III has the structure: In some cases, X2 is independently CR2 or N. In some cases, each of X5 and X6 is independently CR3, N, NR4, O, or S. In some cases, each of X5 and X6 is independently N, NR4, O or S. In some cases, at least one of X5 and X6 is independently N, NR4, O, or S. In some cases, H-III is selected from one of the structures listed in Table 1c. In some cases, H-III is not one or more of the structures listed in Table 1c.

[0211] In a compound of any of Formulas III, IV, V, VI, and IX, H-III may contain one or more heteroatoms. In some cases, H-III contains 0, 1, 2, 3 or 4 ring heteroatoms. In some cases, H-III contains at least 1, 2, 3, or 4 ring heteroatoms. In some cases, H-III contains up to 1, 2, 3 or 4 ring heteroatoms. In some cases, H-III contains 0, 1, 2, 3 or 4 N atoms in the ring. In some cases, H-III contains at least 1, 2, 3, or 4 N atoms in the ring. In some cases, H-III contains up to 1, 2, 3 or 4 N atoms in the ring. In some cases, H-III contains 0 or 1 O atom in the ring. In some cases, H-III contains at least 1 O atom in the ring. In some cases, H-III contains up to 1 O atom in the ring. In some cases, H-III contains 0 or 1 S atom in the ring. In some cases, H-III contains at least 1 S atom in the ring. In some cases, H-III contains up to 1 S atom in the ring. In some cases, H-III contains 5, 6, 7, or 8 carbon atoms in the ring. In some cases, H-III contains at least 5, 6, 7, or 8 carbon atoms in the ring. In some cases, H-III contains up to 5, 6, 7 or 8 carbon atoms in the ring. Table 1c: Non-limiting examples of H-III structures HX Ring

[0212] In a compound of Formula X, HX has a structure selected from: In some cases, each of X1, X2, and X7 is independently CR2 or N. In some cases, each of X3 and X4 is independently C or N. In some cases, each of X5 and NR4, O or S. In some cases, HX does not contain three or more adjacent N atoms in the ring. In some cases, at least one of X5 and X6 is independently N, NR4, O, or S. In some cases, HX is selected from one of the structures listed in Table 1d. In some cases, HX is not one or more of the structures listed in Table 1d.

[0213] In a compound of Formula X, HX may contain one or more heteroatoms. In some cases, HX contains 0, 1, 2, 3, 4, 5 or 6 heteroatoms in the ring. In some cases, H-X contains at least 1, 2, 3, 4, 5, or 6 ring heteroatoms. In some cases, HX contains up to 1, 2, 3, 4, 5 or 6 heteroatoms in the ring. In some cases, HX contains 0, 1, 2, 3, 4, or 5 N atoms in the ring. In some cases, HX contains at least 1, 2, 3, 4, or 5 N atoms in the ring. In some cases, HX contains up to 1, 2, 3, 4 or 5 N atoms in the ring. In some cases, HX contains 0 or 1 O atom in the ring. In some cases, HX contains at least 1 O atom in the ring. In some cases, HX contains up to 1 O atom in the ring. In some cases, HX contains 0 or 1 S atom in the ring. In some cases, HX contains at least 1 S atom in the ring. In some cases, HX contains up to 1 S atom in the ring. In some cases, HX contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms in the ring. In some cases, HX contains at least 2, 3, 4, 5, 6, 7, or 8 carbon atoms in the ring. In some cases, HX contains up to 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the ring. Table 1d: Non-limiting examples of HX structures A-ring

[0214] In a compound of any of Formulas I, II, V, VI, IX, and X, A may be a bond, a saturated 3-7 membered ring, or an unsaturated 3-7 membered ring. In some cases, A is aromatic, non-aromatic, saturated or unsaturated. In some cases, A is an aryl, arylene, cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkylene, heteroaryl, heteroarylene or N-heteroaryl. In some cases, A is a 3-, 4-, 5-, 6-, or 7-membered ring. In some cases, A is at least a 3-, 4-, 5-, 6-, or 7-membered ring. In some cases, A is even a 3-, 4-, 5-, 6-, or 7-membered ring. In some cases, A is a bond.

[0215] In a compound of any of Formulas I, II, V, VI, IX, and X, A may contain one or more heteroatoms. In some cases, A contains 0, 1, 2, 3 or 4 heteroatoms in the ring. In some cases, A contains at least 1, 2, 3, or 4 heteroatoms in the ring. In some cases, A contains up to 1, 2, 3 or 4 heteroatoms in the ring. In some cases, A contains 0, 1, 2, 3 or 4 N atoms in the ring. In some cases, A contains at least 1, 2, 3, or 4 N atoms in the ring. In some cases, A contains up to 1, 2, 3 or 4 N atoms in the ring. In some cases, A contains 0, 1, 2, or 3 O atoms in the ring. In some cases, A contains at least 1, 2, or 3 O atoms in the ring. In some cases, A contains up to 1, 2 or 3 O atoms in the ring. In some cases, A contains 0, 1 or 2 S atoms in the ring. In some cases, A contains at least 1 or 2 S atoms in the ring. In some cases, A contains up to 1 or 2 S atoms in the ring. In some cases, A contains 2, 3, 4, 5, 6, or 7 carbon atoms in the ring. In some cases, A contains at least 2, 3, 4, 5, 6, or 7 carbon atoms in the ring. In some cases, A contains up to 2, 3, 4, 5, 6 or 7 carbon atoms in the ring.

[0216] In a compound of any of Formulas I, II, V, VI, IX, and connected to a ring atom with a bond to L1, L2, L3 or L4). In some cases, A is connected on the same ring atom to two of the group consisting of L1, L2, L3, or L4. In some cases, A is connected at different ring atoms to two of the group consisting of L1, L2, L3, or L4. In some cases, A is connected at a ring heteroatom to L1, L2, L3 and/or L4. In some cases, the ring heteroatom is N. In some cases, A is connected at a ring carbon to L1, L2, L3 and/or L4. In some cases, A is connected on a ring heteroatom to one of L1, L2, L3, and L4 and on a ring carbon to another of L1, L2, L3, and L4. In some cases, A is connected to the ring atom at position 1, 2, 3, 4, 5, 6, or 7 to L1. In some cases, A is connected to the ring atom at position 1, 2, 3, 4, 5, 6, or 7 to L2. In some cases, A is connected to the ring atom at position 1, 2, 3, 4, 5, 6, or 7 to L3. In some cases, A is connected to the ring atom at position 1, 2, 3, 4, 5, 6, or 7 to L4.

[0217] In a compound of any of Formulas I, II, V, VI, IX, and X, A may be optionally substituted with one or more RA groups (for example, by replacing a hydrogen attached to a ring atom with a connection to RA). A can be optionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 RA groups. A may be optionally substituted with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 RA groups. A may be optionally substituted with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 RA groups. In some cases, A is not replaced. In some cases, A is optionally replaced with m RA groups. In some cases, m is an integer from 0 to 12. In some cases, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some cases, m is at least 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some cases, m is even 0, 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 or 12. In some cases, A is optionally replaced with p RA groups. In some cases, p is an integer from 0 to 9. In some cases, p is an integer from 1 to 9. In some cases, p is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9. In some cases, p is at least 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some cases, p is even 1, 2, 3, 4, 5, 6, 7 , 8 or 9. In some cases, RA is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl , alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino . An RA group can be attached to any ring atom of A. In some cases, an RA group is attached to a ring carbon of A. In some cases, a RA group is attached to a heteroatom of the A ring. In some cases, an RA group is attached to the ring atom at position 1, 2, 3, 4, 5, 6, or 7 of A. In some cases, two RA groups may be attached to the same ring atom of A. , only one RA group can be attached to each ring atom of A. In some cases, two RA groups attached to the same or different atoms can together optionally form a bridge or a ring. In some cases, two RA groups bonded to the same or different atoms may together optionally be an alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene or heterocyclylalkylenecarbonyl.

[0218] In some cases, for a compound of any of Formulas I, II, V, VI, IX, and X, A is selected from a ring A with one of the structures listed in Table 2. In some cases, A is selected from A-1 to A-101 and any combination thereof. In some cases, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92, A-95 to A-101, and any combination thereof. In some cases, A is not one or more of the A rings with structures listed in Table 2. In some cases, A is not 1, 2, 3, 4, 5, 6, or 7 A rings with structures selected from the group consisting of ring A with structures A-7, A-8, A-9, A-10, A-16, A-17 and A-18. In some cases, ring A with a structure in Table 2 may contain one or more RA groups and may be optionally replaced with one or more additional RA groups. Table 2: Non-limiting examples of A-Ring structures

[0219] L1, L2, L3, L4, and L5

[0220] In some cases, for a compound of any of Formulas I, III, IV, VI, IX, and X, L1 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C( =O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl. In some cases, for a compound of any of Formulas I, II, III, IV, V, and X, L2 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O) -, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl. In some cases, for a compound of any of Formulas II and V, L3 is a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene , alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl. In some cases, for a compound of Formula VI, L4 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl. In some cases, L4 is not a C1 alkylene. In some cases, an alkylene is a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, or C12 alkylene. In some cases, an alkylene is even a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, or C12 alkylene. In some cases, an alkylene is at least one C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkylene. In some cases, an alkylene contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons in the chain. In some cases, an alkylene contains up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons in the chain. In some cases, an alkylene contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons in the chain. In some cases, an alkylene contains 0, 1, 2, 3, 4, 5, 6 or 7 double and/or triple bonds. In some cases, an alkylene contains up to 1, 2, 3, 4, 5, 6 or 7 double and/or triple bonds. In some cases, an alkylene contains at least 1, 2, 3, 4, 5, 6 or 7 double and/or triple bonds. In some cases, an alkylene chain is linked to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. In some cases, an alkylene chain is linked to the rest of the molecule through a single bond and to the radical group through a single bond. In some cases, the points of connection of the alkylene chain to the rest of the molecule and to the radical group are through a carbon or any two carbons within the chain. In some cases, the points of connection of the alkylene chain to the rest of the molecule and to the radical group may be through a carbon within the chain. In some cases, the points of connection of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In some cases, an alkenylene contains 1, 2, 3, 4, 5, 6 or 7 double bonds. In some cases, an alkenylene contains up to 1, 2, 3, 4, 5, 6 or 7 double bonds. In some cases, an alkenylene contains at least 1, 2, 3, 4, 5, 6 or 7 double bonds. In some cases, a heteroalkylene contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 heteroatoms in the chain. In some cases, a heteroalkylene contains up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 heteroatoms in the chain. In some cases, a heteroalkylene contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 heteroatoms in the chain. In some cases, the heteroatom or heteroatoms are inside the alkylene chain. In some cases, the heteroatom or heteroatoms are one or two terminals of the alkylene and join the alkylene to the rest of the molecule and/or the radical group.

[0221] In some cases, for a compound of any of Formulas I, II, III, IV, V, VI, IX, and X, L1, L2, L3, L4 and L5, when present, are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC( O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, 51 51 51 51 51 51 51 -N(R )C(O)N(R )-, -N(R )C(O)O-, -OC(O) N(R )-, -C(NR )-, -N(R )C(NR )-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51 )S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O) 2N(R51)-, -N(R51)S(O)N(R51)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50, wherein two R50 groups attached to the same or different atoms of any of L1, L2, L3, L4 and L5 may together optionally form a bridge or a ring; R50 is independently selected at each occurrence of: halogen, -NO2, -CN, -OR , -SR52, -N(R52)2, -NR R , -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, - NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C (O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, - NR52C(O)R52 , -NR52C(O)OR52, -NR52C(O)N(R52)2, - NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)( OR52)2, - P(O)(R52)2, =O, =S, =N(R52); C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, -N( R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52 , -NR52S(=O)2N(R52)2, 52 53 54 52 52 52 52 - NR S(=O)2NR R , -C(O)R , -C(O)OR , -OC(O)R , -OC(O)OR , 52 53 54 52 52 52 52 - OC(O)N(R )2, -OC(O)NR R , -NR C(O)R , -NR C(O)OR , 52 52 52 53 54 52 53 54 - NR C(O)N(R )2, -NR C(O)NR R , -C(O)N(R )2, -C(O)NR R , - P (O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3-12 membered heterocycle wherein each C3-12 carbocycle and 3-12 membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, - SR52, - N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S (=O)2R52, -NR52S(=O)2N(R52)2, 52 53 54 52 52 52 52 - NR S(=O)2NR R , -C(O)R , -C(O)OR , - OC(O)R , -OC(O)OR , 52 53 54 52 52 52 52 - OC(O)N(R )2, -OC(O)NR R , -NR C(O)R , -NR C (O)OR, or more selected halogen substituents, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, 52 53 54 52 52 52 52 - NR S (=O)2NR R , -C(O)R , -C(O)OR , -OC(O)R , -OC(O)OR , 52 53 54 52 52 52 52 - OC(O)N(R )2, -OC(O)NR R , -NR C(O)R , -NR C(O)OR , 52 52 52 53 54 52 53 54 - NR C(O)N(R )2, -NR C (O)NR R , -C(O)N(R )2, -C(O)NR R , - P(O)(OR52)2, -P(O)(R52)2, =O, =S , =N(R52), C3-12 carbocycle and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3-12 membered heterocycle, wherein each C3-12 carbocycle and 3-12 membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, -NO2, -CN, -OR52, -SR52, - N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, - S(=O)2NR53R54, - NR52S(=O)2R52, -NR52S(=O)2N(R52)2, 52 53 54 52 52 52 52 - NR S(=O)2NR R , -C(O)R , -C(O)OR , -OC(O)R , -OC(O)OR , 52 53 54 52 52 52 52 - OC(O)N(R )2, -OC(O)NR R , -NR C(O)R , -NR C(O)OR , 52 52 52 53 54 52 53 54 - NR C(O)N(R )2, -NR C(O)NR R , -C(O)N(R )2, -C(O )NR R , - P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl; R52 is independently selected at each occurrence of hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2 , -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 3- to 6-membered carbocycle and heterocycle; and R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50. B-Ring

[0222] In some cases, for a compound of any of Formulas I, II, III, IV, V, VI, IX, and X, B is monocyclic or bicyclic (e.g., two fused rings). In some cases, B is a bicyclic ring system comprising a 6-membered ring. In some cases, B is a bicyclic ring system comprising a 6-membered to 5-membered fused ring. In some cases, B is a bicyclic ring system comprising a 6-membered ring fused to a 6-membered ring. In some cases, one or two of the B rings are aromatic, non-aromatic, saturated or unsaturated. In some cases, one or two rings of B are an aryl, arylene, cycloalkyl, heterocyclyl, N-heterocyclyl, heteroaryl, heteroarylene or N-heteroaryl. In some cases, B is selected from BI, B-II, B-III, B-IV, and any combination of these, where BI is B-II is N. In some cases, each of Z6, Z7, and Z8 is independently CR8, N, NR9, O, or S. In some cases, each of Z9, Z10, and Z11 is independently CR10, CR11R12, NR13, O, or S.

[0223] In a compound of any of Formulas I, II, III, IV, V, VI, IX, and X, B or any of B-I, B-II, B-III and B-IV may contain one or more heteroatoms. In some cases, B or any of B-I, B-II, B-III and B-IV contains 0, 1, 2, 3, 4 or 5 heteroatoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains at least 1, 2, 3, 4 or 5 heteroatoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains up to 1, 2, 3, 4 or 5 heteroatoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains 0, 1, 2, 3 or 4 N atoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains at least 1, 2, 3 or 4 N atoms in the ring. In some cases, B or any of B-I, B-II, B-III, and B-IV contains up to 1, 2, 3, or 4 N atoms in the ring. In some cases, B or any of B-I, B-II, B-III, and B-IV contain 0, 1, or 2 O atoms in the ring. In some cases, B or any of BI B-II, B-III and B-IV contains at least 1 or 2 O atoms in the ring. In some cases, B or any of B-I, B-II, B-III, and B-IV contain up to 1 or 2 O atoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains 0, 1 or 2 S atoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains at least 1 or 2 S atoms in the ring. In some cases, B or any of B-I, B-II, B-III and BIV contains up to 1 or 2 S atoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains at least 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the ring. In some cases, B or any of B-I, B-II, B-III and B-IV contains up to 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the ring.

[0224] In a compound of any of Formulas I, II, III, IV, V, VI, IX, and X, B or any of B-I, B-II, B-III and B-IV may be connected into any ring atom to L2 or L4 (e.g., by replacing a hydrogen bonded to a ring atom with a bond to L2 or L4). In some cases, B or any of B-I, B-II, B-III, and BIV is connected on a ring heteroatom to L2 or L4. In some cases, the ring heteroatom is an N. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on a ring carbon to L2 or L4. In some cases, B or any of B-I, B-II, B-III and B-IV is connected on a ring atom of an aromatic ring to L2 or L4. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on a ring atom of a non-aromatic ring to L2 or L4. In some cases, B or any of B-I, B-II, B-III and B-IV is connected on a ring atom of a 6-membered ring to L2 or L4. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on a ring atom of a 5-membered ring to L2 or L4. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on a ring atom of a benzene ring. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on a ring atom of a non-benzene ring. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on the ring atom at position 1, 2, 3, 4, 5, 6, 7, or 8 to L2. In some cases, B or any of B-I, B-II, B-III, and B-IV is connected on the ring atom at position 1, 2, 3, 4, 5, 6, 7, or 8 to L4.

[0225] In some cases, for a compound of any of Formulas I, II, III, IV, V, VI, IX and X, BI or any one of BI-2 to BI-20 is connected to L2 or L4 in a position selected from the group consisting of , and any combination of these. In some cases, B-I or anyone from BI-2 to BI-24 is connected to L2 or L4 at a position selected from the group consisting of and any combination of these. In some cases, B-II or any one of B-II-2 to B-II-52 is connected to L2 or L4 at a position selected from the group consisting of and any combination of these. In some cases, B-III or any one of B-III-2 to B-III-12 is connected to L2 or L4 at a position selected from the group consisting of any combination of these. In some cases, B-III or any one of B-III-2 through B-III-13 is connected to L2 or L4 at a position selected from the group consisting of and any combination of these. In some cases, B-IV or any one of B-IV-2 to B-IV-27 is connected to L2 or L4 at a position selected from the group consisting of and any combination of these.

[0226] In a compound of any of Formulas I, II, III, IV, V, VI, IX, and X, B may be optionally substituted with one or more RB groups (for example, by replacing a hydrogen attached to a ring atom with a bond to RB). B can be optionally substituted with 0, 1, 2, 3, 4, 5 or 6 RB groups. B may be optionally substituted with at least 1, 2, 3, 4, 5 or 6 RB groups. B can be optionally substituted with up to 1, 2, 3, 4, 5 or 6 RB groups. In some cases, B is not replaced. In some cases, B is optionally replaced with n RB groups. In some cases, n is an integer from 0 to 6. In some cases, n is 0, 1, 2, 3, 4, 5, or 6. In some cases, n is at least 0, 1, 2, 3, 4, 5, or 6. In some cases, n is even 0, 1, 2, 3, 4, 5, or 6. In some cases, RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, oxide dialkylphosphine, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl , aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. An RB group can be attached to any ring atom of B. In some cases, an RB group is attached to a ring carbon of B. In some cases, an RB group is attached to a heteroatom of the B ring. In some cases, an RB group is connected to the ring atom at position 1, 2, 3, 4, 5, 6, 7, or 8 of B. In some cases, two RB groups can be connected to the same ring atom of B. In some cases, two RB groups can be connected to the same ring atom of B. In some cases, only one RB group can be attached to each ring atom of B. In some cases, two RB groups attached to the same or different atoms can together optionally form a bridge or a ring. In some cases, two RB groups bonded to the same or different atoms may together optionally be an alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene or heterocyclylalkylenecarbonyl.

[0227] In some cases, for a compound of any of Formulas I, II, III, IV, V, VI, IX, and X, B is selected from a B ring with one of the structures listed in Table 3. In some cases, B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B- IV, B-IV-2 to B-IV-27, and any combination thereof. In some cases, B is not one or more of the B rings with the structures listed in Table 3. In some cases, B is not 1, 2, 3, 4, 5, 6, 7, or 8 B rings with the selected structures of B-II-20, B-II-27, B-II-28, B-II-29, B-II-30, B-II-38, B-II-52, and B-III-13.

[0228] In some cases, a B ring with the structure in Table 3 may contain one or more RB groups and may be optionally replaced with one or more additional RB groups. Table 3: Non-limiting examples of Ring B structures Formula I compounds

[0229] In some embodiments, a compound having the structure of Formula I is provided here: or a pharmaceutically acceptable salt thereof, where: HI is each of X1 and X2 is independently CR2 or N; each of X3 and X4 is independently C or N; each of Y1 and Y2 is independently CR3, N, NR4, O or S; provided that when X1 is CR2, X2 is CR2 or N, X3 is C, X4 is C, and one of Y1 and Y2 is S, then the other of Y1 or Y2 is N; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3, and Z4 is independently CR7, N, or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 each of R, R, R, R, R, R, R, R, R, R, R, R, and R is, in each occurrence, independently selected of H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, 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; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkyl-amino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroaryl-amino and heteroarylalkylamino, where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or a ring.

[0230] In certain embodiments, the compound of Formula I has an HI selected from one of HI-2 to HI-34 in Table 1a. In particular, HI can be selected from HI-18 and HI-20. In certain embodiments, HI of a compound of Formula I is represented by Formula HI-18: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; and each of Y1 and Y2 is independently selected from CR3, N, NR4 and O. One of Y1 and Y2 may additionally be selected from S if the other of Y1 or Y2 is N. In certain embodiments, at most one of Y1 and Y2 is O or S.

[0231] In certain embodiments, HI of a compound of Formula I is represented by Formula HI-20: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R2, in each occurrence, is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as H, halo, hydroxyl and amino; and each of Y1 and Y2 is independently selected from CR3, N, NR4 and O. One of Y1 and Y2 can be additionally selected from S if the other of Y1 or Y2 is N. In certain embodiments, at most one of Y1 and Y2 is O or S.

[0232] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, R1 of a compound of Formula I may be selected from H, halo , hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as alkyl and haloalkyl. In some cases, when H-I of Formula I is selected from one of H-I-2 to H-I-34, such as from HI-18 and H-I-20, R2 of a compound of Formula I may be, in each occurrence, selected from H , halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as H, halo, hydroxyl and amino.

[0233] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, L1 may be selected from a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L1 may be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl.

[0234] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, Ring A may be selected from a 3-6 membered ring , such as a 5-6 membered ring, such as a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 6-membered aryl, 5-membered heteroaryl and 6 members. In certain embodiments, A is a saturated 5- or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, A is selected from A-1 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92 and A-95 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17, A-41, A-44, A- 57 and A-78 to A-87. In certain embodiments, A contains 0, 1 or 2 N atoms in the ring. In certain embodiments, A contains 0, 1 or 2 ring N atoms and no other ring heteroatoms. In certain embodiments, A is connected on the same ring atom to L1 and L2. In certain embodiments, A is connected at different ring atoms to L1 and L2. In certain embodiments, A is connected at a ring heteroatom to L1 and/or L2. In certain embodiments, A is connected at a ring carbon to L1 and/or L2. In certain embodiments, RA, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain realizations, m is 0 to 3.

[0235] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, L2 may be selected from a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In particular, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene and C1-C4 heteroalkylene.

[0236] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, Ring B may be selected from B-I, B-I-2 to B-I -24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27 , such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 heteroatoms in the ring, such as O and N atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected at a ring heteroatom to L2, such as a ring N atom. In certain embodiments, B is connected at a ring carbon to L2, such as a ring carbon in an aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0237] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, each of R2, R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy , cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0238] In some cases, when H-I of Formula I is selected from one of H-I-2 to HI-34, such as from H-I-18 and H-I-20, each of R4, R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, such as from H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0239] In particular embodiments, H-I of Formula I is selected from H-I-18 and H-I-20; R1 is selected from alkyl and haloalkyl; L1 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L2 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B- III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0240] In certain embodiments, a compound of Formula I has the structure of Formula IA:

[0241] A compound of Formula I can be selected from any of compounds I-1 to I-14 listed in Table 4a. In certain embodiments, a compound of Formula I is other than those with the structures listed in Table 4a. Table 4a: Exemplary compounds of Formula I

Formula II Compounds

[0242] In other embodiments, a compound has the structure of Formula II: or a pharmaceutically acceptable salt thereof, wherein: H-II is H-II is X2 is CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; L3 is a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; L2 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 each of R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, 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 or heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino , cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino or heteroaryl arylalkylamino , where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring; and R14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl , heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino or heteroarylalkylamino.

[0243] In certain embodiments, the compound of Formula II contains an H-II selected from one of H-II-2 to H-II-32 in Table 1b. In particular, H-II can be selected from H-II-2 and H-II-3. In certain embodiments, the H-II of a compound of Formula II is represented by Formula H-II-2: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R14 is selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from halo, hydroxyl, alkoxy, alkylamino , amino, cyano, amido, alkyl, heteroalkyl and haloalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0244] In certain embodiments, H-II of a compound of Formula II is represented by Formula H-II-3: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R14 is selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from halo, hydroxyl, alkoxy, alkylamino , amino, cyano, amido, alkyl, heteroalkyl and haloalkyl; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl , amino, alkyl and heteroalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0245] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, R1 of a compound of Formula II can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl. In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, R2 of a compound of Formula II may be, at each occurrence, selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl, amino, alkyl and heteroalkyl. In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, R14 of a compound of Formula II can be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from halo, hydroxyl, alkoxy, alkylamino , amino, cyano, amido, alkyl, heteroalkyl and haloalkyl.

[0246] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, L3 may be selected of a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2- C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L3 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl.

[0247] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, Ring A may be selected from a 3-6 membered ring, such as a 5-6 membered ring, such as a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, aryl 6-membered, 5-membered heteroaryl and 6-membered heteroaryl. In certain embodiments, A is a saturated 5- or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, A is selected from A-1 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92 and A-95 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17, A-41, A-44, A- 57 and A-78 to A-87. In certain embodiments, A contains 0, 1 or 2 N atoms in the ring. In certain embodiments, A contains 0, 1 or 2 ring N atoms and no other ring heteroatoms. In certain embodiments, A is connected on the same ring atom to L3 and L2. In certain embodiments, A is connected at different ring atoms to L3 and L2. In certain embodiments, A is connected at a ring heteroatom to L3 and/or L2. In certain embodiments, A is connected at a ring carbon to L3 and/or L2. In certain embodiments, RA, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, m is from 0 to 3.

[0248] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, L2 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In particular, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene and C1-C4 heteroalkylene.

[0249] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, Ring B may be selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B -IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected at a ring heteroatom to L2, such as a ring N atom. In certain embodiments, B is connected at a ring carbon to L2, such as a ring carbon in an aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0250] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, each from R2 , R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl , hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0251] In some cases, when H-II of Formula II is selected from one of H-II-2 to H-II-32, such as from H-II-2 and H-II-3, each from R4 , R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, as of H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0252] In particular embodiments, H-II of Formula II is selected from H-II-2 and H-II-3; R1 is selected from alkyl and haloalkyl; R2, when present, is, at each occurrence, selected from H, halo, hydroxyl, amino, alkyl and heteroalkyl; R14 is selected from halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl and haloalkyl; L3 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L2 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0253] In certain embodiments, a compound of Formula II has the structure of Formula II-A:

[0254] A compound of Formula II can be selected from any of compounds II-1 to II-18 listed in Table 4b. In certain embodiments, a compound of Formula II is other than one with the structures listed in Table 4b. Table 4b: Exemplary compounds of Formula II Table 4g: IC50 values for Formula II menin inhibitors

Formula III Compounds

[0255] In still other embodiments, a compound has a structure of Formula III: or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; p is an integer from 1 to 9; (i) at least one RA is present on a carbon at position 2, 4 or 6 of the piperidine ring; (ii) at least one RA is present on each of the carbons at position 3 or 5 of the piperidine ring, provided that when one RA is present on one of the carbons at position 3 or 5 and at least one RA is present on the other of the carbons at position 3 or 5, an RA on the carbon at position 3 and an RA on the carbon at position 5 do not together form a bridge; or (iii) two RA are present on one of the carbons in position 3 or 5 of the piperidine ring, provided that when one RA is present on one of the carbons in position 3 or 5 and at least one RA is present on the other of the carbons in position 3 or 5, an RA on the carbon at position 3 and an RA on the carbon at position 5 do not together form a bridge; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl heteroalkylenecarbonyl; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkyl-amino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroaryl-amino and heteroarylalkylamino, where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or a ring.

[0256] In certain embodiments, the compound of Formula III has an H-III selected from one of H-III-2 to H-III-33 in Table 1c. In particular, H-III can be selected from H-III-2 and H-III-3. In certain embodiments, H-III of a compound of Formula III is represented by Formula H-III-2: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0257] In certain embodiments, H-III of a compound of Formula III is represented by Formula H-III-3: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl , amino, alkyl and heteroalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0258] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R1 of a compound of Formula III can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl. In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R2 of a compound of Formula III may be, at each occurrence, selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl, amino, alkyl and heteroalkyl. In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R15 of a compound of Formula III can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino.

[0259] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L1 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L1 may be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl.

[0260] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, at least one RA is present on a carbon in position 2, 4 or 6 of the piperidine ring. In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, at least one RA is present in each of the carbons at position 3 or 5 of the piperidine ring, provided that when an RA is present on one of the carbons at position 3 or 5 and at least one RA is present on the other of the carbons at position 3 or 5, an RA on the at position 3 and an RA on the carbon at position 5 do not together form a bridge. In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, two RA are present in one of the carbons at position 3 or 5 of the piperidine ring, provided that when an RA is present on one of the carbons at position 3 or 5 and at least one RA is present on the other of the carbons at position 3 or 5, an RA on the carbon at position 3 and an RA on the carbon at position 5 do not together form a bridge. In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, RA, in each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, p is from 1 to 3.

[0261] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L2 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In particular, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene and C1-C4 heteroalkylene.

[0262] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B -IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected on a ring heteroatom to L2, such as a ring atom of N. In certain embodiments, B is connected on a ring carbon to L2, such as a ring carbon on an aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0263] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R2 , R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl , hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0264] In some cases, when H-III of Formula III is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R4 , R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, as of H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0265] In particular embodiments, H-III of Formula III is selected from H-III-2 and H-III-3; R1 is selected from alkyl and haloalkyl; R2, when present, is selected from H, halo, hydroxyl, amino, alkyl and heteroalkyl; R15 is selected from H, halo, hydroxyl or amino; L1 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L2 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0266] A compound of Formula III can be selected from any of compounds III-1 to III-22 listed in Table 4c. In certain embodiments, a compound of Formula III is other than those with the structures listed in Table 4c. Table 4c: Exemplary compounds of Formula III Table 4h: IC50 values for Formula III inhibitors of menin Compounds of Formula IV

[0267] In still more embodiments, a compound has a structure of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; p is an integer from 0 to 9; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl ; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; provided that for B-II when Z1 is CR7 or N, Z2 is CR7 or N, Z6 is NR9, Z7 is CR8 and Z8 is CR8, then Z5 is N; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino , cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylamino arylalkylamino , where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring; and provided that the compound of Formula IV is not any of the compounds IV-27, IV-28, IV-29, IV-30, IV-31 and IV-32 listed in Table 4d.

[0268] In certain embodiments, the compound of Formula IV contains an H-III selected from one of H-II-2 to H-III-33 in Table 1c. In particular, H-III can be selected from H-III-2 and H-III-3. In certain embodiments, H-III of a compound of Formula IV is represented by Formula H-III-2: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0269] In certain embodiments, H-III of a compound of Formula IV is represented by Formula H-III-3: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl , amino, alkyl and heteroalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0270] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R1 of a compound of Formula IV can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl. In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R2 of a compound of Formula IV may be, at each occurrence, selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl, amino, alkyl and heteroalkyl. In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R15 of a compound of Formula IV can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino.

[0271] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L1 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L1 may be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl.

[0272] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, RA, in each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, p is from 0 to 3.

[0273] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L2 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In particular, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene and C1-C4 heteroalkylene.

[0274] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-19, B-II-21 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, provided that the compound of Formula IV is not any of compounds IV27, IV-28, IV-29, IV-30, IV-31 and IV-32 listed in Table 4d. In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I-2 to B-I-24, B-II-2 to B-II-19, B-II-21 to B-II-52, B-III-2 to B-III-13 and B-IV-2 to B-IV-27, provided that the compound of Formula IV is not any of compounds IV-27, IV-28, IV-29, IV-30, IV-31 and IV-32 listed in Table 4d. In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I, B- I-2 to B-I-24, B-II, B-II-2 to B-II-19, B-II-21 to B-II-26, B-II-31 to B-II- 37, B-II-39 to B-II-51, B-III, B-III-2 to B-III-12, B-IV and B-IV-2 to B-IV-27, provided that B does not be a B ring of structure selected from the group consisting of structures B-II-20, B-II-27, B-II-28, B- II-29, B-II-30, B-II-38, B- II-52 and B-III-13. In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I-14 to B-I-24, B-II-21 to B-II-26, B-II-31 to B-II-37, B-II-39 to B-II-51, B-III-10, B-III-12, B-IV-20 and B-IV-22 to B-IV-27. In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be B-I. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected on a ring heteroatom to L2, such as a ring atom of N. In certain embodiments, B is connected on a ring carbon to L2, such as a ring carbon on an aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0275] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R2 , R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl , hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0276] In some cases, when H-III of Formula IV is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R4 , R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, as of H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0277] In particular embodiments, H-III of Formula IV is selected from H-III-2 and H-III-3; R1 is selected from alkyl and haloalkyl; R2, when present, is selected from H, halo, hydroxyl, amino, alkyl and heteroalkyl; R15 is selected from H, halo, hydroxyl or amino; L1 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L2 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-19, B-II-21 to B-II-52, B-III, B-III -2 to B-III-13, B-IV and B-IV-2 to B-IV-27, provided that the compound of Formula IV is not any of compounds IV27, IV-28, IV-29, IV- 30, IV-31 and IV-32 listed in Table 4d.

[0278] In some cases, H-III is selected from Table 1c. A compound of Formula IV can be selected from any of the compounds IV-1 to IV-26 and IV-33 to IV-34 listed in Table 4d. In certain embodiments, a compound of Formula IV is other than those with the structures listed in Table 4d. In certain embodiments, a compound of Formula IV is not any of the compounds IV-27 to IV-32 listed in Table 4d. Table 4d: Exemplary compounds of Formula IV Table 4i: IC50 values for Formula IV menin inhibitors Formula V Compounds

[0279] In other embodiments, a compound has a structure of Formula V: or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; L3 is a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; L2 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a saturated 3-7 membered ring or an unsaturated 3-7 membered ring, provided that when L3 is -NR5-, A is not a piperidine ring which is connected at the carbon at position 4 of the piperidine ring a L3 (where the N of the piperidine ring is in position 1) and connected at the N atom of the piperidine ring to L2; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkyl-amino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroaryl-amino and heteroarylalkylamino, where two RA groups or two RB groups attached to the same or different atoms may together optionally form a bridge or a ring.

[0280] In certain embodiments, the compound of Formula V contains an H-III selected from one of H-III-2 to H-III-33 in Table 1c. In particular, H-III can be selected from H-III-2 and H-III-3. In certain embodiments, H-III of a compound of Formula V is represented by Formula H-III-2: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0281] In certain embodiments, H-III of a compound of Formula V is represented by Formula H-III-3: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl , amino, alkyl and heteroalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0282] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R1 of a compound of Formula V can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl. In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R2 of a compound of Formula V may be, at each occurrence, selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl, amino, alkyl and heteroalkyl. In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R15 of a compound of Formula V can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino.

[0283] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L3 may be selected of a carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2- C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L3 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl. In some cases, L3 is not -NR5- or -NR6CH2-. In some cases, L3 may be selected from a carbonyl, O, S, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C2-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2- C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl.

[0284] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring A may be selected from a 3-6 membered ring, such as a 5-6 membered ring, such as a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, aryl 6-membered, 5-membered heteroaryl and 6-membered heteroaryl. In certain embodiments, A is a saturated 5- or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, A is selected from A-1 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92 and A-95 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17, A-41, A-44, A- 57 and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-8, A-11, A-12, A-15 to A-17, A-41, A-44, and A- 57. In certain embodiments, A is not selected from A-9, A-13 and A-78 to A-87, such as A-9. In certain embodiments, A contains 0, 1 or 2 N atoms in the ring. In certain embodiments, A contains 0, 1 or 2 ring N atoms and no other ring heteroatoms. In certain embodiments, A is connected on the same ring atom to L3 and L2. In certain embodiments, A is connected at different ring atoms to L3 and L2. In certain embodiments, A is connected at a ring heteroatom to L3 and/or L2. In certain embodiments, A is connected at a ring carbon to L3 and/or L2. In certain embodiments, RA, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, m is from 0 to 3.

[0285] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L2 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In particular, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene and C1-C4 heteroalkylene. In some cases, when L3 is -NR5- or -NR6CH2-, L2 is not a C1 alkylene. In some cases, when L3 is -NR5- or -NR6CH2-, L2 can be selected from a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C2 -C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In some cases, when L3 is -NR5- or -NR6CH2-, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C2-C4 alkylene and C1-C4 heteroalkylene.

[0286] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I, B-I-2 to B- I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected on a ring heteroatom to L2, such as a ring atom of N. In certain embodiments, B is connected on a ring carbon to L2, such as a ring carbon on an aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0287] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R2 , R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl , hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0288] In some cases, when H-III of Formula V is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R4 , R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, as of H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0289] In particular embodiments, H-III of Formula V is selected from H-III-2 and H-III-3; R1 is selected from alkyl and haloalkyl; R2, when present, is selected from H, halo, hydroxyl, amino, alkyl and heteroalkyl; R15 is selected from H, halo, hydroxyl or amino; L3 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L2 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0290] A compound of Formula V can be selected from any of compounds V-1 to V-26 listed in Table 4e. In certain embodiments, a compound of Formula V is other than those with the structures listed in Table 4e. Table 4e: Exemplary compounds of Formula V Table 4j: IC50 Values for Menin Inhibitors of Formula V Compounds of Formula VI

[0291] In still other embodiments, a compound has a structure of Formula VI: or a pharmaceutically acceptable salt thereof, characterized by the fact: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; L1 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; L4 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl, provided that L4 is not a C1 alkylene; A is a bond, a saturated 3-7 membered ring or an unsaturated 3-7 membered ring, provided that when L1 is -NR5-, A is not a piperidine ring which is connected at the carbon at position 4 of the piperidine ring a L1 (where the N of the piperidine ring is in position 1) and connected at the N atom of the piperidine ring to L4; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L4; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; 1 2 3 4 5 6 7 8 9 10 11 12 13 15 each of R, R, R, R, R, R, R, R, R, R, R, R, R and R is, in each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino , heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino , cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylamino arylalkylamino , where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring; and provided that the compound of Formula VI is not the compound VI-43 listed in Table 4f.

[0292] In certain embodiments, the compound of Formula VI contains an H-III selected from one of H-III-2 to H-III-33 in Table 1c. In particular, H-III can be selected from H-III-2 and H-III-3. In certain embodiments, H-III of a compound of Formula VI is represented by Formula H-III-2: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0293] In certain embodiments, H-III of a compound of Formula VI is represented by Formula H-III-3: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl , amino, alkyl and heteroalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0294] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R1 of a compound of Formula VI can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl. In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R2 of a compound of Formula VI may be, at each occurrence, selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl, amino, alkyl and heteroalkyl. In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R15 of a compound of Formula VI can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino.

[0295] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L1 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L1 may be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl. In some cases, L1 is a link. In some cases, L1 is not -NR5-. In some cases when L1 is -NR5-, A is not a piperidine ring which is connected at the carbon at position 4 of the piperidine ring to L1 (where the N of the piperidine ring is at position 1) and connected at the N atom of the piperidine ring to L4.

[0296] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring A may be selected from a 3-6 membered ring, such as a 5-6 membered ring, such as a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, aryl 6-membered, 5-membered heteroaryl and 6-membered heteroaryl. In certain embodiments, A is a saturated 5- or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, A is selected from A-1 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92 and A-95 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17, A-41, A-44, A- 57 and A-78 to A-87, as well as from A-1 to A-4, A-6, A-15, A-16, A-41, A-44 and A-57. In some cases, A is A-7, A-8, A-9, or A-10. In some cases, A is not A-17. In some cases, A is not A-17, where A-17 is connected on one ring atom from N to L1 and on the other ring atom from N to L4. In some cases, A is not selected from A-7 to A-9, A-11 to A-13, A-17, and A-78 to A-87. In certain embodiments, A is a saturated heterocyclic ring with 1 N atom in the ring. In certain embodiments, A contains 0, 1 or 2 N atoms in the ring. In certain embodiments, A contains 0, 1 or 2 ring N atoms and no other ring heteroatoms. In certain embodiments, A is connected on the same ring atom to L1 and L4. In certain embodiments, A is connected at different ring atoms to L1 and L4. In certain embodiments, A is connected at a ring heteroatom to L1 and/or L4. In certain embodiments, A is connected at a ring carbon to L1 and/or L4. In certain embodiments, when L1 is a bond, L4 is -NR5-, R5 is H and m is 0, A is not a piperidine ring which is connected at the carbon at position 4 of the piperidine ring to L4 (where the N of the piperidine ring is in position 1) and connected to the N atom of the piperidine ring to H-III. In certain embodiments, RA, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, m is from 0 to 3.

[0297] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L4 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C2-C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C2-C4 alkylene. In particular, L4 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C2-C4 alkylene and C2-C4 heteroalkylene. In some cases, L4 is O, S, -NR5-, -NR6CH2-, -NR6C(=O)- or -NR6SO2-. In some cases, L4 is -NR6CH2-, -NR6C(=O)- or -NR6SO2-. In some cases, L4 includes an N atom. In some cases, L4 is not , where q is 0 or 1; Q is NH, N(alkyl), O or a bond; Q' is NH, N(alkyl) or CH2; and Q' is connected to B.

[0298] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B -IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected on a ring heteroatom to L4, such as a ring atom of N. In certain embodiments, B is connected on a ring carbon to L4, such as a ring carbon on an aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0299] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R2 , R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl , hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0300] In some cases, when H-III of Formula VI is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R4 , R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, as of H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0301] In particular embodiments, H-III of Formula VI is selected from H-III-2 and H-III-3; R1 is selected from alkyl and haloalkyl; R2, when present, is selected from H, halo, hydroxyl, amino, alkyl and heteroalkyl; R15 is selected from H, halo, hydroxyl or amino; L1 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L4 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C2-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0302] A compound of Formula VI can be selected from any of compounds VI-1 to VI-42 listed in Table 4f. In certain embodiments, a compound of Formula VI is other than those with the structures listed in Table 4f. In certain embodiments, a compound of Formula VI is not a compound VI-43 or VI-44 listed in Table 4f. Table 4f: Exemplary compounds of Formula VI Compounds of Formula IX

[0303] In certain embodiments, a compound has a structure of Formula IX: or a pharmaceutically acceptable salt thereof, wherein: X2 is independently CR2 or N; each of X5 and X6 is independently CR3, N, NR4, O or S; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; L1 is a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to –C(R16R16a)–; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R15 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, oxide dialkylphosphine, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl , aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; each of R16 and R16a is independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; or R16 and R16a together with the carbon atom to which they are attached, unite to form an optionally substituted C3-10 carbocycle or an optionally substituted 3-10 membered heterocycle; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylamino arylalkylamino, where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring; provided that when one of X5 and X6 is CR3, the other of X5 or of the piperidine ring to -CR16R16a-, B is B-II, Z1 and Z2 are CR7, Z5 is C, Z6 is N and Z7 and Z8 are CR8, Z6 is not substituted with an RB comprising a functional group that reacts in a covalent with one or more of the menin residues.

[0304] In certain embodiments, the compound of Formula IX contains an H-III selected from one of H-III-2 to H-III-33 in Table 1c. In particular, H-III can be selected from H-III-2 and H-III-3. In certain embodiments, H-III of a compound of Formula IX is represented by Formula H-III-2: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0305] In certain embodiments, H-III of a compound of Formula IX is represented by Formula H-III-3: where R1 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl; R15 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino; R2 is selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl , amino, alkyl and heteroalkyl; and each of X5 and X6 is independently selected from CR3, N, NR4, O and S. In certain embodiments, at most one of X5 and X6 is O or S.

[0306] In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R1 of a compound of Formula IX can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl and haloalkyl, such as from alkyl and haloalkyl. In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R2 of a compound of Formula IX may be, at each occurrence, selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl, amino, alkyl and heteroalkyl. In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, R15 of a compound of Formula IX can be selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as from H, halo, hydroxyl and amino.

[0307] In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, L1 may be selected of a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene, C1C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2- C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L1 may be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl.

[0308] In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring A may be selected from a 3-6 membered ring, such as a 5-6 membered ring, such as a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 6-membered aryl members, 5-membered heteroaryl and 6-membered heteroaryl. In certain embodiments, A is a saturated 5- or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, A is selected from A-1 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92 and A-95 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17, A-41, A-44, A- 57 and A-78 to A-87. In certain embodiments, A contains 0, 1 or 2 N atoms in the ring. In certain embodiments, A contains 0, 1 or 2 ring N atoms and no other ring heteroatoms. In certain embodiments, A is connected on the same ring atom to L1 and -C(R16R16a)- In certain embodiments, A is connected on different ring atoms to L1 and -C(R16R16a)- In certain embodiments, A is connected to a ring heteroatom to L1 and/or -C(R16R16a)- In certain embodiments, A is connected at a ring carbon to L1 and/or -C(R16R16a)- In certain embodiments, RA, in each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, m is from 0 to 3.

[0309] In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, Ring B may be selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B -IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0310] In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R2 , R3, R7, R8, R10, R11 and R12 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl , hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroaryl ylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, starch, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0311] In some cases, when H-III of Formula IX is selected from one of H-III-2 to H-III-33, such as from H-III-2 and H-III-3, each of R4 , R5, R6, R9 and R13 is, at each occurrence, independently selected from H, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, as of H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0312] In particular embodiments, H-III of Formula IX is selected from H-III-2 and H-III-3; R1 is selected from alkyl and haloalkyl; R2, when present, is selected from H, halo, hydroxyl, amino, alkyl and heteroalkyl; R15 is selected from H, halo, hydroxyl or amino; L1 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B- III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0313] In certain embodiments, a compound of Formula IX has a structure of Formula IX-A:

[0314] In certain embodiments, a compound of Formula IX or IX-A does not comprise a functional group that reacts covalently with one or more of the menin residues. Formula X Compounds

[0315] In certain embodiments, a compound has a structure of Formula X: or a pharmaceutically acceptable salt thereof, wherein: HX is selected from each of X1, X2 and X7 is independently CR2 or N; each of X3 and X4 is independently C or N; each of X5 and X6 is independently CR3, N, NR4, O or S; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of X5 and X6 is independently CR3, N, NR4, O or S; each of L1 and L2 is independently a bond, carbonyl, O, S, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl or heteroalkylenecarbonyl; A is a bond, a 3-7 membered saturated ring or a 3-7 membered unsaturated ring; m is an integer from 0 to 12; B is selected from BI, B-II, B-III and B-IV; where B is connected on any ring atom to L2; each of Z1, Z2, Z3 and Z4 is independently CR7, N or NR9; Z5 is C or N; each of Z6, Z7 and Z8 is independently CR8, N, NR9, O or S; each of Z9, Z10 and Z11 is independently CR10, CR11R12, NR13, O or S; n is an integer from 0 to 6; each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide , oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl , aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino; and each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylamino arylalkylamino, where two RA groups or two RB groups bonded to the same or different atoms may together optionally form a bridge or a ring.

[0316] In certain embodiments, the compound of Formula X contains an H-X selected from one of H-X-1 to H-X-91 in Table 1d. In certain embodiments, H-X can be selected from H-X-1 and H-X-4 to H-X-31. In certain embodiments, H-X can be selected from H-X-2 and H-X-32 to H-X-62. In certain embodiments, H-X can be selected from H-X-3 and H-X-63 to H-X-91.

[0317] In some cases, R1 of a compound of Formula of alkyl and haloalkyl. In some cases, R2 of a compound of Formula aminoalkyl, hydroxyalkyl, alkoxy and alkylamino, such as H, halo, hydroxyl and amino.

[0318] In some cases, for a compound of Formula C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl. In particular, L1 may be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene, such as -NR5- where R5 is selected from hydrogen and alkyl.

[0319] In some cases, for a compound of Formula 6-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 6-membered aryl, 5-membered heteroaryl and 6-membered heteroaryl. In certain embodiments, A is a saturated 5- or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, A is selected from A-1 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A- 92 and A-95 to A-101. In certain embodiments, A is selected from A-1 to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A is selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17, A-41, A-44, A- 57 and A-78 to A-87. In certain embodiments, A contains 0, 1 or 2 N atoms in the ring. In certain embodiments, A contains 0, 1 or 2 ring N atoms and no other ring heteroatoms. In certain embodiments, A is connected on the same ring atom to L1 and L2. In certain embodiments, A is connected at different ring atoms to L1 and L2. In certain embodiments, A is connected at a ring heteroatom to L1 and/or L2. In certain embodiments, A is connected at a ring carbon to L1 and/or L2. In certain embodiments, RA, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RA groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, m is from 0 to 3.

[0320] In some cases, for a compound of Formula C4 alkylene, C2-C4 alkenylene, C1-C4 heteroalkylene, C1-C4 alkylenecarbonyl, C2-C4 alkenylenecarbonyl and C1-C4 heteroalkylenecarbonyl, such as C1-C4 alkylene. In particular, L2 can be selected from a carbonyl, O, -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene and C1-C4 heteroalkylene.

[0321] In some cases, for a compound of Formula , B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring heteroatoms, such as O and N ring atoms. In certain embodiments, B contains 0, 1, 2, 3 or 4 N atoms in the ring. In certain embodiments, B contains 0, 1, 2, 3 or 4 ring N atoms and no other ring heteroatoms. In certain embodiments, B is connected on a ring heteroatom to L2, such as a ring atom of N. In certain embodiments, B is connected on a ring carbon to L2, such as a ring carbon on the aromatic ring. In certain embodiments, RB, at each occurrence, may be selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl and heteroarylalkyl. In certain embodiments, two RB groups bonded to the same or different atoms may optionally form a bridge or ring. In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to 2.

[0322] In some cases, for a compound of Formula dialkylphosphine, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aralkyl, aryloxy, aralkyloxy , arylamino, aralkylamino, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino and heteroarylalkylamino, such as H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino, aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy and heteroarylalkylamino.

[0323] In some cases, for a compound of Formula , cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, such as H, acyl, alkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroarylalkyl.

[0324] In particular embodiments, R1 is selected from alkyl and haloalkyl; L1 is selected from O, -NR5-, -NR6CH2-, -NR6C(=O)- and -NR6SO2-, as well as from O and -NR5-; A is selected from a 5- or 6-membered ring, such as from a cycloalkyl and heterocyclic ring; L2 is selected from -NR5-, -NR6CH2-, -NR6C(=O)-, -NR6SO2-, C1-C4 alkylene, C2-C4 alkenylene and C1-C4 heteroalkylene; and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV and B-IV-2 to B-IV-27, such as indole, benzimidazole, benzoxazole and imidazopyridine.

[0325] In certain embodiments of a compound of Formula X, HX is

[0326] In certain embodiments of a compound of Formula X, HX is

[0327] In certain embodiments of a compound of Formula X, HX is

[0328] In certain embodiments of a compound of Formula

[0329] In certain embodiments of a compound of Formula X, R2 in X1 is amino.

[0330] In certain embodiments of a compound of Formula X1 is methyl.

[0331] In certain embodiments of a compound of Formula X, X6 is CR3 and R3 in X6 is selected from H, halo, amino, carboxyl and alkyl. It is selected from F, amino, carboxyl and methyl.

[0332] In certain embodiments, a compound of Formula X has a structure of Formula XA:

[0333] In certain embodiments, a compound of Formula X has the structure of Formula XB:

[0334] In certain embodiments, a compound of Formula X has the structure of Formula XC:

[0335] Compounds of Formulas I, II, III, IV, V, VI, IX and X

[0336] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, the compound comprises an RB selected from: where: G is selected from a bond, alkylene, heteroalkylene, C3-12 carbocycle, 3- to 12-membered heterocycle and combinations thereof, where G is optionally substituted with one or more R32 groups; V is absent or selected from a C3-12 carbocycle and 3- to 12-membered heterocycle; where V is optionally substituted with one or more R32 groups; each of R21 and R32 is, at each occurrence, independently selected from: H, halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20, -C(O)R20 , -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, - S(O)2N(R20)2, -N(R20)S (O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(0)(R20)2, -OP(O)(OR20)2 and -CN; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 3- to 10-membered carbocycle and heterocycle; where two R32 on the same carbon atom can join together to form a 3- to 10-membered C3-10 carbocycle or heterocycle; wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R32 is independently optionally substituted with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N(R20)C(O) R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S(O)2N(R20) 2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP (O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; R20 in each occurrence is independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR30, -SR30, -N(R30)2, -N (R30)C(O)R30, -C(O)R30, -C(O)OR30, -C(O)N(R30)2, -OC(O)R30, -S(O)2R30, -S (O)2N(R30)2, -N(R30)S(O)2R30, -NO2, -P(O)(OR30)2, -P(O)(R30)2, -OP(O)(OR30 )2 and -CN; and 3 to 10 membered heterocycle and C3-10 carbocycle; and R30 in each occurrence is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0337] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R21 is a radical with from 5 to 50 atoms, such as a radical with 5 to 40 atoms.

[0338] In some embodiments, V is selected from a 3-8 membered saturated ring, 3-8 membered unsaturated ring, 4-10 membered fused bicyclic ring and 5-11 membered spiro bicyclic ring. V may be optionally substituted with one or more R32 groups, such as 1, 2, 3, 4 or 5 R32 groups. In some embodiments, V is a 3-7 membered saturated ring, such as a 3-7 membered cycloalkyl or 3-7 membered aromatic or non-aromatic heterocycle. In some embodiments, V is a 3-7 membered unsaturated ring, such as a 6-membered aryl, 5-6 membered heteroaryl or 3-7 membered cycloalkenyl.

[0339] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from a saturated 3-8 membered ring optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and one of which is optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from: is optionally substituted with one or more R32 groups.

[0340] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is a saturated heterocycle of 4, 5, 6, 7 or 8 members, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from azetidine, oxetane, piperidine, oxane, piperazine, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, morpholine, thiomorpholine, azepane and homopiperazine, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from: any of which is optionally replaced with a

[0341] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is a bicyclic heterocycle, optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or salts any of which is optionally substituted with one or more R32 groups.

[0342] In certain embodiments, V is a 4-10 membered fused bicyclic ring, such as an 8-10 membered fused bicyclic ring. In certain embodiments, the fused bicyclic ring includes one or more heteroatoms such as one or more atoms selected from N, O and S. In certain embodiments, the fused bicyclic ring includes two heteroatoms such as two nitrogen atoms. Each of the rings of the fused bicyclic ring can be saturated or unsaturated. In particular embodiments, both rings of the fused bicyclic ring are saturated. Non-limiting examples of V comprising a fused bicyclic ring include

[0343] In some embodiments, V is a 5-11 membered spiro bicyclic ring, such as a 7-11 membered spiro bicyclic ring. In certain embodiments, the fused bicyclic ring includes one or more heteroatoms such as one or more atoms selected from N, O and S. In particular embodiments, the fused bicyclic ring includes two heteroatoms such as two nitrogen atoms. Non-limiting examples of V comprising a spiro bicyclic ring include

[0344] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from an unsaturated aromatic or heteroaromatic ring, any one of which is optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline, cinoline, phthalazine, furan, dihydrofuran, thiophene, dihydrothiophene, imidazole, imidazoline, oxazole, oxazoline, pyrrole, dihydropyrrole, thiazole, dihydrothiazole, pyrazole, dihydropyrazole, isoxazole, dihydroisoxazole, isothiazole, dihydroisothiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole and benzothiazole, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is phenyl, optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is a heteroaromatic ring optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from pyridine, pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline, cinoline, phthalazine, furan, thiophene, imidazole, oxazole, pyrrole, thiazole, pyrazole, isoxazole, isothiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole and benzothiazole, any of which is optionally substituted with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is selected from optionally substituted with one or more R32 groups.

[0345] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, V is absent.

[0346] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is a bond.

[0347] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is alkylene optionally substituted with one or more R32 groups.

[0348] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is selected from methylene, ethylene, propylene and butylene, any of which is optionally replaced with one or more R32 groups. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is selected from: , where any of which is optionally substituted with one or more R32 groups.

[0349] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is a heteroalkylene optionally substituted with one or more R32 groups.

[0350] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is a C3-10 carbocycle or 3 to 10 membered heterocycle, any of which is optionally substituted with one or more R32 groups.

[0351] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is a C3-10 saturated carbocycle or saturated heterocycle of 3 to 10 members, any of which is optionally substituted with one or more R32 groups.

[0352] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, G is selected from: , and , where any of which is optionally substituted with one or more R32 groups.

[0353] In some embodiments, the compound is selected from Table 4a, Table 4b, Table 4c, Table 4d, Table 4e or Table 4f. In some cases, the compound is not any of the compounds selected from IV-27 listed in Table 4d, IV-28 listed in Table 4d, IV-29 listed in Table 4d, IV-30 listed in Table 4d, IV-31 listed in Table 4d, IV-32 listed in Table 4d, VI-43 listed in Table 4f, and VI-44 listed in Table 4f.

[0354] In certain aspects, the compounds of the report covalently linked to menin inhibit the interaction of menin with MLL. Such binding can lead to an increase in the affinity of the compound for menin, which is an advantageous property in many applications, including therapeutic and diagnostic uses. In certain embodiments, the compounds of the report comprise electrophilic groups capable of interacting with a nucleophilic group present in a menin protein. Suitable electrophilic groups are described throughout the application, while suitable nucleophilic groups include, for example, cysteine radicals present in the binding domain of a menin protein. Without wishing to be bound by theory, a cysteine residue in the menin binding domain can react with the electrophilic group of a compound in the report, leading to the formation of a conjugated product. In certain embodiments, the compounds of the report are capable of covalently binding to the cysteine residue at position 329 of a menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO: 1 ). In certain embodiments, the report provides a conjugate of a compound of the report with a menin protein. For example, the report provides a conjugate of a compound of the invention with menin, linked to cysteine residue 329 of menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO: 1).

[0355] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, one or more of R1, R2, R3, R4 5 6 7 8 9 10 11 12 13 14 15 16 16a A B , R , R , R , R , R , R , R , R , R , R , R , R , R , R and R , when present, comprise a functional group that reacts covalently with one or more of the menin residues. In some embodiments of a compound provided herein, the functional group reacts covalently with one or more cysteine residues on menin. In some embodiments of a compound provided herein, the functional group reacts covalently with a cysteine in menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned. In certain embodiments, the functional group reacts covalently with one or more of the menin residues selected from cysteine 329, cysteine 241 and/or cysteine 230 in the menin relative to SEQ ID NO: 2 when optimally aligned. In certain embodiments, the functional group reacts covalently with cysteine 329 of SEQ ID NO: 2 when optimally aligned.

[0356] In certain embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, one or more of R1, R2, R3, R4, R5 6 7 8 9 10 11 12 13 14 15 16 16a A B , R , R , R , R , R , R , R , R , R , R , R , R , R and R , when present, comprise a radical that reacts in the form covalent with one or more of the residues of 1 2 3 4 5 6 7 8 9 10 menin. In particular embodiments, one or more of R, R, R, R, R, R, R, R, R, R, R11 12 13 14 15 16 16a A B, R, R, R, R, R, R, R and R, when present, comprise a radical that reacts covalently with any one or more of the menin isoforms, for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 ( SEQ ID12345678 NO: 3) of the girl. In certain embodiments, one or more of R, R, R, R, R, R, R, R, R9 10 11 12 13 14 15 16 16a AB, R, R, R, R, R, R, R, R , R and R , when present, comprise a radical that reacts covalently with menin, where the menin protein shares 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more or 99% or more sequence identity with isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3).

[0357] In certain embodiments, for a compound or salt of any of Formulas I, II1 2 3 4 5 6 7 8 9 10 11 12, III, IV, V, VI, IX and X, one or more of R, R, R, R, R, R, R, R, R, R, R, R, R13, R14, R15, R16, R16a, RA and RB, when present, comprise an electrophilic group that is susceptible to nucleophilic attack of a residue on the girl. Included in the present report are all electrophilic radicals that are known to one skilled in the art to bind to nucleophilic residues, for example, any electrophilic radical known to bind to cysteine residues. In certain embodiments, for a compound or salt of any of Formulas I, II, III, IV, V, VI, IX and X, one or more of R1, R2, R3 4 5 6 7 8 9 10 11 12 13 14 15 16 16a A B , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R and R , when present, comprise a radical other than an electrophile where the radical is capable of binding or reacting covalently with a residue in menin. In particular embodiments, for a compound or salt of any of Formulas I, II, III, IV, V, VI, IX and more than R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R and R, when present, comprise a radical that reacts in a covalent with one or more cysteine residues in menin, for example, one or more of cysteine 329, cysteine 241 and cysteine 230 relative to SEQ ID NO: 2 when optimally aligned. In certain 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 embodiments, one or more of R, R, R, R, R, R, R, R, R, R, R, R, R, R , R , R16, R16a, RA and RB, when present, comprise a radical that reacts covalently with cysteine 329 in menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO: 1). In certain embodiments, a compound or salt of any of Formulas I, II, III, IV, V, VI, IX and X, is capable of (a) covalently binding to menin and (b) inhibiting the interaction of menin and MLL.

[0358] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, the compound is capable of (a) covalently binding to menin and (b) inhibit the interaction of menin and MLL.

[0359] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R21 comprises a functional group that reacts covalently with one or more of the girl's waste. In some embodiments of a compound provided herein, the functional group reacts covalently with one or more cysteine residues in menin. In some embodiments of a compound provided herein, the functional group reacts covalently with a cysteine in menin at position 329 relative to SEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ ID NO: 1 when optimally aligned.

[0360] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R21 is a radical comprising an alpha, beta unsaturated carbonyl; an alpha, beta unsaturated sulfonyl; an epoxide; an aldehyde; sulfonyl fluoride; a halomethylcarbonyl; a dihalomethylcarbonyl or a trihalomethylcarbonyl.

[0361] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R21 is selected from: where: L5 is selected from a link; and C1-6 alkylene, C1-6 heteroalkylene, C26 alkenylene and C2-6 alkynylene, each of which is independently optionally substituted with one or more R32 groups; R22 and R23 are selected from hydrogen, halogen, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C (O)N(R20)2, -OC(O)R20, -S(O)2R20, - S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O , =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2 and -CN; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, - C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 carbocycle and 3-10 membered heterocycle, wherein each C3-10 carbocycle and 3-10 membered heterocycle of R22 and R23 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, - N(R20)2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, - S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20 )2, -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; or R22 and R23, together with the carbon atoms to which they are attached, form a carbocyclic ring; R24 is selected from: hydrogen, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20 and -S(O )2N(R20)2; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 carbocycle and 3-10 membered heterocycle, wherein each C3-10 carbocycle and 3-10 membered heterocycle of R24 is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N( R20)2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S( O)2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2 , -P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0362] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, L5 is a bond. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, L5 is optionally substituted C1-6 alkylene. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, L5 is selected from methylene, ethylene or propylene. In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, L5 is substituted with one or more substituents selected from halogen, -NO2, =O, =S, -OR20, -SR20 and -N(R20)2.

[0363] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R23 is selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, - N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 3- to 10-membered carbocycle and heterocycle, wherein each C3-10 3- to 10-membered carbocycle and heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20) 2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O) 2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0364] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R23 is selected from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20)2, =O, =S, =N(R20) and -CN; and 3- to 10-membered heterocycle optionally substituted with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N(R20)C(O)R20, -C(O)R20, - C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S(O)2N(R20)2, -N(R20)S(O )2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, -P(O)(R20)2, -OP(O)(OR20)2, -CN , C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0365] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R23 is selected from hydrogen and C1-6 alkyl optionally substituted with one or plus selected halogen substituents, -OR20, -SR20, -N(R20)2, =O, =S, =N(R20) and -CN.

[0366] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R22 is selected from: hydrogen and -CN; C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more selected halogen substituents, -OR20, -SR20, -N(R20)2, -N (R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O)2R20, -S (O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O) (R20)2, -OP(O)(OR20)2, -CN, C3-10 3- to 10-membered carbocycle and heterocycle; and C3-10 3- to 10-membered carbocycle and heterocycle, wherein each C3-10 3- to 10-membered carbocycle and heterocycle is independently optionally substituted with one or more substituents selected from halogen, -OR20, -SR20, -N(R20) 2, -N(R20)C(O)R20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -OC(O)R20, -S(O) 2R20, -S(O)2N(R20)2, -N(R20)S(O)2R20, -NO2, =O, =S, =N(R20), -P(O)(OR20)2, - P(O)(R20)2, -OP(O)(OR20)2, -CN, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0367] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R22 is selected from hydrogen; -CN; and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, -OR20, -SR20 and -N(R20)2.

[0368] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R22 and R23, together with the carbon atoms to which they are attached , form a 5-, 6- or 7-membered carbocyclic ring.

[0369] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R24 is selected from hydrogen and C1-6 alkyl optionally substituted with one or plus selected halogen substituents, -OR20, -SR20, -N(R20)2, -NO2, =O and -CN.

[0370] In some embodiments of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, R21 is selected from: Pharmaceutical Compositions

[0371] The compositions and methods of the present invention can be used 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 of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0372] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still further embodiments, the pharmaceutical compositions comprise a compound as described herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0373] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, optical, nasal and topical administration. In addition, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injection.

[0374] In certain embodiments, a composition of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is administered locally rather than systemically, e.g. by injecting the compound directly into an organ, often in a depot preparation or sustained-release formulation. In specific embodiments, long-acting formulations are administered by implant (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is administered in a targeted drug delivery system, e.g., in a liposome coated with an antibody specific to the organ. In such embodiments, liposomes are selectively oriented and absorbed by the organ. In still other embodiments, the composition is provided in the form of a rapid release formulation, in the form of an extended release formulation or in the form of an intermediate release formulation. In still other embodiments, the composition is administered topically.

[0375] The compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof can 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 can be used in some realizations. The exact dosage will depend on the route of administration, the form in which the compound is administered, the individual being treated, the body weight of the individual being treated and the preference and experience of the attending physician.

[0376] In some embodiments, a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is administered in a single dose. Typically, such administration will be by injection, for example, intravenous injection, in order to introduce the agent quickly. However, other routes are used as appropriate. In some embodiments, a single dose of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is used for treating an acute condition.

[0377] In some embodiments, a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is administered in multiple doses. In some embodiments, the dosage is about once, twice, three times, four times, five times, six times or more than six times a day. In other embodiments, the dosage is about a month, once every two weeks, once a week, every other day. In another embodiment, a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof and another agent are administered together about once daily at about 6 times a day. In another embodiment, administration of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof and an agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6 days, more than about 10 days, more than about 14 days, more than about 28 days, more than about two months, more than about six months or a year or more. In some cases, a continuous dosage is obtained and maintained as long as necessary.

[0378] Administration of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof can continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, more than 2, more than 3, more than 4, more than 5, more than 6, more than 7, more than 14 or more than 28 days. In some embodiments, a compound of the invention is administered for 28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less or 1 day or a part thereof. In some embodiments, a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is administered in a chronic or continuous form, for example, for the treatment of chronic effects.

[0379] In some embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are administered in dosages. It is known in the art that due to variability between individuals in the pharmacokinetics of the compound, individualization of the dosage regimen is necessary to optimize therapy. The dosage for a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof can be found by routine experimentation in light of the present report.

[0380] In some embodiments, compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds into preparations that can be used pharmaceutically. An appropriate formulation is dependent on the chosen route of administration. Any pharmaceutically acceptable techniques, vehicles and excipients are used as appropriate to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, 19th 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, 17th Ed. (Lippincott Williams & Wilkins1999).

[0381] Provided herein are pharmaceutical compositions comprising a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof and diluent(s), excipient(s) or carrier(s). ) pharmaceutically acceptable(s). In certain embodiments, the described compounds or salts are administered as pharmaceutical compositions in which a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is mixed with other active ingredients, as in combination therapy. Included here are all active combinations presented in the combination therapies section below and throughout this report. In specific embodiments, the pharmaceutical compositions include one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof.

[0382] A pharmaceutical composition, as used herein, refers to a mixture of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof with other chemical components, such as carriers, diluent stabilizers, dispersing agents, suspending agents, thickening agents and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, in practice of the methods of treatment or use provided herein, therapeutically effective amounts of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the individual, the potency of the compound used and other factors. The compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are used individually or in combination with one or more therapeutic agents as components of the mixtures.

[0383] In one embodiment, one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution or physiological saline buffer. In other embodiments, one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrating agents that are appropriate to the barrier to be penetrated. In still other embodiments in which the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.

[0384] In another embodiment, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for oral administration. The compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated by combining the active compounds with, for example, pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated into oral dosage forms including, by way of example only, tablets, powders, pills. , tablets, capsules, liquids, gels, syrups, elixirs, pastes, suspensions and the like.

[0385] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, optionally grinding the resulting mixture and processing the mixture into granules, after addition of suitable auxiliaries, if desired, to obtain tablet or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0386] In one embodiment, dosage forms, such as tablet cores and tablets, are provided with one or more suitable coatings. In specific embodiments, concentrated sugar solutions are used to coat the dosage form. Sugar solutions, optionally containing additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes and/or pigments are also optionally added to the coatings for identification purposes. Additionally, dyes and/or pigments are optionally used to characterize different combinations of doses of the active compound.

[0387] In certain embodiments, therapeutically effective amounts of at least one of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated in other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, the “push-fit” capsules contain the active ingredients in admixture with one or more fillers. Fillers include, by way of example only, lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds that are dissolved or suspended without a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0388] In other embodiments, therapeutically effective amounts of at least one of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, tablets or gels. In still other embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, injection formulations are presented in unit dosage form (e.g., in ampoules) or in multiple dose containers. Preservatives are optionally added to injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as suspensions, sterile solutions or emulsions in oily or aqueous vehicles. Formulations for parenteral injection optionally contain formulating agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In further embodiments, suspensions of compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are prepared as oily suspensions suitable for injection. Suitable lipophilic solvents or carriers for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds to enable the preparation of highly concentrated solutions. In certain embodiments, the active agent is in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0389] In still other embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are administered topically. The compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof can be formulated into a variety of compositions to be administered topically, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizing agents, stabilizers, tonicity-enhancing agents, buffers and preservatives.

[0390] In still other embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for transdermal administration. Transdermal formulations may employ transdermal application devices and transdermal application patches and may be lipophilic or buffered emulsions, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are made for continuous, pulsed or on-demand release of pharmaceutical agents. In further embodiments, transdermal application of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled release of the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof. In specific embodiments, the rate of absorption is reduced by the use of rate-controlling membranes or by entrapment of the compound within a polymeric matrix or gel. In alternative embodiments, absorption amplifiers are used to increase absorption. Absorption enhancers or vehicles include absorbable pharmaceutically acceptable solvents that aid passage through the skin. For example, in one embodiment, the transdermal devices are in the form of a bandage comprising a supporting member, a reservoir containing the compound of any of Formulas I, II, III, IV, V, VI, IX and Acceptable thereof optionally with carriers, optionally a rate controlling barrier for releasing the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and means for securing the device to the skin.

[0391] In other embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are conveniently administered in the form of an aerosol spray from pressurized packets or a nebulizer, with the use of a suitable propellant (e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to release a metered amount. In certain embodiments, capsules and cartridges, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a mixture of powders of the compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof and a suitable powder base such as lactose or starch.

[0392] In still other embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG and the like. In suppository forms of the compositions, a low melting point wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

[0393] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds into preparations that can be used pharmaceutically. An appropriate formulation is dependent on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers and excipients may optionally be used as appropriate. Pharmaceutical compositions comprising a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are manufactured in a conventional manner, such as, by way of example only, by means of mixing, dissolving, granulating, obtaining tablets, spraying, emulsification, encapsulation, entrapment or conventional compression.

[0394] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, sometimes called active agent or ingredient here. The active ingredient may be in the form of a free acid or free base or in a pharmaceutically acceptable salt form. Additionally, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof may be in unsolvated forms or solvated with pharmaceutically acceptable solvents such as water and ethanol. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts for regulating osmotic pressure, buffers and/or other therapeutically valuable substances.

[0395] Methods for preparing compositions comprising the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof include formulating the compounds with one or more inert excipients or carriers pharmaceutically acceptable forms to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, lozenges and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound or a solution containing liposomes, micelles or nanoparticles comprising a compound of any of Formulas I, II, III, IV, V, VI, IX and X or salts pharmaceutically acceptable of these. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid before use or as emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so on.

[0396] In some embodiments, the pharmaceutical composition comprising at least one compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof illustratively takes the form of a liquid wherein the agents are present in solution, suspension or both. Typically 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, suspended in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0397] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. The polymers include water-soluble polymers such as cellulosic polymers, for example, hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[0398] Pharmaceutical compositions also optionally include solubilizing agents to assist in the solubility of a compound described herein. The term “solubilizing agent” generally includes agents that result in the formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, such as glycols, ophthalmically acceptable polyglycols, for example polyethylene glycol 400 and glycol ethers.

[0399] The pharmaceutical compositions optionally include one or more pH-adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and trishydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain the pH of the composition in an acceptable range.

[0400] Additionally, useful compositions also optionally include one or more salts in an amount required to impart osmolarity to the composition in an acceptable range. Such salts include those containing sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0401] The pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0402] Pharmaceutical compositions may include one or more surfactants to increase physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene hydrogenated castor oil (60); and polyoxyethylene alkyl ethers and alkyl phenyl ethers, for example, octoxynol 10, octoxynol 40.

[0403] Pharmaceutical compositions may include one or more antioxidants to increase chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfide.

[0404] In certain embodiments, aqueous suspension compositions are packaged in single-dose, non-resealable containers. Alternatively, multi-dose resealable containers are used, in which case it is typical to include a preservative in the composition.

[0405] In certain embodiments, delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful here. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In further embodiments, the compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof are applied using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers. containing the therapeutic agent. Various sustained release materials can be used here. In some embodiments, sustained-release capsules release the compounds for anywhere from a few weeks to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies are employed to stabilize the protein.

[0406] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol-containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v glycerol, (b) about 0.1% to about 1% w/v v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about of 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. of polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc or (n ) combinations of these.

[0407] In some embodiments, the concentration of the one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof provided in the pharmaceutical compositions 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, p/v or v/v.

[0408] In some embodiments, the concentration of the one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof provided in a 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.

[0409] In some embodiments, the concentration of the one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof 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/ p, p/v or v/v.

[0410] In some embodiments, the concentration of the one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof 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 0.9% w/w, w/v or v/v. approximately 0.1% to

[0411] In some embodiments, the amount of the one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof is equal to or less than about: 10 g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 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 0.0001 g.

[0412] In some embodiments, the amount of the one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof 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.

[0413] In some embodiments, the amount of the one or more compounds of the invention 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.

[0414] Manufacturing Kits/Items

[0415] For use in the therapeutic applications described here, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a vehicle, package or container that is compartmentalized to receive one or more containers such as vials, tubes and the like, each of the containers comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes and test tubes. Containers are formed from a variety of materials such as glass or plastic.

[0416] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found, for example, in US patent 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packaging, bottles, tubes, inhalers, pumps, pouches, vials, containers, syringes, bottles and any packaging material suitable for a selected formulation and mode of intended administration and treatment. For example, the container(s) includes one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof, optionally in a composition or in combination with another agent as described herein. The container(s) optionally contain a sterile access port (e.g., the container is an intravenous solution bag or a vial containing a stopper to be pierced by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions regarding its use in the methods described herein.

[0417] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user perspective for use of a compound described here. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; vehicle, packaging, container, bottle and/or tube labels listing contents and/or instructions for use and packaging leaflets with instructions for use. A set of instructions will typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers, or other characters forming the label are affixed, molded, or engraved on the container itself; a label is associated with a container when it is present on the inside of a receptacle or vehicle that also contains the container, for example as a supplement to the packaging. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates guidelines for using the contents, as in the methods described here. In certain embodiments, the pharmaceutical composition is presented in a package or dispensing device that contains one or more unit dosage forms containing a compound provided herein. The packaging, for example, contains a metal or plastic foil, such as a blister pack. Or, the packaging or dispensing device is accompanied by instructions for administration. Or, the package or dispensing device is accompanied with a notification associated with the container in the form prescribed by a governmental agency regulating the manufacture, use and sale of pharmaceutical products, which notification reflects the agency's approval of the form of the drug for human administration or veterinary. Such notification, for example, is the labeling approved by the U.S. Food and Drug Administration for prescribing drugs or the approved product leaflet. In some embodiments, compositions containing a compound provided herein are prepared, formulated in a compatible pharmaceutical carrier, placed in an appropriate container and labeled for treating an indicated condition. Methods

[0418] The present invention provides a method for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein or a Partial Tandem Duplication of MLL) comprising contacting a cell with an effective amount of one or more compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof. Inhibition of the interaction of menin and 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 wide variety of forms known in the art. Non-limiting examples include a demonstration of (a) a reduction in binding of menin to one or more proteins or protein fragments (e.g., MLL1, MLL2, an MLL fusion protein, an MLL Partial Tandem Duplication, or a fragment of these peptides); (b) a reduction in cell proliferation and/or cell viability; (c) an increase in cell differentiation; (d) a reduction in the levels of downstream targets of MLL1, MLL2, an MLL fusion protein and/or an MLL Partial Tandem Duplication (e.g., Hoxa9, DLX2 and Meis1) and/or (e) reduction in tumor volume and/or tumor volume growth rate. Commercially available kits and assays can be used to determine one or more of the above.

[0419] The invention also provides methods for using the compounds or pharmaceutical compositions of the present invention to treat diseased conditions, including, but not limited to, conditions implicated by menin, MLL, MLL1, MLL2 and/or MLL fusion proteins (e.g. cancer).

[0420] In some embodiments, a method for treating cancer is provided, the method comprising administering an effective amount of any of the above pharmaceutical compositions comprising a compound of any of Formulas I, II, III, IV, V , VI, IX and X or pharmaceutically acceptable salts thereof to an individual in need of such treatment. In some embodiments, 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.

[0421] In some embodiments, the invention provides a method for treating a disorder in an individual in need of such treatment, wherein the method comprises determining whether the individual has an MLL fusion protein and whether it is determined that the individual presents an MLL fusion protein, then administering to the subject a therapeutically effective dose of at least one compound of any of Formulas I, II, III, IV, V, VI, IX and X or a pharmaceutically acceptable salt, ester or its prodrug.

[0422] MLL fusion proteins have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow and/or lymph nodes). Likewise, certain embodiments are directed to administering a compound of any of Formulas I, II, III, IV, V, VI, IX and X to a patient in need of such treatment of a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently described compounds can be used for the treatment of 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 Hodgkins lymphoma or non-Hodgkins lymphoma.

[0423] Determining whether a tumor or cancer comprises an MLL fusion protein can be accomplished by evaluating the nucleotide sequence encoding the MLL fusion protein, by evaluating the amino acid sequence of the MLL fusion protein, or by evaluation of the characteristics of a putative MLL fusion protein.

[0424] Methods for detecting a nucleotide sequence for the MLL fusion protein are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays , real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification assays (MASA), direct sequencing, primer extension reactions, electrophoresis, oligonucleotide binding assays, hybridization assays, TaqMan assays, assays of SNP genotyping, high-resolution fusion assays and microarray analysis. In some embodiments, the MLL fusion protein is identified by using a direct method of sequencing specific regions (e.g., exon 2 and/or exon 3) in the MLL or fusion partner gene, for example. This technique will identify all possible mutations in the sequenced region.

[0425] Methods for detecting an MLL fusion protein are known to those skilled in the art. These methods include, but are not limited to, detection of an MLL fusion protein using a binding agent (e.g., an antibody) specific to the fusion protein, protein electrophoresis Western blotting, and direct peptide sequencing.

[0426] Methods for determining whether a tumor or cancer comprises an MLL fusion protein can utilize a variety of samples. In some embodiments, the sample is taken from an individual having a tumor or cancer. In some embodiments, the sample is taken from an individual having a cancer or tumor. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed for DNA or RNA.

[0427] The invention also relates to a method for treating a hyperproliferative disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or a pharmaceutically acceptable salt, ester or prodrug thereof. In some embodiments, the method relates to the treatment of cancers such as acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, cancer of the appendix, astrocytomas. , atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous cell lymphoma T, extrahepatic duct carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer , fibrous histiocytoma of bone, bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, cancer of the oral cavity and lips, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, oral cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, fungal mycosis, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, cell carcinoma Merkel's disease, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oral cavity cancer and lips, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, central nervous system (CNS) lymphoma, prostate cancer , rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T cell lymphoma , testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and urethra, trophoblastic tumor, unusual childhood cancers, cancer of the urethra, uterine sarcoma, vaginal cancer, vulvar cancer or cancer virus-induced. In some embodiments, the method relates to treating a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)). In some cases, the method relates to the treatment of leukemia, hematologic malignancy, solid tumor cancer, prostate cancer (e.g., castration-resistant prostate cancer), breast cancer, Ewing's sarcoma, bone sarcoma, primary bone disease, T-cell prolymphocytic leukemia, glioma, glioblastoma, liver cancer (e.g. hepatocellular carcinoma) or diabetes. In some cases, leukemia comprises AML, ALL, Mixed Lineage Leukemia or leukemias with Partial Tandem Duplications of MLL.

[0428] In certain particular embodiments, the invention relates to methods for treating lung cancers, the methods comprising administering an effective amount of any of the compounds described above (or a pharmaceutical composition comprising the same) to an individual requiring such treatment. In certain embodiments the lung cancer is a non-small cell lung carcinoma (NSCLC), for example, adenocarcinoma, squamous cell lung carcinoma or large cell lung carcinoma. In other embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers treatable with the described compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

[0429] Individuals who can be treated with the compounds of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, stereoisomer, isotopologue, hydrate or derivative of the compounds, in accordance with the methods of this invention include, for example , individuals who have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, cancer of the appendix, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor , primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, carcinoma of the extrahepatic ducts in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone , bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, cancer of the oral cavity and lips, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, squamous cell cancer metastatic with occult primary, midline tract carcinoma, oral cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, fungal mycoses, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, mesothelioma malignant, malignant bone fibrous histiocytoma and osteosarcoma, cancer of the nasal cavity and paranasal sinus, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, cancer of the oral cavity and lips, oropharyngeal cancer , ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, central nervous system (CNS) lymphoma, prostate cancer, rectal cancer , transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer , throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and urethra, trophoblastic tumor, unusual childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, virus-induced cancer , leukemia, hematologic malignancy, solid tumor cancer, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer or diabetes. In some embodiments subjects who are treated with the compounds of the invention include subjects who have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis or prostate (e.g., benign prostatic hypertrophy). (BPH)).

[0430] The invention further provides methods for modulating the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein or a Partial Tandem Duplication of MLL) by contacting the menin with a effective amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof. The modulation can be inhibitory or activating the activity of the menin protein, one or more of its binding partners and/or one or more of the downstream targets of menin or one or more of its binding partners. In some embodiments, the invention provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a Partial Tandem Duplication of MLL) by contacting the menin with an amount effectiveness of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof. In some embodiments, the invention provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a Partial Tandem Duplication of MLL) by contacting a cell, tissue or organ that expresses menin, MLL1, MLL2, an MLL fusion protein and/or a Partial Tandem Duplication of MLL. In some embodiments, the invention provides methods for inhibiting protein activity in a subject including, but not limited to, rodents and mammals (e.g., human) by administering an effective amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof to the individual. In some embodiments, the modulation percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0431] In some embodiments, the invention provides methods for inhibiting the interaction of 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 invention sufficient to inhibit the interaction of 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 invention provides methods for inhibiting the interaction of 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 contact of the tissue with an amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1 , MLL2, an MLL fusion protein or a Partial Tandem Duplication of MLL) in tissue. In some embodiments, the invention provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a Partial Tandem Duplication of MLL) in an organism by contact of the organism with an amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1 , MLL2, a fusion protein of MLL or a Partial Tandem Duplication of MLL) in the body. In some embodiments, the invention provides methods for inhibiting the interaction of 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 contact of the animal with an amount of a compound of the invention sufficient to inhibit the interaction of 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 invention provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a Partial Tandem Duplication of MLL) in a mammal by contact of the mammal with an amount of a compound of the invention sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein or an MLL Partial Tandem Duplication) in the mammal. In some embodiments, the invention provides methods for inhibiting the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a Partial Tandem Duplication of MLL) in a human by contact of the human with an amount of a compound of the invention sufficient to inhibit the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein or a Partial Tandem Duplication of MLL) in the human. The present invention provides methods for treating a disease mediated by the interaction of menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial Tandem Duplication) in an individual in need of such treatment.

[0432] The invention further provides methods for stabilizing menin, comprising contacting menin with a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof. In some embodiments, the contacting step comprises contacting the menin with an amount of the compound sufficient to stabilize the menin. In some embodiments, the contact step occurs in vivo. In some embodiments, the contact step occurs in vitro. In some embodiments, the contact step occurs in a cell.

[0433] The invention also provides methods for treating a disorder mediated by the interaction of menin with one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein or a Partial Tandem Duplication of MLL) by administering a therapeutically effective amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof to an individual in need of such treatment.

[0434] The invention further provides methods for treating a disorder mediated by chromosomal rearrangement on chromosome 11q23 in an individual in need of such treatment by administering a therapeutically effective amount of a compound of any of Formulas I, II, III, IV , V, VI, IX and X or pharmaceutically acceptable salts thereof to the individual.

[0435] The invention also provides methods for treating a disease or condition by administering an effective amount of a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof to an individual suffering from the disease or condition.

[0436] The invention further provides methods for treating a disease or condition by administering a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof to an individual who suffers from the disease or condition where the compound binds to menin and inhibits the interaction of menin with one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or a Partial Tandem Duplication of MLL).

[0437] The present invention also provides methods for combination therapies in which an agent known to modulate other pathways or other components of the same pathway or even sets of overlapping target enzymes are used in combination with a compound of any of Formulas I , II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof. In one aspect, such therapy includes, but is not limited to, combining one or more compounds of the invention with chemotherapeutic agents, therapeutic antibodies and radiation treatment, so as to provide a synergistic or additive therapeutic effect.

[0438] Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with Notch inhibitors and/or c-Myb inhibitors. Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with MLL-WDR5 inhibitors and/or Dot11 inhibitors.

[0439] Many chemotherapeutic agents are presently known in the art and can be used in combination with the compounds of the invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti -hormones, angiogenesis inhibitors and anti-androgens.

[0440] Non-limiting examples are 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 a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornafazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquine, phenesterine, prednimustine, trophosphamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophylline, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin , idarubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitin; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM; razoxane; sizophyran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobroman; gacytosin; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamycins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable cell-conditioning chemotherapeutic agents are anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens including, for example, tamoxifen, (NolvadexTM), raloxifene, 4(5)- aromatase inhibitor imidazoles, 4-hydroxytamoxifen, trioxyfen, cheoxifen, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbina; novantrona; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE , Abagovomab, Acridino carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alfaradin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastics, antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine , Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostalicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin, cell cycle non-specific anticancer agents, dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Phorodesin, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucantone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebecamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine , Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

[0441] This invention further relates to a method for using compounds of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof or pharmaceutical compositions provided herein, in combination with radiation therapy to inhibit abnormal cell growth or treat a mammalian hyperproliferative disorder. Techniques for administering radiation therapy are known in the art and these can be used in the combination therapy described above. Administration of the compound of the invention in this combination therapy can be determined as described herein.

[0442] Radiation therapy may be administered by one of several methods or a combination of methods, including, without limitation, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiation surgery, systemic radiation therapy , radiotherapy and permanent or temporary interstitial brachytherapy. The term “brachytherapy” as used herein refers to radiation therapy administered by a spatially confined radioactive material inserted into the body at or near the tumor or other site of proliferative tissue disease. The term is intended to include without limitation exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and radioactive isotopes of Lu). Suitable radiation sources for use as the cell conditioner of the present invention include both solids and liquids. As a non-limiting example, the radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source or other radionuclides that emit photons, beta particles, gamma radiation or other therapeutic rays. The radioactive material may also be a fluid made from any solution of radionuclide(s), for example, a solution of I-125 or I-131, or a radioactive fluid may be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Furthermore, the radionuclide(s) can be incorporated into a gel or radioactive microspheres.

[0443] The compounds or pharmaceutical compositions of the invention can be used in combination with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors or autophagy inhibitors.

[0444] Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-11 (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the invention and pharmaceutical compositions described herein. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed 8 July 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98 /34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998) , European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published 21 October 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998) , European Patent Application no. 99302232.1 (filed March 25, 1999), British Patent Application No. 9912961.1 (filed June 3, 1999), US Provisional Application No. 60/148,464 (filed August 12, 1999), US Patent 5,863,949 ( published January 26, 1999), US Patent 5,861,510 (published January 19, 1999) and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein in their entirety by reference. Preferred MMP-2 and MMP-9 inhibitors are those that exhibit little or no MMP-1 inhibitory activity. More preferred are those that selectively inhibit MMP-2 and/or AMP-9 over other matrix metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7 , MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the invention are AG-3340, RO 32-3555 and RS 13-0830.

[0445] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazole carboxamido riboside (AICAR), okadaic acid, algal toxins suppressing autophagy that inhibit type 2A or type 1 protein phosphatases, cAMP analogues and drugs that increase cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside and vinblastine. In addition, siRNA or antisense RNA that inhibit the expression of proteins including, but not limited to, ATG5 (which are implicated in autophagy), can be used.

[0446] In some embodiments, the compounds described here are formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed, and hyaluronic acid.

[0447] In some embodiments, medications that are administered together with the compounds described herein include any suitable drugs administered by inhalation, for example, analgesics, for example, codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, for example, cromolyn, ketotifen or nedocromil; anti-infectives, for example, cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, for example, beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, for example, noscapine; bronchodilators, e.g. epedrine, 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]benzenemethanol; diuretics, e.g. amiloride; anticholinergics, for example, ipratropium, atropine or oxitropium; hormones, for example, cortisone, hydrocortisone or prednisolone; xanthines, for example, aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, for example, insulin or glucagon. It will be clear to one skilled in the art that, where appropriate, medicaments are used in the form of salts (e.g. as alkali metal or amine salts or acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g., hydrates) in order to optimize the activity and/or stability of the drug.

[0448] Other exemplary therapeutic agents useful for a combination therapy include, but are not limited to, agents such as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins , androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogues; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas, agents that affect calcification and bone remodeling: calcium phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins , vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents that act on the neuromuscular junction and/or autonomic ganglion; catecholamines, sympathomimetic drugs and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0449] Therapeutic agents may also include agents against pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of selective hydrolysis of membrane phospholipids , eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory agents, analgesic-antipyretic agents, agents 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 interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, sodium channel blockers calcium, membrane stabilizers and leukotriene inhibitors.

[0450] Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting renal water conservation, renin, angiotensin, agents useful in treating myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, receptor antagonists and -adrenergic, agents for the treatment of hypercholesterolemia and agents for the treatment of dyslipidemia.

[0451] Other therapeutic agents contemplated include drugs used to control gastric 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 disease, agents used for pancreatic disease. Therapeutic agents used to treat protozoal infections, drugs used to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis and/or Leishmaniasis and/or drugs used in helminthiasis chemotherapy. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones and agents for the treatment of urinary tract infections, penicillins, cephalosporins and others, antibiotics based on β-lactam, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease and leprosy, antifungal agents, antiviral agents including non-retroviral agents and antiretroviral agents.

[0452] Examples of therapeutic antibodies that can be combined with a compound of the invention include, but are not limited to, anti-tyrosine kinase receptor antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab) and other antibodies such as alemtuzumab, bevacizumab and gemtuzumab.

[0453] Furthermore, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens and immunostimulants are contemplated by the methods here. In addition, therapeutic agents that act on the blood and blood-forming organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulant, thrombolytic and antiplatelet drugs.

[0454] For the treatment of renal carcinoma, a compound of the present invention can be combined with sorafenib and/or avastin. For the treatment of an endometrial disorder, a compound of the present invention can be combined with doxorubincin, taxotere (taxol) and/or cisplatin (carboplatin). For the treatment of ovarian cancer, a compound of the present invention can be combined with cisplatin (carboplatin), taxotere, doxorubincin, topotecan and/or tamoxifen. For the treatment of breast cancer, a compound of the present invention can be combined with taxotere (taxol), gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901, avastine, herceptin, OSI-906 and/or OSI- 930. For the treatment of lung cancer, a compound of the present invention can be combined with taxotere (taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901 and/or avastin.

[0455] Additional therapeutic agents that can be combined with a compound of the invention are found in Goodman & Gilman's “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein as reference in its entirety.

[0456] The compounds described here can be used in combination with the agents described here or other suitable agents, depending on the condition being treated. Thus, in some embodiments the one or more compounds of the invention will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. Such combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the invention and any of the agents described above may be administered simultaneously, where both agents are present in separate formulations. In another alternative, a compound of the present invention can be administered immediately followed by any of the agents described above or vice versa. In some embodiments of the separate administration protocol, a compound of the invention and any of the agents described above are administered within a few minutes of each other or within a few hours of each other or within a few days of each other.

[0457] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and the methods of preparing such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the examples and below and throughout the report and claims, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers can be obtained by methods known to one skilled in the art.

EXAMPLES

[0458] Non-limiting examples of compound synthesis

[0459] Synthesis of a compound of Formula I

[0460] Synthesis of a compound of Formula I, compound I-9

[0461] General Synthesis Route: C

[0462] Compounds including, but not limited to, II-1, II-3, II-4, II-7, II-10, II-11, II14, II-15, II-16, II-17, II-18 and II-19 can be synthesized using a procedure similar to the general synthesis route: C.

[0463] A solution of II-14-1 (2.24 g) and triphosgene (1.80 g) in 50 ml of dioxane was refluxed overnight. The reaction mixture was concentrated to yield crude II-14-2 (3.0 g, 100%), which was used in the next step without further purification.

[0464] To a solution of crude II-14-2 (1.0 g) in POCl3 (25 ml) was added PCl5 (1.7 g). The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with DCM before ice-cold water was slowly added. The mixture was extracted with DCM three times and the organic solution was washed with saturated NaHCO3, dried and concentrated. The crude II-14-3 obtained was used in the next step for further purifications.

[0465] A solution of II-14-3 (750 mg), tert-butyl 4-aminopiperidine-1-carboxylate (680 mg) and DIEA (680 mg) in 20 ml of THF was refluxed overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic solution was dried and concentrated. The residue was purified by chromatography (PE/EA = 5:1) to yield II-14-4 (500 mg, 42%).

[0466] The solution of II-14-4 (450 mg), Zn(CN)2 (80 mg), DPPF (100 mg), Pd2(dba)3 (100 mg) and Zn (13 mg) in 20 ml of NMP was heated to 100 oC overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic solutions were dried and concentrated. The residue was purified by chromatography (PE/EA = 3:1) to yield II-14-5 (200 mg, 45%).

[0467] A solution of II-14-5 (100 mg) in 6 ml of a 1:1 TFA/DCM co-solvent was stirred at room temperature for 2 hours. The solvent was removed and the residue was diluted with NH3/MeOH. The mixture obtained was concentrated to produce 120 mg of crude II-14-6, which was used without further purification.

[0468] A solution of crude II-14-6 (77 mg), 5-formyl-4-methyl-1- ((1-trityl-1H-pyrazol-4-yl)methyl)-1H-indol-2- carbonitrile (137 mg), NaBH(OAc)3 (290 mg) and TEA (140 mg) in 10 ml of DCM was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic solution was washed with water and brine, dried and concentrated. The residue was purified by chromatography (DCM/MeOH = 50:1) to yield II-14-7 (60 mg, 32%).

[0469] A solution of II-14-7 (60 mg) in 6 mL of 1:1 TFA/DCM was stirred at room temperature for 2 hours. The solvent was removed and the residue was diluted with NH3/MeOH. The obtained mixture was concentrated and the residue was purified by chromatography (DCM/MeOH = 20:1) to yield II-14 (25mg, 59%). ESI-MS m/z: 590 (M+H). 1H NMR (400 MHz, DMSO) 12.83 (s, 1H), 8.40 (d, J = 7.2 Hz, 1H), 7.75 (m, 2H), 7.57 (m, 2H) , 7.45 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 5.39 (s, 2H), 4.18 (m, 2H), 4.07 (m, 1H), 3.55 (s, 2H), 2.83 (m, 2H), 2.50 (s, 3H), 2.12 (m, 2H), 1.88 (m, 2H), 1 .56 (m, 2H).

[0470] Synthesis of a compound of Formula II, compound II-1

[0471] Synthesis of a compound of Formula II, compound II-3

[0472] General Synthesis Route: B

[0473] Compounds including, but not limited to, III-3, IV-2, IV-8, IV-9, V-13 and V-15 can be synthesized using a procedure similar to the synthetic route general: B.

[0474] Synthesis of a compound of Formula III, compound III-3

[0475] To a solution of III-3-1 (750 mg, 3.2 mmol) in DCM (20 ml) were added phenylmethanamine (440 mg, 4.1 mmol) and NaBH(OAc)3 (298 mg, 15 .0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with saturated NaHCO3 and extracted with DCM. The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE/EA= 5:1) to yield III-3-2 (500 mg, yield: 48%) as a colorless oil. ESI-MS m/z:327 (M+H).

[0476] A mixture of III-3-2 (500 mg, 1.53 mmol) and dry Pd/C (10%) in MeOH (10 ml) was stirred under a H2 atmosphere at room temperature for one night. The reaction mixture was filtered through celite and the cake was washed with MeOH and ethyl acetate. The filtrate was concentrated to yield III-3-3 (334 mg, yield: 92%) as a colorless oil. ESI-MS m/z: 181 (M-56+H).

[0477] A mixture of III-3-3 (360 mg, 1.42 mmol), tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (334 mg, 1.42 mmol) in isopropanol ( 10 ml) was stirred under reflux for one night. The reaction mixture was concentrated and the residue was purified on a silica gel column (PE/EA = 2:1) to yield III-3-4 (110 mg, yield: 17%). ESI-MS m/z:453 (M+H).

[0478] The mixture of III-3-4 (110 mg, 0.24 mmol) in HCl/MeOH (4 N) (10 ml) was stirred at room temperature for 2 hours. The mixture was concentrated to yield 100 mg of crude III-3-5 hydrochloride as a white solid. ESI-MS m/z:353 (M+H).

[0479] A mixture of crude III-3-5 hydrochloride (100 mg, 0.24 mmol), 5-formyl-4-methyl-1H-indol-2-carbonoitrile (87 mg, 0.48 mmol), TEA ( 0.20 ml, 1.44 mmol), NaBH(OAc)3 (300 mg, 1.44 mmol) in DCM (15 ml) was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE/EA = 2:1) to yield III-3 (17 mg, yield: 14%). ESIMS m/z:521 (M+H). 1H NMR (400 MHz, CDCl3) δ: 8.78 (br, 1H), 8.51 (s,1H), 7.33 (d, 1H), 7.25 (d, 1H), 7.14 ( s, 1H), 5.31(d, 1H), 4.76-4.90 (m, 1H), 3.52-3.77 (m, 4H), 3.203.26 (m, 1H), 2 .95-3.02 (m, 3H), 2.59 (s, 3H), 2.33-2.53 (m, 2H), 2.13-2.17 (m, 1H), 1,771.81 (m, 1H).

[0480] Synthesis of a compound of Formula IV, compound IV-2

[0481] Synthesis of a compound of Formula IV, compound IV-8

[0482] Synthesis of a compound of Formula IV, compound IV-9

[0483] General Synthesis Route: A

[0484] Compounds including, but not limited to, V-1 can be synthesized using a procedure similar to the general synthesis route: A.

[0485] Synthesis of a compound of Formula V, compound V-1

[0486] A mixture of V-1-1 (250 mg, 1.0 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (250 mg, 1.2 mmol), KF (298 mg, 15.0 mmol) in DMSO (15 ml) was stirred at 100oC overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column (PE/EA = 3:1) to yield V-1-2 (130 mg, yield: 31%) as a colorless oil. ESI-MS m/z:418 (M+H).

[0487] A mixture of V-1-2 (130 mg, 0.31 mmol) in HCl/MeOH (10 ml) was stirred at room temperature for 1 hour. The mixture was concentrated to give crude V-1-3 hydrochloride (98 mg, yield: 89%) as a white solid. ESI-MS m/z: 318 (M+H).

[0488] A mixture of crude V-1-3 hydrochloride (98 mg, 0.28 mmol), 5-formyl-4-methyl-1H-indol-2-carbonoitrile (86 mg, 0.42 mmol), TEA ( 0.26 ml, 1.68 mmol), NaBH(OAc)3 (394 mg, 1.68 mmol) in DCM (150 ml) was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by silica gel column (DCM/MeOH = 30:1) to yield V-1 (10 mg, yield: 7.5%). ESI-MS m/z: 486 (M+H). 1H NMR (400 MHz, CDCl3) δ: 8.82 (br, 1H), 7.62 (s, 1H), 7.38 (d, 1H), 7.32 (s, 1H), 7.27 ( s, 1H), 7.22 (d, 1H), 5.39-5.41 (m, 1H), 3.65-3.74 (m, 4H), 2.78-2.86 (m, 2H), 2.59 (s, 3H), 2.37-2.48 (m, 5H), 2.08-2.14 (m, 2H), 1.86-1.96 (m, 2H) .

[0489] General Synthesis Route: D

[0490] Compounds including, but not limited to, V-3 can be synthesized using a procedure similar to the general synthesis route: D.

[0491] Synthesis of a compound of Formula V, compound V-3

[0492] A mixture of V-1-1 (125 mg, 0.5 mmol), Zn(CN)2 (60 mg, 0.5 mmol), Pd2(dba)3 (5 mg, 0.005 mmol), Zn (3 mg, 0.05 mmol) and Pd(dppf)Cl2 (4 mg, 0.005 mmol) in NMP (5 ml) were stirred at 130oC under N2 atmosphere for 10 hours. TLC showed that the reaction was incomplete. The reaction mixture was partitioned between EA and H2O and the organic layer was washed by brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA = 5:1~1:1) to yield V-3-1 (60 mg, yield: 49%).

[0493] A suspension of V-3-1 (500 mg, 2 mmol) in 20 ml of an aqueous solution of about 10 N H2SO4 was stirred at 100oC for 6 hours. TLC showed that the reaction was complete. The reaction mixture was extracted by EA, dried over Na2SO4. The solvent was removed in vacuo to yield crude V-3-2 as a brown solid (200 mg, 40%), which was used in the next step without further purification.

[0494] To a solution of crude V-3-2 (400 mg, 1.53 mmol) in DCM (20 ml) was added (COCl)2 (194 mg, 1.53 mmol) and a drop of DMF. The reaction was stirred at room temperature for 10 hours. The solvent was removed to produce crude V-3-3 chloride, which was used in the next step without further purification.

[0495] To a solution of tert-butyl piperazine-1-carboxylate (854 mg, 4.6 mmol) and TEA (929 mg, 9.2 mmol) in DCM (20 ml) was added V-chloride solution 3-3 crude in DCM (20 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with DCM and washed with NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3:1~1:1) to yield V-3-4 as a solid (300 mg, yield: 46%, 2 steps).

[0496] A solution of V-3-4 (120 mg, 0.3 mmol) in HCl/MeOH (8 ml) was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was diluted with DCM and washed with NaHCO3. The organic solution was washed with brine, dried over Na2SO4 and concentrated to give crude V-3-5 as a yellow oil (120 mg).

[0497] A mixture of crude V-3-5 (120 mg, 0.3 mmol), 5-formyl-4-methyl-1H-indol-2-carbonitrile (130 mg, 0.6 mmol) and TEA (300 mg, 3 mmol) in DCM (20 ml) was stirred at room temperature for 1 hour before NaBH(OAc)3 (0.5 g, 1.8 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and NaHCO3. The organic solution was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH = 20:1) to give V-3 as a yellow solid (20 mg, yield: 19%). ESI-MS m/z: 499.15 (M+H). 1H NMR (400 MHz, CDCl3) 9.22 (br, 1H), 9.10 (s, 1H), 7.74 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 3.8 8(m, 2H), 3.76 (m, 2H), 3.65 (s, 2H), 3.50 (m, 2H), 2 .64 (m, 2H), 2.57 (s, 3H), 2.50 (m, 2H).

Non-limiting examples of experimental trials

[0498] Fluorescence polarization assay. This example illustrates an effective assay for monitoring the binding of MLL to menin. Fluorescence polarization (FP) competition experiments are performed to determine how effectively a compound inhibits menin-MLL interaction, reported as an IC50 value. A fluorescein-labeled peptide containing high affinity menin-binding motif found in MLL is produced according to Yokoyama et al. (Cell, 2005, 123(2): 207218), incorporated herein by reference in its entirety. Binding of the labeled peptide (1.7 kDa) to the much larger menin (~67 kDa) is accompanied by a significant change in the rotating correlation time of the fluorophore, resulting in a substantial increase in fluorescence polarization and fluorescence anisotropy (excitation at 500 nm, emission at 525 nm). The effectiveness with which a compound inhibits the menin-MLL interaction is measured in an FP competition experiment, in which a reduction in fluorescence anisotropy is correlated with inhibition of the interaction and is used as a readout for determining IC50.

[0499] Timed homogeneous fluorescence (HTRF) assay. A timed homogeneous fluorescence (HTRF) assay is used as a secondary assay to determine the results of the FP assay. In some embodiments, the HTRF assay is the primary assay and the FP assay is used as a secondary assay to confirm the results. HTRF is based on the transfer of non-radioactive energy from long-term emission from the Europium cryptate donor (Eu3+-cryptate) to the allophycocyanin acceptor (XL665), combined with time-resolved detection. A Eu3+-cryptate donor is conjugated to mouse monoclonal anti-6His antibody (which binds His-oriented menin) and the XL665 acceptor is conjugated to streptavidin (which binds the biotinylated MLL peptide). When these two fluorophores are brought into contact by the interaction of menin with the MLL peptide, the transfer of energy to the acceptor results in an increase in fluorescence emission at 665 nm and increased HTRF ratio (emission intensity at 665 nm/emission intensity at 620 nm). Inhibition of the menin-MLL interaction separates the donor from the acceptor, resulting in a reduction in emission at 665 nm and reduced proportion of HTRF.

[0500] Girl's commitment test. Sample Preparation: 2.5 μl of 100 μM compound is added to 47.5 μl of 526 nM menin in PBS (5 μM 500 nM menin compound in 5% DMSO for final concentration). The reaction is incubated at room temperature for varying lengths of time and stopped with 2.5 μL of 4% formic acid (FA, 0.2% for final concentration). Method: A Thermo Finnigan Surveyor Autosampler, PDA Plus UV detector and MS pump along with an LTQ linear ion trapping spectrometer were used to collect sample data under the control of XCalibur software. A 5 μL sample in “no waste” mode was injected into a Phenomenex Jupiter 5u 300A C5 (quarda column) 2 x 4.00 mm at 45°C. Mobile phase composition: Buffer A (95:5 water:acetonitrile, 0.1% FA) and Buffer B (acetonitrile, 0.1% FA). An elution gradient was used with an initial mobile phase of 85:15 (Buffer A:B) and a flow rate of 250 μl/min. By injection, 85:15 A:B was held for 1.3 min, Buffer B was increased to 90% for 3.2 min, held for 1 min and then returned to initial conditions in 0.1 min and held for 2 .4 min. Total running time is 8 min. A bypass valve after the column employed a direct void volume in waste salts was used for the first 2 min of the sampling method. A blank injection of Buffer A is used between each of the sample injections. A needle wash of 1:1 acetonitrile:water with 0.1% FA was used. The electrospray ionization (ESI) source utilized a capillary temperature of 300oC, 40 units of shielding gas flow, 20 units of auxiliary gas flow, 3 units of scavenging gas flow, 3.5 kV of spray, tube lenses at 120 V. Data Collection: Data collection was performed in positive ion full scan mode 550-1500 Da, 10 microscans, 200 ms maximum ion time. Data analysis: Protein mass spectrum was obtained as XCalibur data files. The best scans were combined using XCalibur Qual Browser. Spectra were displayed using “View/Spectrum List” with a Display option to display all peaks. The Edit/Copies menu was used to copy the mass spectrum to the PC clipboard. The spectrum on the PC clipboard was copied into Excel. The first two columns (m/z and Intensity were kept and the third column (Relative) was eliminated. The remaining two columns were then saved as a delimited table file (m/z and intensity) with Excel's filename.txt. The Masslynx program Datapont was then used to convert the delimited table file filename.txt to Masslynx format. In some cases, an external calibration was applied using a myoglobin spectrum (similarly converted) in Masslynx to correct the m/z values of the menin protein m/z data. MaxEnt1 software from the MassLynx software suite was used for deconvolution of the mass spectrum to produce the average MW of the protein(s). The percentage of covalent product formation was determined from the spectrum deconvolved and used to calculate the reaction rate (k) of the covalent reaction.

[0501] Cell proliferation assay. The ability of a compound of the present invention to inhibit the growth of cells, such as human leukemia, VCaP, LNCaP, 22RV1, DU145, LNCaP-AR, MV4;11, KOPN-8, ML-2, MOLM-13, cells cells (BMCs), MLL-AF9, MLL-ENL, MLL-CBP, MLL-GAS7, MLL-AF1p, MLL-AF6, HM-2, E2A-HLF, HL-60 and NB4 cells, is tested using a cell viability assay, such as the Promega CellTiter-Glo® Luminescent Cell Viability Assay (Promega Technical Bulletin, 2015, “CellTiter-Glo® Luminescent Cell Viability Essay”: 1-15, incorporated herein by reference in its entirety). Cells are plated at relevant concentrations, for example about 1 x 105 - 2 x 105 cells per well in a 96-well plate. A compound of the present invention is added at a concentration of up to about 2 μM with eight, 2-fold serial dilutions for each compound. The cells are incubated at 37°C for a period of time, for example 72 hours, then the cells in the control wells were counted. The medium is changed to restore the number of viable cells to the original concentration and the compounds are supplied again. Proliferation is measured approximately 72 hours after using Promega CellTiter-Glo® reagents, according to the instructions per kit.

[0502] RT-PCR analysis of downstream targets of the MLL fusion protein. The effect of a compound of the present invention on the expression of one or more downstream targets of the MLL fusion protein is assessed by RT-PCR. Cells such as VCaP, LNCaP, 22RV1, DU145, LNCaP-AR, MV4;11, KOPN-8, ML-2, MOLM-13, bone marrow cells (BMCs), MLL-AF9, MLL-ENL, MLL- CBP, MLL-GAS7, MLL-AF1p, MLL-AF6, HM-2, E2A-HLF, HL-60, and NB4 cells, are treated with an effective concentration of a compound for about 7 days or less, then the total RNA is extracted from cells using an RNeasy mini kit (QIAGEN). Total RNA is reverse transcribed using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems) and relative quantification of relevant gene transcripts (e.g., Hoxa9, DLX2, and Meis1) is determined by real-time PCR. Effective inhibition of menin-MLL interaction is expected to result in the downregulation of downstream targets of MLL, including Hoxa9, DLX2, and Meis1.

[0503] Pharmacokinetic studies in mice. The pharmacokinetics of menin-MLL inhibitors are determined in female C57BL/6 mice after intravenous (iv) dosing at 15 mg/kg and oral (po) dosing at 30 mg/kg. The compounds are dissolved in the vehicle containing 25% (v/v) DMSO, 25% (v/v) PEG-400 and 50% (v/v) PBS. Serial blood samples (50 μl) are collected over 24 h, centrifuged at 15000 rpm for 10 min and saved for analysis. Plasma concentrations of compounds are determined by the LC-MS/MS method developed and validated for this study. The LC-MS/MS method consists of an Agilent 1200 HPLC system and chromatographic separation of the tested compound is achieved using an Agilent Zorbax Extend-C18 column (5 cm x 2.1 mm, 3.5 μm; Waters). An AB Sciex QTrap 3200 mass spectrometer equipped with an electrospray ionization source (ABI-Sciex, Toronto, Canada) in positive ion multiple reaction monitoring (MRM) mode is used for detection. All pharmacokinetic parameters are calculated by non-compartmental methods using WinNonlin® version 3.2 (Pharsight Corporation, Mountain View, CA, USA).

[0504] Efficacy study in mouse xenograft tumor model. Immunodeficient mice, such as 8-10 week old female nude mice (nu/nu), are used for in vivo efficacy studies in accordance with IACUC-approved guidelines. Leukemic cells, such as MV4-11 human leukemic cells available from the ATCC, are implanted subcutaneously via needle into female nude mice (5 x 106 cells/mouse). When the tumor reaches a size of approximately 150 to 250 mm3 in mice, the tumor-bearing mice are randomly included in a vehicle control group or a compound treatment group (8 animals per group). Animals were treated with a compound of the present invention by oral gavage or intraperitoneal injection in an appropriate amount and frequency as can be determined by one skilled in the art without excessive experimentation. The subcutaneous tumor volume in the nude mice and the body weight of the mice are determined twice a week. Tumor volumes are calculated by measuring two perpendicular diameters with calipers (V = (length x width2)/2). The percentage of tumor growth inhibition (%TGI =1 - [change in tumor volume in the treatment group/change in tumor volume in the control group]*100) is used to evaluate the anti-tumor efficacy. Statistical significance is assessed using a two-sample one-tailed t-test. P < 0.05 is considered statistically significant.

[0505] Efficacy study in the prostate tumor xenograft model. Immunodeficient mice, such as 4-6 week old male CB17 mice with severe combined immunodeficiency (SCID), are used for in vivo efficacy studies according to IACUC-approved guidelines. Parental prostate cancer cells, such as VCaP or LNCaP-AR cells, are implanted subcutaneously into male CB,17.SCID mice (3-4 x 106 cells in 50% Matrigel). When the tumor reaches a palpable size of approximately 80 mm3, tumor-bearing mice are randomly assigned to a vehicle control group and a compound treatment group (6 or more animals per group). Animals were treated with a compound of the present invention by intraperitoneal injection in an appropriate amount and frequency as can be determined by one skilled in the art without excessive experimentation. In one example, mice are treated with 40 mg/kg of a compound of the present invention daily by i.p. injection. for two weeks, then thereafter for 5 days a week. The subcutaneous tumor volume and body weight of the mice are determined twice a week. Tumor volumes are calculated by measuring two perpendicular diameters with calipers (V = (length x width2)/2).

[0506] Efficacy study in a castration-resistant prostate tumor (VCaP) xenograft model. Immunodeficient mice, such as 4-6 week old male CB17 mice with severe combined immunodeficiency (SCID), are used for in vivo efficacy studies according to IACUC guidelines. Parental prostate cancer cells, such as VCaP cells, are implanted subcutaneously into male CB,17.SCID mice (3-4 x 106 cells in 50% Matrigel). When the tumor reaches a size of approximately 200-300 mm3, tumor-bearing mice are physically castrated and the tumors are observed for regression and regrowth to approximately 150 mm3. Tumor-bearing mice are randomly assigned to a vehicle control group and a compound treatment group (6 or more animals per group). Animals are treated with a compound of the present invention by intraperitoneal injection in an appropriate amount and frequency as can be determined by one skilled in the art. In one example, mice are treated with 40 mg/kg of a compound of the present invention daily by i.p. injection. The subcutaneous tumor volume and body weight of the mice are determined twice a week. Tumor volumes are calculated by measuring two perpendicular diameters with calipers (V = (length x width2)/2).

[0507] Efficacy study in castration-resistant prostate tumor xenograft model (LNCaP-AR). Immunodeficient mice, such as 4-6 week old male CB17 mice with severe combined immunodeficiency (SCID), are used for in vivo efficacy studies according to IACUC guidelines. CB,17.SCID mice are surgically castrated and allowed to recover for 2-3 weeks before implantation of parental prostate cancer cells, such as LNCaP-AR cells, subcutaneously (3-4 x 106 cells in 50% Matrigel ). When the tumor reaches a size of approximately 80-100 mm3, tumor-bearing mice are randomized into a vehicle control group and a compound treatment group (6 or more animals per group). Animals are treated with a compound of the present invention by intraperitoneal injection in an appropriate amount and frequency as can be determined by one skilled in the art without undue experimentation. In one example, mice are treated with 60 mg/kg of a compound of the present invention daily by i.p. injection for 27 days. The subcutaneous tumor volume and body weight of the mice were measured twice a week. Tumor volumes are calculated by measuring two perpendicular diameters with calipers (V = (length x width2)/2).

[0508] Cellular thermal exchange test (CETSA). For cell lysate CETSA experiments, cells cultured from cell lines (e.g., HEK293, bone marrow samples) are harvested and washed with PBS. Cells are diluted in kinase buffer (KB) (25 mM Tris(hydroxymethyl)-aminomethane hydrochloride (Tris-HCl, pH 7.5), 5 mM beta-glycerophosphate, 2 mM dithiothreitol (DTT), 0.1 mM of sodium vanadium oxide, 10 mM magnesium chloride) or in phosphate buffered saline (PBS) (10 mM phosphate buffer (pH 7.4), 2.7 mM potassium chloride and 137 mM chloride sodium). All buffers are supplemented with a complete protease inhibitor blend. Cell suspensions are freeze-thawed three times using liquid nitrogen. The soluble fraction (lysate) is separated from the cell pieces by centrifugation at 20,000 x g for 20 minutes at 4°C. Cell lysates are diluted with the appropriate buffer and divided into two aliquots, with one aliquot being treated with drug (e.g., a compound of any of Formulas I, II, III, IV, V, VI, IX and X or pharmaceutically acceptable salts thereof) and the other aliquot with the inhibitor diluent (control). After 10-30 minutes of incubation at room temperature, the respective lysates are divided into smaller aliquots (50 μL) and heated individually at different temperatures for 3 minutes and subsequently cooled for 3 minutes at room temperature. Appropriate temperatures are determined in preliminary CETSA experiments. The heated lysates are centrifuged at 20,000 x g for 20 minutes at 4°C in order to separate the soluble fractions from the precipitates. The supernatants are transferred to new micro tubes and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by western blot analysis.

[0509] For the intact cell experiments, the drug-treated cells from the above in vitro experiments are heated as previously described after which KB (30 μL) is added and the cells are lysed using 2 freeze-thaw cycles with Liquid nitrogen. The soluble fractions are isolated and analyzed by western blot.

[0510] For in vivo experiments with mice, frozen tissue lysates are used. Frozen organs (e.g., liver or kidney) are thawed on ice and briefly rinsed with PBS. Organs are homogenized in cold PBS using tissue grinders followed by 3 freeze-thaw cycles in liquid nitrogen. Tissue lysates are separated from cell pieces and lipids. Tissue lysates are diluted with PBS containing protease inhibitors, divided into 50 μL aliquots, and heated to different temperatures. The soluble fractions are isolated and analyzed by western blot.

[0511] CETSA-like dot-blot experiments on purified proteins. Purified protein (0.5 μg) is added to the wells of a PCR plate and the volume is adjusted to 50 μL by adding buffer or cell lysates and ligands depending on the experimental setup. Samples are heated for the designated time and temperature in a thermal cycler. After heating, samples are immediately centrifuged for 15 min at 3000 x g and filtered using a 0.65μm Multiscreen HTS 96-well filter plate. 3 μL of each filtrate is placed on a nitrocellulose membrane. Primary antibody and secondary conjugate are used for immunoblotting. All membranes are blocked with blocking buffer; The standard transfer and western blot protocols recommended by the manufacturers are used. All antibodies are diluted in blocking buffer. The dot-blot is developed. Chemiluminescence intensities are detected and imaged. The raw dot blot images are processed. The background is subtracted and the intensities are quantified. Graphs are plotted and adjusted using sigmoid dose-response (variable slope).

[0512] Although preferred embodiments of the present invention have been shown and described here, it will be clear to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The following claims are intended to define the scope of the invention and that the methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims (9)

1. Compound characterized by the fact that it presents Formula II-A: or a pharmaceutically acceptable salt thereof, wherein: X2 is N; X5 is S; X6 is CR3; L3 is -NR5-; L2 is -CH2-; m is 0; where each of Z1 and Z2 is CR7; Z5 is C; Z6 is NRB; and each of Z7 and Z8 is CR8; n is 1; R1 is -CH2CF3; R3 is H; R5 is H; each R7 and R8 are, at each occurrence, independently selected from H, cyano, and methyl; G is selected from a bond and C1-C2 alkylene optionally substituted with one, two or three R32 groups; V is absent or a 3- to 12-membered heterocycle; R21 is selected from: H, -N(R20)C(O)R20, -C(O)R20, -C(O)N(R20)2, -S(O)2R20, -S(O) 2N(R20)2, -N(R20)S(O)2R20, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; R32 is methyl; R20 is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; and R14 is halo, hydroxyl, -O-C1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, amino, cyano, amido, C1-C6 alkyl, C1-C6 heteroalkyl, or C1- C6 haloalkyl. 2. Compound according to claim 1, characterized in that Z1 is CCH3; Z2 and Z8 are each CH; Z5 is C; Z6 is NRB; and Z7 is CCN. 3. Compound according to claim 1, characterized in that V is selected from: any of which is optionally substituted with one, two, or three R32 groups. 4. Compound according to claim 1, characterized in that G is a C1-C2 alkylene optionally substituted with one, two or three R32 groups. 5. Compound according to claim 1, characterized by the fact that R14 is hydroxyl, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2 or amino. 6. Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any of the preceding claims and a pharmaceutically acceptable carrier. 7. Use of a compound as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that it is for preparing a medicament for treating a leukemia, hematological malignancy, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain tumor or diabetes. 8. Use according to claim 7, characterized in that the leukemia is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monycytic leukemia (AMoL) and hairy cell leukemia. 9. Use according to claim 8, characterized by the fact that the leukemia is acute myeloid leukemia (AML).