WO2014200479A1 - Menin-mll inhibitors and methods of use thereof - Google Patents

Menin-mll inhibitors and methods of use thereof Download PDF

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Publication number
WO2014200479A1
WO2014200479A1 PCT/US2013/045417 US2013045417W WO2014200479A1 WO 2014200479 A1 WO2014200479 A1 WO 2014200479A1 US 2013045417 W US2013045417 W US 2013045417W WO 2014200479 A1 WO2014200479 A1 WO 2014200479A1
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Prior art keywords
ci
alkyl
composition
mll
cj
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PCT/US2013/045417
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French (fr)
Inventor
Jolanta Grembecka
Tomasz Cierpicki
Sunil Kumar UPADHYAY
Shaun R. Stauffer
Rocco D. Gogliotti
Timothy J. SENTER
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The Regents Of The University Of Michigan
Vanderbilt University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine

Abstract

The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperdine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.

Description

MENIN-MLL INHIBITORS AND METHODS OF USE THEREOF

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under R03 MH084875 awarded by the

National Institutes of Health. The government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates generally to compounds that inhibit the binding of menin and MLL and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperdine- cont aining compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLLl, MLL2, MLL-fusion

oncoproteins), for example, for the treatment of leulcemia, solid cancers and other diseases dependent on activity of MLLl, MLL2, MLL fusion proteins and/or menin.

BACKGROUND OF THE INVENTION

Mixed lineage leukemia (MLL) presents a heterogeneous group of acute myeloid leukemia and acute lymphoblastic leulcemia bearing features of more than one hematopoietic cell lineages. MLL accounts for about 80% of infant acute leukemia cases (Tomizawa, 2007; herein incorporated by reference in its entirety) and 10% of ail acute leukemia cases (Marschalek, 2011 : herein incorporated by reference in its entirety). Under current treatment protocols, MLL leulcemia patients have a very poor prognosis with overall 5-year survival ratio stagnated around 35%, (Dimartino, 1999; Put, 2003; Tomizawa, 2007; herein incorporated by reference in their entireties).

MLL is composited of heterogeneous cell lineages with different molecular biology, cell biology and immunology features. However, MLL does share a common feature, which involves the chromosomal rearrangement of Mixed Lineage Leukemia (MLL) gene. MLL gene locates on chromosome 1 lq23 and the encoded MLL protein is a homolog of Drosophila trithorax (Trx) (Tkach.uk, 1992; herein incorporated by reference in its entirety). Wild type MLL binds to regulatory regions of homeox (HOX) genes (Milne, 2005; herein incorporated by reference in its entirety) through the amino terminal fragment while the catalytic C-terminal domain catalyzes the Histone 3 lysine 4 (H3K4) methylation and up regulates target genes transcription

(Nakamura, 2002; Yokoyama, 2004: Milne, 2002: herein incorporated by reference in their entireties). Wild type MLL is required for maintenance HOX genes expression and is widely expressed not only during embryo development but also in adult tissues including myeloid and lymphoid cells (Butler, 1997;Yu, 1998; herein incorporated by reference in their entireties). Reciprocal translocations of MLL gene result in-- frame fusion of 5' -end MLL with the 3 ' -end of another partner gene. Currently, more than 60 partner genes have been identified, with MLL- AF4, MLL-AF9 and MLL-ENL being the three most frequently found fusion genes (Pui, 2003; herein incorporated by reference in its entirety). Expression of MLL fusion proteins promotes over expression of target genes such as HOXA9 and METSl , which blocks differentiation, enhances blast expansion and ultimately leads to leukemic transformation (Caslini,

20()7;Yokoyama, 2005; herein incorporated by reference in their entireties). Partial tandem duplication and MLL gene amplification present a small portion of MLL leukemia cases where no partner gene is involved. However, studies revealed that these genetic changes also lead to over expression of HOX or MEiS l genes (Dorrance, 2006; Poppe, 2004; herein incorporated by reference in their entireties).

The numerous chromosomal translocation of MLL gene and partner genes diversity add to the complexity to MLL leukemia treatment, though HOX9 and MEiS l overexpression are commonly observed among MLL leukemia patients, each rearrangement leading to distinct deregulated target genes expression pattern and downstream events (Slany, 2009; herein incorporated by reference in its entirety). Clinical researches suggested that MLL of different chromosomal translocation are associated with different prognosis and are treated differently under current protocols (Tamai, 2010; Balgobind, 201 1 ; Pigazzi, 201 1 ; herein incorporated by reference in their entireties). However, boih wild type MLL and MLL fusion proteins retain N terminal domain, which contains the specific menin binding motifs (MBMs), Men in is a tumor repressor protein encoded by Multiple Endocrine Neoplasia 1 (ΜΈΝ 1) gene. The loss function of menin is closely tied with human neoplasms in multiple endocrine organs (Chandrasekharappa, 1997; herein incorporated by reference in its entirety). Menin is also a critical leukemogenic cofactor of MLL fusion proteins, MLL fusion protein with MBMs deletion is incapable of inducing leukemic transformation in progenitor cells (Yokoyama, 2005; herein incorporated by reference in its entirety). Expression of a dominant negative peptide representing the MBM region down-regulates Meis l expression and inhibits MLL leukemic cells proliferation (Caslini, 2007; herein incorporated by reference in its entirety). Furthermore, depletion of menin results in acute down regulation of HOXA9 expression and revives differentiation in MLL leukemic cells (Yokoyama, 2004; Yokoyama, 2005; herein incorporated by reference in their entireties). In normal hematopoiesis, steady hematopoiesis is largely preserved in menin deficient mice (Maiilarci, 2009; Maiilar i, 2009; herein incorporated by reference in their entireties), providing a therapeutic window for MLL leukemia

The leukemogenic activity of MLL oncoproteins is dependent on association with menin. Therefore, selective targeting of this interaction could provide an attractive therapeutic approach to develop novel drags for leukemias with translocations of MLL gene and other leukemias with upreguiation of BOX genes.

SUMMARY OF THE INVENTION

The present invention relates generally to compounds that inhibit the binding of menin and MLL and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperdine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL and MLL oncoproteins (e.g., MLL i , MLL2, MLL-fusion oncoproteins, MLL-PTDs), for example, for the treatment of leukemia, solid cancers and other diseases dependent on activity of MLL1,MLL2, MLL fusion proteins and/or menin. In some embodiments, compositions are provided for the treatment of leukemia or other cancers, which inhibit binding of one or more MLL or MLL fusion proteins to menin.

In some embodiments, the present invention provides a one or more of compounds B l - B76 (see Table 1 ).

In some embodiments, the present invention provides a compound comprising the general structure of formula I:

Figure imgf000005_0001

wherein Y, R1 , R , R 1, R4, R5, R°, A, and X are independently selected from any of the suhstituents depicted for each postion in Table I . in such emboidments, compounds are not limited to those depicted in Table I ; rather, provided herein are compounds comprising or consisting of any combination of the suhstituents of the compounds of Table l , at iheir respective positons. In some embodiments, compounds exhibit the characteristic of inhibiting the interaction of menin with MIX oncoproteins (e.g., MLLl , MLL2, MLL-fusion oncoproteins).

In some embodiments, the present invention provides composi ions comprising a compound of formula T, wherein Y, R1, R7', R R4, R5, R6, A, and X are independently selected from any of the respective suhstituents described herein or depicted in Table 1 , in any combination.

In some embodiments, the present invention pro vides compositions comprising a compound of formula I,

wherein Y is independently selected from OH, OR ', H>, NHR' , or R'"R '°;

wherein R' selected from d-6-alkyl, monohalo-Cj-e-alkyl, polyhalo-Cj-e-alkyl, (d-4- alkyloxy)-Ci-6-aIkyl,

Figure imgf000005_0002
d-4~( Cs-e-cycloalkyl), Ci4-(C¾- heteroaiyl), d-4-(d-6-aryl)> d-4-OH, C1-4-NH2, and C1 -CN;

wherein R '¾ and R' are selected from Cj-6-alkyl, monohalo-d-6-aikyl, polyhalo-d -6- alkyl,

Figure imgf000005_0003
(Ci- -dialkyIamino)-C1-6-alkyl, CM-( d-6-cycloalkyl), d-4-(Cs- 6-heteroaiyl), d-4-(Cs.«-aryl), C1..4-QH, ..4-NH2, and C;.4~CN, or may form a ring between R7a and R ?b with C3.7 carbons;

wherein R1 is aryl or heteroaryl and substituted with 0, 1 , 2, or 3 groups each

independently selected from cyano, halo, hydroxyl, d-3-alkyi, d-3-alkyloxy, monohalo-d-3- alkyi, polyhalo-d-3-aJkyl, and sulfonyl-Cu-alkyl;

wherein R2 is selected from aryl, heteroaryl, heterocycle, carbocycle containing a C3-6 ring size, or acyclic Ci-6-alkyl; wherein R2 is substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, liydroxyl, Ci-3-alkyI, Ci-3-a3kyloxy, raonohalo-Cj .3- alkyl, polyhalo-Cj-3-alkyl, and sulfonyl-Ci-j-alkyl;

wherein A is a 1 ,4-disubstituted aryl or heteroaryi ring substituted with X and R' and may contain a third group R6 independently selected from cyano, halo, hydroxy!, Ci .j-a kyl, C1-3- a!kyloxy, monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, and sulfonyl-Ci-3-alkyl;

wherein X is O, NH, or R8; wherein when X is NR8, R8 may be independently selected from Cj -3-alkyl, Ci-3-alkyloxy, monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, and sulfonyl-Ci -3-alkyl wherein R3 is C , SO2NH2, S02NR¾R9b, CQNR¾R9b, SO2CH3, OCF3, CF3, CL CH3, CH2C , CH2 H2, CH2 HC(0)R10, CH2NHSO2R i0, N02, 4-pyridyl, 3-pyridyf, C(0)R, 1 ,2,3- triazole, OCH3; wherein R9d and R9o may be independently selected from hydrogen, Cj-3-alkyl, or polyhalo-Ci-3-alkyl, or may for a ring between R9a and R9b with C3..5 carbons; wherein ,0 is Cj.. 3-alkyl; or polyhaIo-Ci-3-alkyI;

wherein R'* is hydrogen, or C i-3-alkyl; and

wherein R"1 is hydrogen, OH, or Cu-alkyl.

In some embodiments, one or both of R' and R" are not phenyl. In some embodiments, when Y comprises or consists of OH, one or both of R1 and are not phenyl. In some embodiments, one or both of R* and R" are heteroaromatic (e.g., comprising 1 , 2, or more O, N, S, etc. on ring structure). In some embodiments one or both of R1 and R are cycloalkanes.

In some embodiments, the piperdine ring of formula 1 comprises one or more substituents at the 2, 3, 5, or 6 positions. Suitable substituents include the functional groups provided herein, for example: halogen, Cj-3 alkyl, OH, alkyl-OH (e.g., d^-OH, etc.), NH2, alkyl-NHu (e.g., C1-3- NH2, etc.), cyano, halo (e.g., Ci, Br, F, 1, etc.), polyhalo, SH, alkyl-SH (e.g., ..3-SH, etc.), etc.

In some embodiments, Y comprises or consists of halogen, OH, R 'OH, OR 'a, R 'OR 'aOH, NH2, R7NH2, R7NHR7a, R7NR7aR7b, NHR7a, NR7aR7b, R7OR7aNH2; wherein R7, R7a, and/or R7b, R7c are independently selected from a linear alkane (Cj -Ce), branched alkane (Ci -Ce), monolialo- Ci-6-alk}'1, polyhalo-C \ ^-alky 1, (C1-3-alkyloxy)-Ci-6-alkyl, or combinations thereof.

In some embodiments, R1 and R independently comprise or consist of: an aryl (e.g., phenyl), heteroaryi group (e.g., furan, pyrrole, thiophene, imidazole, pyrazole, oxazoie, thiazole, pyrazine, pyrimidine, pyridine, pyridazine, 1 ,2,3-triazine, 1 ,2,4-triazine, 1 ,3,5-triazine, etc.), cycloalkane (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc), CJ-heterocycle (e.g., aziridine, azirme, oxtrane, oxtrene, thiirane, thiirene, diazirine, oxaziridine, dioxirane, etc.), C -heterocycle (e.g., a azetidine, azete, oxetane, oxete, thietane, thiete, diazetidine, dioxetane, dioxete, dithietane, dithiete, etc.), C5-heterocycle (e.g., pyrrolidine, tetrahydrofuran, thiolane, borolane, phospholane, arsolane, siiboiane, bismolane, siloiane, stannolane, imidazolidine, pyrazolidine, oxazoiidine, isoxazolidine, thiazolidine, isothiazoJidine, dioxolane, dithiolane, tetrazole, etc.), C6-heterocycle (e.g., Piperidine, oxane, Thiane, piperazine, morpholine, thiomorpholine dioxane, dithiane, trioxane, tetrazine, etc.), and/or an acyclic (e.g., branched or straight chain) alkane. In some embodiments, an aryl, heteroaryl, cycloalkane, heteroeycle, and/or acyclic alkane is substituted with 1, 2, 3, 4, 5, 6, or more substituents independently selected from one or a combination of cyano, halo (e.g., CI, Br, F, T, etc.), OH, Ci-3-alkyl, Ci-j- alkyloxy, monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, and sulfonyi-Ci-3-alkyl, or any other suitable substituents described herein.

In some embodiments, R4 and RD independently comprise or consist of: H, C1..3 alkyl, OH, halogen, alkyl-OH (e.g., C1-3-QH, etc.), NH2, alkyl-NH? (e.g., C1-3-NH2, etc.), cyano, halo (e.g., CI, Br, F, I, etc.), polynalo, SH, alkyl-SH (e.g., C;-3-SH, etc.), etc

In some embodiments, X is O, R80, OR8a, R8OR8a, NH, RSNH, R8NHR8a, HR8a, S, R-

8S, SR8a, R8SR8a, CH2, CHR8a; wherein R8 and/or RSa are independently selected from a linear alkane (Cj-Ce), branched alkane (Ci -Cs), monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, (C1 -3- alkyloxy)-C}-3~alkyl, sulfonyl- Ci..3-alkyl, or combinations thereof.

In some embodiments, A is a 6-membered ring. In some embodiments, A is a 6- membered: aryl (e.g., 1 ,4-benzene), heteroaryl (pyridine, pyrazine, pyridazine, 1 ,2,3-triazine,

1,2,4-triazine, 1,3,5-triazine, etc. ), cycloalkane (e.g., cyclohexane), etc. In some embodiments, A is a 6-membered ring comprising a substituent at the para position (e.g., 4 position) with respect to the connection point of the ring to the rest of the compound (e.g., 1 position), m some embodiments, R3 is a substituent at the para position of A. In some embodiments, A further comprises substituents at ortho (e.g., 2 and/or 6 positions) and /or meta (e.g., 3 and/or 5 positions) positions. In some embodiments, R6 is a substituent at the ortho and/or para positions of A. In some embodiments, 0, 1, 2, 3, or 4, RJ groups are present on an A group. In some embodiments, R6 groups are present or absent from any of the ortho and/or meta posiions of A. In some embodiments, R comprises or consist of CN, S02NH2, SChNR^R96, CONR aR9°, SO2CH3, SO2CF3, OCF3, CFj, CI, CHj, CH2CN, CH2NH2, CH2OH, CH2 HC(0)R ! °,

CH NHSO2R10, N02, 4-pyridyi, 3-pyridyl, CfO)R, 1 ,2,3-triazole, OCH3; wherein R9 and R9b may be independently selected from hydrogen, Ci.3-alkyL or polyhaIo-Ci.3-alkyI, or may form a ring between R9a and Rl'b with C3-7 carbons; wherein RlC' is Ci-3-alkyl; or polyhalo-Ci-3-alkyl. In some embodiments, one or more R6 groups independently comprise of consist of CN, SO2NH2, S02NR1 !aRi l b, CONR! laRnb, S02CH3, S02CF3, OCF3, CF3, CI, C¾, CH2CN, CH2NH2, CH2NHC(0)R12, CH2NHSO2R12, N02, 4-pyridyl, 3-pyridyL C(0)R, 1 ,2,3-triazole, OC¾;

wherein R: :a and R: lb may be independently selected from hydrogen, Ci-3-alkyl, or polyhalo-C-i-j- alkyl, or may form a ring between R1 , a nd R"b with C3-7 carbons; wherein R'2 is Ci-3-alkyl; or polyhalo-Ci-3-alkyl.

Tn some embodiments, the present invention provides methods for the treatment of a disease or condition comprising: administering a composition comprising a menin-MLL inhibitory compound to a subject suffering from said disease or condition. In some

embodiments, the compounds comprise one the general structure of formula T:

Figure imgf000008_0001

wherein Y, R\ R2, RJ, R4, X, A, Rc, and RJ independently comprise any suitable functional groups described herein. In some embodiments, compounds comprise one of compounds Bl- B76. In some embodiments, the disease or condition comprises leukemia or a solid tumor cancer (e.g., breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, glioblastoma, myeloma and melanoma, etc.). In some embodiments, the leukemia comprises acute feukemias, chronic leukemias, lymphoblastic leukemias, lymphocytic leukemias, myeloid leukemias, myelogenous leukemias, Acute lymphoblastic leukemia (ALL), Chronic lymphocytic leukemia (CLL), Acute myelogenous leulcemia (AML), Chronic myelogenous leukemia (CML), Hairy cell leukemia (HCL), T-cell prolymphocyte leukemia (T-PLL), Large granular lymphocytic leukemia, MLL-positive leukemias, MLL-induced leukemias, MLL -rearranged leukemias, MLL- PTD leukemias, etc.

Tn some embodiments, the present invention provides methods of inhibiting the interaction of MLL (e.g., MLLl and/or MLL2 and/or MLL fusion protein) and menin comprising: (a) providing: (i) a sample comprising MLL (or MLL fusion proteins) and menin; and (ii) a composition comprising a me in-MLL inhibitor; (b) administering said composition to said sample; and (c) inhibiting the interaction between said MIX and said menin, or said MLL fusion proteins and said menin. In some embodiments, the menin-MLL binding inhibitor comprises the general structure of formula I with any suitable substi.tuen.ts. In some

embodiments, the menin-MLL inhibitor comprises one of the compounds B I-B76.

In some embodiments, the present invention provices compositions comprising a compound having the structure of formula II:

Figure imgf000009_0001
wherein R 'a and R '° are independently selected from H, d-6-a kyl, monohaIo-Ci-6-alkyI, polyhaio-Ci-6-alkyi, (d-3-alkyloxy)-d-6-alkyl, or may form a ring between R?a and R?b with C3-7 carbons; wherein RJ is aryl or heteroaryi and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxy!, Ci-3-alkyi, Ci-3-a.ikyloxy, monohaio-d-3- alky], polyhalo-Ci-3-alky], and sulfonyl-Cj-3-alkyl; wherein R2 is selected from heteroaryi, heterocycle, carbocycle containing a C3-8 ring size, or acyclic Cj-6-alkyl; wherein R2 is substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxy.!, Ci.. 3-alkyl, Ci-3-alkyloxy, monohalo-Cj-3-a!kyl, polyhalo-Ci-3-a!kyl, and suifonyl-Ci-3-alkyi; wherein A is a 1 ,4-disubstituted aryl or heteroaryi ring substituted with X and RJ and may contain a third group R° independently selected from cyano, halo, hydroxy!, Ci-3-alkyi, Ci-3-alkyioxy, monoha.Io-C}..3-aikyI, polyha!o-Ci j-aikyl, suifonyJ-C1.3-al.kyd and sulfonamide; wherein X is O, H, or NRd; wherein when X is NR.", R6 may be independently selected from Cj-3-alkyi, C1-3- alkyloxy, monohalo-Ci -3-alkyl, pol halo-Ci -3-alkyl, and sulfonyl-d-3-alkyl; wherein R* is CN, SO2NH2, S02 R9aR9 , CON 9aR9b, SO2CH3, OCF3, CF3, CI, CFL, CH2CN, CH2NH2,

CH2NHC(O)R!0, CH.2NHSO2R10, N02, 4-pyridyl, 3-pyridyl, C(0)R, 1,2,3-triazole, OCH.3;

wherein R9a and R9omay be independently selected from hydrogen, -3-alkyl, or polyhalo-Ci_:,- alkyl, or may form a ring between R¾ and R9j with C3-7 carbons; wherein R10 is Cj-3-alkyI; or polyhalo-Ci-3-alkyl; wherein R4 is hydrogen, or d .3-alkyl; and wherein Rs is hydrogen, OH, or Ci-3-a!kyl. In some embodiments, one or both of R1 and R" are phenyl. In some embodiments, R1 is phenyl, in some embodiments, A is a disubstituted phenyl group. In some embodiments, A is al ,4-disubstituted phenyl group. In some embodiments, A is a phenyl group connected to the rest of the scaffold at the 1 position and comprising a substituent of 20 or fewer aioms at the 4 position. In some embodiments, the phenyl has a substituent of 10 or fewer atoms at the 4 position, in some embodiments, the substituent at the 4 position comprises a heteroaryl. in some embodiments, the substituent at the 4 position comprises 5 or fewer atoms. In some

embodiments, substituent at the 4 position selected from (he list consisting of CN, Ci, Br, CF3, OCF3. In some embodiments, R° is a halogen. In some embodiments, X is O, In some embodiments, one or both of R' and R are H. In some embodiments, R" is H, In some embodiments, both R' and R are H.

In some embodiments, the present invention provides methods for the treatment of a disease or condition comprising administering a composition of formula II, as described above, to a subject suffering from said disease or condition. In some embodiments, thedisease or condition comprises a leukemia, solid tumor cancer, or diabetes. In some embodiments, leukemia comprises AML or ALL. In some embodiments, the present invention provides methods of inhibiting the interaction of MLL or MLL fusion protein and menin comprising administering composition of formula II, as described above, to a sample comprising MLL or MLL fusion protein and menin.

In some embodiments, the present invention provides compositions comprising a compound having the structure of formula I:

Figure imgf000010_0001

wherein A is heieroaryl ring; wherein X is O, NH, or NR8; wherem when X is NR8, R8 may be independently selected from Ci..3-alkyi, Ci .j-aikyloxy, monohalo-Ci-3-alkyi, polyhalo-Ci-3-alkyl, and sulfonyl-C1-3-alkyl; wherein R3 is CN, S02NH2, 802NR9aR9b, CONR9aR9" , S02C¾, OCF3, CF3, C , CH3, CILCN, CH2NH2, CIi7NI:IC(0)R10, CH2NHSO2R10, N02, 4-pyridyl, 3-pyridyl,

C(0)R, 1 ,2,3-iriazole, OCH3; wherein R9a and R9 may be independently selected from hydrogen, Cj .3-alky], or polyhalo-Ci-3-alkyl, or may form a ring between Ry and R9D with C3.7 carbons; wherein R;0 is Cs-3-aIkyl; or polyhalo-C i-3-alkyl; wherein R6 is selected from FT, cyano, halo, hydroxy!, Ci-3-alkyl, C-i-j-alkyloxy, monohalo-d-3-aikyl, polyhalo-d-3-aikyl, sulfonyl-Ci-3-alkyl and sulfonamide; wherein Y is independently selected from OH, OR7, N¾, NHR ', or NR'aR?b; wherein R' selected from d-6-alkyi, monohalo-Cj-s-alkyl, poiyhalo-Cj-g-alkyl, (Cj-3-alkyloxy)- d -6-alkyl; wherein R'a and R 'b are selected from d-6-alkyl, monohaio-Ci-e-alkyi, polyhaio-d-6- alkyl, or may form a ring between R7a and R7° with C3..7 carbons; wherein R1 is aryl or heteroaryl and substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxy 1, d-3-alkyl, d-3-alkyloxy, monohalo-d .3-alkyl, polyhalo-d .3-alkyL and sulfonyl-d-a-alkyl; wherein Rz is selected from heteroaryl, heterocycle, earbocyeJe containing a C3-8 ring size, or acyclic d-6-alkyl; wherein R is substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxy!, Cj-3-alkyl, Cj-3-alkyloxy, monohalo-d-3-alkyl, polyhalo-d-3-alkyl, and sulfonyl-C;-3~alkyl; wherein R4 is hydrogen, or Ci-3-alkyi; and wherein RJ is hydrogen, OH, or d-3-alkyl. in some embodiments, one or both of R1 and R2 are phenyl. In some

embodiments, R1 is phenyl. In some embodiments, Y is OH. In some embodiments, A is a pyridine. In some embodiments, A is connected to X at its 3 position and R' at is 6 position. In some embodiments, R6 is a halogen. In some embodiments, X is O. In some embodiments, one or both of R4 and RD are H. In some embodiments, R4 is H. In some embodiments, both R4 and Rs are H. In some embodiments, the compound is selected from compounds B37, B61, and B64.

In some embodiments, the present invention provides methods for the treatment of a disease or condition comprising administering a composition of formula I, as described in the preceding paragraph, to a subject suffering from said disease or condition. In some

embodiments, thedisease or condition comprises a leukemia, solid tumor cancer, or diabeies. In some embodiments, leukemia comprises AML or ALL. In some embodiments, the present invention provides methods of inhibiting the interaction of MLL or MLL fusion protein and menin comprising administering composition of formula II, as described in the preceding paragraph, to a sample comprising MLL or MLL fusion protein and menin.

Suitable compositions may comprise combination of any of the compounds described herein with one another or with other compounds of interest. Stereoisomers, salts, and derivates of the compounds are further contemplated.

In some embodiments, the present invention provides a method comprising administering a composition for the treatment of leukemia (e.g., which inhibits binding of one or more MLL fusion proteins to menin or MLL wild type to menin) to a subject suffering from leukemia. In some embodiments, the leukemia comprises AML or ALL, in some embodiments, the composition comprises a menin-MLL inhibitor. In some embodiments, the composition comprises a compound of the general structure of formula I or formula II. In some embodiments, the composition comprises one of compounds B1 -B76, a compound comprising formula I with a rearrangement of the substituents of compound B 1 -B76, a compound comprising formula 1 comprising any suitable substituents described herein, and/or derivatives thereof.

In some embodiments, the present invention provides a method of screening compounds effective in treating leukemia comprising assaying one or more compounds for inhibition of the interaction between MLL and menin and/or MLL fusion proteins and menin. In some embodiments, the screening is performed in vitro. In some embodiments, the screening is performed in vivo. In some embodiments, the assaying comprises a fluorescence polarization assay, in some embodiments, the assaying comprises a time-resolved fluorescence resonance energy transfer assay. In some embodiments, the assaying comprises nuclear magnetic resonance (NMR) methods. In some embodiments, the assaying comprises cellular assays and/or animal (e.g., mice) studies.

In some embodiments, the present invention provides a method of inhibiting the interaction of MLL and menin and/or MLL fusion protein and menin comprising: (a) providing: (i) a sample comprising MLL and/or MLL fission protein and menin and (ii) a composition configured to inhibit the interaction of MLL and/or MLL fusion protein and menin, (b) administering the composition to the sample, (c) contacting MLL or MLL fusion protein and/or menin with the composition, and (d) inhibiting the interaction between MLL and menin, and between MLL fusion proteins and menin. In some embodiments, the sample comprises cells from a subject suffering from leukemia. In some embodiments, the subject is a human subject or a human patient. In some embodiments, the ceils are within a subject suffering from leukemia. In some embodiments, the composition comprises a compound of formula I or formula II with suitable substituents as provided herein. In some embodiments, the present invention comprises any structural derivatives of compounds B 1 -B76.

In some embodiments, the present invention provides methods comprising the use of a composition and/or compound described herein (e.g., a derivative of one of formula I, a derivative of formula II, one of compounds B1-B76, a rearrangement of 2 or more of compounds B 1-B76, etc.). In some embodiments, the present invention provides methods comprising the use of a composition and/or compound described herein for the treatment of leukemia or other cancer.

In some embodiments, the present invention provides compositions comprising a compound of formula I:

Figure imgf000013_0001

wherein R1 -R6, A, Y, and X are independently selected from the substituents and functional groups provided herein, but one or more of the following limitations apply: R1 or R2 is a heterocycle, A is a heterocycle, Y is OR'' and R ' does not equal H, or Y is NH2, NHR 'a, or NR'aR7b. in some embodiments in which Y is OR7 (and R' does not equal H), NHR'a, and/or NR 'aR 'b, R7 (or R7a or R7°) is selected from C-i-e-alkyi, monohalo-Cj -6-alkyl, poiyhalo-Ci-6- alkyl, (C-i-j-alkyloxyJ-Ci-e-alkyl), Ci-3-amino, C j .3-diaIk lamino (e.g., C i-3-dimethy lamino), Ci-j- cycloalkyls-e, saturated or unsaturated alkyl and/or cycloalcyl chains and/or rings, OH, C OH, amino (e.g.,NH2, NHCj -e, N Ci-eCi^), Ci ^-amino (e.g. , (e.g., Ci^-NHa, Ci-e-NHCi-e, Ci-e-NCj . eCi-e), or C i-e-CN. In some embodiments in which R1, R", and/or A is a heterocycle, the heterocycle is a pyridine. In some embodiments in which R1, R2, and/or A is a heterocycle, a heterocycle is selected from any sutable heterocycles described herein and/or known in the art. In some embodiments, the compound is selected from compounds B54, B55, B56, B57, B58, B60, B62, B64, 1367, B69, B71 , B72, B73, 1374, and B75. In some embodiments, the compound comprises any suitable rearrangement of the substituents of compounds B54, B55, B56, B57, B58, B60, B62, B64, B67, B69, B71, B72, B73, B74, and B75 (e.g., wherein R1 or R2 is a heterocycle, A is a heterocycle, Y is OR/ and R ' does not equal H, and/or Y is NH2, NHR 'a, or NR' aR'b). In some embodiments, a composition comprises a compound of formula I, wherein Y is not H or OH. In some embodiments, a composition comprises a compound of formula I, wherein A is not phenyl.

BREIF DESCRIPTION OF THE DRAWINGS

Figiire 1. Cellular activity of menin-MLL inhibitors. A. B 19 and B20 but not NC inhibit the menin interaction with MLL-AF9 in HEK293 cells transfected with Flag-MLL-AF9. B. Treatment with B19 and B20 strongly downregulates the expression level of Hoxa9 and MeisI in MLL-AF9 transformed bone marrow cells.

Figure 2. B19 and B20 inhibit proliferation of MLL-AF9 and MLL-ENL transformed murine bone marrow cells. No such effect is observed for the negative control compound NC.

Figure 3. B .19 and B20 but not NC inhibit proliferation of human MLL leukemia cells: MV4;1 1 , KOPN8, ML-2, MonoMac6. No effect was observed for the treatment of non-MLL leukemia cells (Kasumi-1 and REH) upon treatment with these menin-MLL inhibitors.

Figure 4. A, B.Treatment with B19 and B20 menin-MLL inhibitors induces

differentiation of the MLL-AF9 transformed murine bone marrow cells as assesed by increased expression of the CD I lb differentiation marker.

Figure 5, Treatment with B 19 and B20 menin-MLL inhibitors induces differentiation of the MLL-AF9 transformed murine bone marrow cells as assessed by significant change in morphology of these cells.

Figure 6, 'Treatment with B19 and B2.0 induces differentiation of human MLL leukemia cell lines: MV4;1 i as reflected by increased expression level of CD1 lb (A) and morphology change of these cells (B).

Figure 7. B 19 and B20 induce differentiation in a panel of human MLL leukemia cell lines with different MLL translocations: MV4; 1 1, Ml-2, KOPN8 and MonoMac-6 as assessed by change in the GDI l b expression (A) and change in morphology of cells (B).

Figure 8, A. B19 and B20 but not the control compound (NC) induce apoptosis in human MLL leukemia cell lines with different MLL translocations (MV4; 1 and ML-2). B. No effect on apoptosis was observed in the control cell fine (Kasumi-1) without MLL translocation upon treatemtn with B19, B20 or NC.

Figure 9. B 19 and B20 induce cell cycle arrest in differnet MLL leukemia cells. No such effect was observed for NC compound.

Figure 18. B 19 and B20 but not NC reduce transforming properties of MLL-AF9 fusion protein as reflected by decreased colony number in the colony forming assay (A) and change in morphology of colonies (B) in MLL-AF9 transformed murine bone marrow cells upon treatment with these compounds.

Figure 11. MTT cell viability assay in MLL-AF9 transformed murine bone marrow cells revealing inhibition of cell proligeration induced by: A) B58, B) B67, C) B75 after 7 days of treatment with these compounds.

Figure 12. MTT cell viability assay in MLL-AF9 transformed murine bone marrow cells revealing inhibition of ceil proligeration induced by B71 after 7 days of treatment with this compound.

DEFINITIONS

The term "system" refers a group of objects, compounds, methods, and/or devices that form a network for performing a desired objective.

As used herein a "sample" refers to anything capable of being subjected to the compositions and methods provided herein. The sample may be in vitro or in vivo. In some embodiments, samples are "mixture" samples, which samples from more than one subject or individual. In some embodiments, the methods provided herein comprise purifying or isolating the sample. In some embodiments, the sample is purified or unpurified protein. In some embodiments, a sample may be from a clinical or research setting. In some embodiments, a sample may comprise cells, fluids (e.g. blood, urine, cytoplasm, etc.), tissues, organs, lysed cells, whole organisms, etc. In some embodiments, a sample may be derived from a subject. In some embodiments, a sample may comprise one or more partial or whole subjects.

As used herein, the term "subject" refers to any animal including, but not limited to, humans, non-human primates, bovines, equines, felines, canines, pigs, rodents (e.g., mice), and the like. The terms "subject" and "patient" may be used interchangeably, wherein the term "patient" generally refers to a human subject seeking or receiving treatment or preventative measures from a clinician or health care provider.

As used herein, the terms "subject at risk for cancer" or "subject at risk for leukemia" refer to a subject with one or more risk factors for developing cancer and/or leukemia. Risk factors include, but are not limited to, gender, age, genetic predisposition, environmental exposure, and previous incidents of cancer, preexisting non-cancer diseases, and lifestyle. As used herein, the terms "characterizing cancer in subject" "characterizing leukemia in subject" refers to the identification of one or more properties of a cancer and/or leukemia sample in a subject, including but not limited to, the presence of benign, pre-cancerous or cancerous tissue or cells and the stage of th e cancer (e.g., leukemia). Cancers (e.g., leukemia) may be characterized by identifying cancer cells with the compositions and methods of the present invention.

The terms "test compound" and "candidate compound" refer to any chemical entity, pharmaceutical, drag, and the like that is a candidate for use to treat or prevent a disease, illness, sickness, or disorder of bodily function (e.g., cancer). Test compounds comprise both known and potential therapeutic compounds. A test compound can be determined to be therapeutic by screening using the screening methods of the present invention.

As used herein, the term "effective amount" refers to the amount of a compound (e.g., a compound having a structure presented above or elsewhere described herein) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not limited to or intended to be limited to a particular formulation or administration route.

As used herein, the term "co-administration" refers to the administration of at least two agent(s) (e.g., a compound having a structure presented above or elsewhere described herein) or therapies to a subject. In some embodiments, the co-administration of two or more

agents/therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy. Those of skill in the art understand that the formulations and/or routes of administration of the various agents/therapies used may vary. The appropriate dosage for coadministration can be readily determined by one skilled in the art, in some embodiments, when agents/therapies are co-administered, the respective agents/therapies are administered at lower dosages than appropriaie for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents/therapies lowers the requisite dosage of a known potentially harmful (e.g., toxic) agent(s).

As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo, in vivo or ex vivo. As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants. (See e.g. , Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]).

As used herein, the term "pharmaceutically acceptable salt" refers to any

pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphtha lene -2 - sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW4', wherein W is C1. alkyi, and the iike.

Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, fiucoheptanoate, glycerophosphate, hemisulfaie, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthafenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoaie, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as a;, N 4 , and NW4' (wherein W is a C alkyl group), and the like. For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound,

As used herein, the term "instructions for administering said compound to a subject," and grammatical equivalents thereof, includes instructions for using the compositions contained in a kit for the treatment of conditions characterized by viral infection (e.g., providing dosing, route of administration, decision trees for treating physicians for correlating patient-specific characteristics with therapeutic courses of action). The compounds of the present invention (e.g. as shown in structures above and elsewhere presented herein) can be packaged into a kit, which may include instructions for administering the compounds to a subject.

As used herein, the term "alkyl", unless defined more specifically herein, refers to a moiety consisting of carbon and hydrogen containing no double or triple bonds. An alkyl may be linear, branched, cyclic, or a combination thereof, and may contain from one to fifty carbon atoms. Examples of alkyl groups include but are not limited to methyl , ethyl, propyl, isopropyl, cyclopropyl, butyl isomers (e.g. n-butyl, iso-huty!, tert-butyl, etc.) cyclobutyi isomers (e.g. cyclobutyi, methylcyclopropyi, etc.), pentyi isomers, cyclopentane isomers, hexyl isomers, cyciohexane isomers, and the like. Unless specified otherwise (e.g., substituted alkyl group, heteroalkyf, afkoxy group, hafoafkyl, alkylamine, thioalkyl, etc.), an alkyl group contams carbon and hydrogen atoms only .

As used herein, the term "linear alkyl" , unless defined more specifically herein, refers to a chain of carbon and hydrogen atoms (e.g., ethane, propane, butane, pentane, hexane, etc.). A. linear alkyl group may be referred to by the designation -(CH^qCHb, where q is 0-49. The designation "Cj-r_ alkyl" or a similar designation, refers to alkyl having from 1 to 12 carbon atoms such as methyl, ethyl, propyl isomers (e.g. n-propyi, isopropyl, etc.), butyl isomers, cyclobutyi isomers (e.g. cyclobutyi, methylcyclopropyi, etc.), pentyi isomers, cyclopenty] isomers, hexyl isomers, cyclohexyl isomer, hepryl isomers, cycloheptyl isomers, octyl isomers, eyclooctyl isomers, nonyl isomers, cyclononyl isomers, decyl isomer, cyclodecyl isomers, etc. Similar designations refer to alkyl with a number of carbon atoms in a different range.

As used herein, the term "branched alkyl", unless defined more specifically herein, refers to a chain of carbon and hydrogen atoms, without double or triple bonds, that contains a fork, branch, and/or split in the chain (e.g., 3,5-dimethyl-2-etbylhexane, 2-methyl-pentane, 1 -methyl- cyclobutane, ortho-diethyl-cyclohexane, etc.). "Branching" refers to the divergence of a carbon chain, whereas "substitution" refers to the presence of non-carbon non-hydrogen atoms in a moiety. Unless specified otherwise (e.g., substituted branched alkyi group, branched heteroaikyl, branched alkoxy group, branched haloalkyl, branched aikylamme, branched thioalkyi, etc.), a branched alkyi group contains carbon and hydrogen atoms only.

As used herein, the term "cycloaikyl", unless defined more specifically herein, refers to a completely saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloaiky l groups of the present application may range from three to ten carbons (€'3 to Cjo). A cycloaikyl group may be unsubstituted, substituted, branched, and/or unbranched. Typical cycloaikyl groups include, but are not limited to, cyciopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyi or selected from those indicated above with regard to substitution of an alkyi group unless otherwise indicated. Unless specified otherwise (e.g., substituted cycloaikyl group, heterocyciyl, cycioaikoxy group, halocycloalkyi, cycloalkylamine, thiocycloalkyl, etc.), an alkyi group contains carbon and hydrogen atoms only.

As used herein, the term "heteroaikyl", unless defined more specifically herein, refers to an alkyi group, as defined herein, wherein one or more carbon atoms are independently replaced by one or more heteroatoms (e.g., oxygen, sulfur, nitrogen, phosphorus, silicon, or combinations thereof). The alkyi group containing the non-carbon substitution^) may be a linear alkyi, branched alkyi, cycloaikyl (e.g., cycloheteroalkyi), or combinations thereof. Non-carbons may be at terminal locations (e.g., 2-hexanoi) or integral to an alkyi group (e.g., diethyl ether).

As used herein, the term ''substituted" , unless defined more specifically herein, (e.g., substituted alyklene) means that the referenced group (e.g., alkyi, aryl, etc) comprises a substituent group (e.g., carbon/hydrogen-only substituent, heterosubstituent, halosubstituent, etc.). The term "optionally substituted", as used herein, means that the referenced group (e.g., alkyi, cycloaikyl, etc.) may or may not be substituted with one or more additional group(s). Substituent groups may be selected from, but are not limited to: alkyi, alkenyi, aikynyl, cycloaikyl, aryl, heteroaryi, heterocycloalkyl, hydroxy!, alkoxy, mercaptyl, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, and amino, including mono- and di -substituted amino groups, and the protected derivatives thereof. Non-limiting examples of substituents include, halo, --CN,—OR,—C(0)R, - OC(0)R,••(•: ( ) ) . OC(0)NHR, --C(0)N(R)2, --SR-, ■■■'. { O sR.→{ O bR . --NHR, --N(R)2,· -NHC(0)», NHC(0)0--, -C(0)NH-, S(=0)2NHR, -S(0)2N(R)2! ~NHS(=0)2, -NHS(0)2R, C'-C6a]kyl, C'-C6alkoxy, aryl, heteroary], cycloalkyl, heterocycloalkyl, halo-substituted C'~

C6alkyi, halo-substituted C^C^alkoxy, where each R is independently selected from H, halo, C'~ C6alkyL C'-C^alkoxy, aryl, heteroaryi, cycloalkyl, heterocycloalkyl, halo-substituted CJ-C6alkyl, halo-substituted C1 -CVlkoxy.

As used herein, the term "substituted alkyl", unless defined more specifically herein, refers to an alkyl group, as defined herein, displaying one or more non-carbon-atom-containing moieties (e.g., a group containing non-carbon atoms, possibly in addition to carbon atoms). The non-carbon-atom-containing moieties atoms may comprise: oxygen, sulfur, nitrogen, phosphorus, silicon, halogens (e.g. chlorine, bromine, flourine, iodine, etc.), or combinations thereof). The non-carbon- atom-containing moieties may also comprise carbon and hydrogen. The alkyl group containing the non-carbon substitution(s) may be a linear aJkyi, branched alkyl, cycloalkyl (e.g., cycloheteroaikyl), or combinations thereof. Examples of substituted alky groups include: 2-hexanol, diethyl ether (also a heteroalkyl), 1-chloro-propane, etc.

As used herein, the terms "heteroaryi" or "heteroaromatic", unless defined more specifically herein, refer to monocyclic, bicyclic, tricyclic, and other multicyclic ring systems (e.g., having four or greater ring members), wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroaioms selected from nitrogen, oxygen and sulfur, and wherein each ring in the system contains 3 to 7 ring members. Unless otherwise defined herein, suitable substituents on the unsaturated carbon atom of a heteroaryi group are generally selected from halogen; -R, -OR, -SR, ~NO¾ -CN, -N(R)2, -NRC(0)R, - NRC(S)R, --NRC(0)N(R)2, --NRC(S)N(R)2, -NRC02R,— NRNRC(0)R, --NRNRC(0)N(R)2, - NRNRC02R, -C(0)C(0)R, -C(0)CH2C(0)R, -C02R, -C(S)R, -C(0)N(R)¾ -C(S)N(R)2, - OC(0)N(R)2, -OC((3)R, -C(0)N(OR)R, -C(NOR)R, -S(0)2R, -S(0)3R, -S02N(R)2, - S(0)R, -NRS02N(R)2, - - N RSQ .R . -N(OR)R, -C(=NH)-N(R)2, --P(0)2R, --PO(R)2, -· OPO(R)2, --{(Ί ί >Κ).ΝΊ !('( )) R . phenyl (Ph.) optionally substituted with R, -O(Pli) optionally substituted with R, -(CH2)i-2(Ph), optionally substituted with R, or ~CH=CH(Ph), optionally substituted with R, wherein each independent occurrence of R is selected from hydrogen, optionally substituted C'-Calkyl, optionally substituted C'-C6alkoxy, an unsubstituted 5-6 membered heteroaryl, phenyl,— O(Ph), or™CH2(Ph), or two independent occurrences of R, on the same substituent or different substituents, taken together with the atom(s) to which each R is bound, to form an optionally substituted 3- 12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Non-limiting examples of heteroaryl groups, as used herein, include benzofuranyi, benzofurazanyi, benzoxazolyl, benzopyranyl, benzihiazolyl, benzothienyl, benzazepinyl, benzimidazolyl, benzothiopyranyl, benzo[l ,3]dioxole, benzo[b]fuiyJ,

benzo[bjthienyf, cmnolinyl, furazanyi, furyi, furopyridinyl, imidazolyl, indolyl, indolizinyl, indolin-2-one, indazolyi, isoindolyl, isoquinoiinyl, isoxazolyl, isothiazolyl, 1,8-naphthyridinyl, oxazolvl, oxaindoJyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthaiazinyi, pteridinyl, purinyi, pyridyl, pyridazinyl, pyrazinyl, pyrimidm l, quinoxaiinyi, quinolinyl, quinazolinyl, 4H-quinolizinyl, thiazolyl, thiadiazolyl, thienyi, triazinyl, triazolyl and tetrazoiyl. Any substituents depicted in structures or examples herein, should be viewed as suitable substituents for use in embodiments of the present invention.

As used herein, the terms "heterocycloalkyl" of "heterocycie", unless defined more specifically herein, refer to a cycloalkyl, as defined herein, wherein one or more of the ring carbons are replaced by a moiety selected from --0--,— N=, --NR.-, ~C(0)— , ~S~, ~S(0)~ or -- S(0)2~, wherein R is hydrogen, C!-C8alkyl or a nitrogen protecting group, with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-limiting examples of heterocycloalkyl groups, as used herein, include morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l ,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2H-pyrro1yl, 2- pyrroliny], 3-pyrrolinyl, 1,3-dioxolanyl, 2-imidazolinyf, imidazolidinyl, 2-pyrazofinyf, pyrazolidinyl, 1,4-dioxanyl, 1,4-dithianyl, thiomorpholinyl, azepanyl, hexahydro- l,4-diazepinyl, tetrahydrofuranyl, dihydrofuranyi, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, oxepanyl, thiepanyl, 1 ,2,3,6- tetrahydropyridinyl, 2H-pyranyi, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyi, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.Ojhe anyl, and 3-azabicyclo[4.1 .0]heptanyl. DETAILED DESCRIPTION

The present invention relates generally to compounds that inhibit the binding of menin and MLL and/or menin. and MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperdine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL and MLL fusion oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers and other diseases dependent on activity of MLL1,MLL2, MLL fusion proteins and/or menin. Embodiments of the present invention directed towad the treatment and'Or prevention of leukemia or recuiTence thereof are described herein; however, it should be understood that the compositions and methods described herein are not limited to the leukemia application. Rather, in some embodiments, the compositions and methods described herein should be understood to also be useful for the treatment and'Or prevention of other cancers, including but not limited to breast, pancreastic, prostate and colon cancers,

glioblastoma, myeloma, diabetes etc. The compounds provided herein are not limited to therapeutic uses; any additional uses for this class of compounds are also contemplated.

Experiments were conducted during development of embodiments of the present invention to develop a class of compounds for the inhibition of the menin-MLL interaction, and for treatment of MLL leukemias, other cancers, and other diseases and conditions. High Throughput Screening was performed at the NIH MLPCN (Molecular Libraries Probe

Production Centers Network) to identify additional lead compounds that target menin and inhibii the menin-MLL interaction. A collection of about 300,000 compounds was screened using a fluorescence polarization assay with a fluorescein-labeled MLL-derived peptide comprising the high affinity menin binding motif (MBM1) (Grembecka et al, 2010; herein incorporated by reference in its entirety). A stepwise procedure, including two fluorescence polarization assays with fluorescein- and Texas Red-labeled ΜΒΜΊ for primary screening, followed by H'T'RF (Homogenous Time Resolved Fluorescence) assay for secondary screening and NMR experiments to validate direct binding of compounds to menin, was applied to identify menin- MLL inhibitors. One of the most potent compounds identified by HTS at MLPCN was B2, with a halfmaximal inhibitory concentration (TC50) value of 14 μΜ for inhibition of the menin-MLL interaction. Experiments were conducted during development of embodiments of the present invention to develop analogues of B2. It was determined that removal of the hydroxy! group from the aliphatic chain did not affect the activity, as B lthat is missing this functional group has almost the same activity as the parent compound (ICso = 1 8 μ.Μ, Example 9). For ease of synthesis, this group was absent in subsequent compounds. R eplacement of one of the phenyl groups in B lwith a cyciopenthyi substituent resulted in more than 10-fold improvement in IC¾ value for B l HICso = 883nM, Example 9). Bl lis a racemie mixture of two enantiomers , which was then separated by HPLC and activity of the enantiomers was tested individually.

Remarkably, both isomers demonstrated similar, submicromolar activity for inhibition of the menm-MLL interaction (ICso 336 nM and 412 nM, for BI9 and B20, respectively, Example 9). The lack of a very significant difference in the activity of these compounds indicates that both phenyl and cyclophenthyl are realatively well tolerated by the binding pockets on menin where these substituents bind. A compound missing the cyciopenthyi ring B76 (NC) was also synthesized, and is about 3 orders of magnitude weaker than the most potent compound (IC50 = 250 μΜ), servingas a negative control compound in cellular experiments.

Similar experiments to the above were performed to investigate the importance of other positions on the B 19 and related structures. Through such experiments, very potent inhibitors of the me in-MLL interaction were developed (see Example 9).

In some embodiments, compounds of the present invention comprise a general formula of formula I:

Figure imgf000023_0001

In some embodiments, substituents Y, X, A, and R' -R" are independently selected from functional groups that comprise or consist of a combination of the following moieties:

Single atoms: H, CI, Br, F, or I;

11 Alkaries (aikyl groups): methane (methyl), ethane (ethyl), propane (propyl), butane (butyl), pentane (pentyl), hexane (hexyl), or any suitable straight chain or branched C:-C20 aikane;

Alkenes: methene, ethene, propene, butene, pentene, hexene, or any suitable C'-C20 alkene; Aikynes: methyne, ethyne, propyne, butyne, pentyne, hexyne, or any suitable C'-C20 alkyne; Cycloalkanes: cyclopropane, cyclobutane, cyclopentane, cyclohexane, or any suitable C'-C20 cycioaikane;

Aromatic rings ..(e.g.. carbon-only or heteroaromatics (e.g., heteroaiyl)): furan, henzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazoie, oxazoie, benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, napthalene, pyridine, quinolone, isoquinoime, pyrazine, quinoxal ne, pyrimidine, quinazoline, pyridazine, cinnoime, phthalazine, triazine (e.g., 1 ,2,3-triazine; 1 ,2,4-triazine; 1 ,3,5 triazine), thiadiazole, etc.;

Haioaikanes: halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomeihane), di-and trihalo methane (e.g., trichl or o ethane, tribromomethane, trifluoromethane, triiodomethane), 1 -hafoethane, 2-haloethane, 1,2-dihaloethane, ! -halopropane, 2- haiopropane, 3-halopropane, 1 ,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1 ,2,3-trihalopropane, and any other sutable combinations of alkanes (or substituted alkanes) an halogens (e.g., CI, Br, F, I, etc.);

Alcohols: OH, methanol, ethanol, propanol, butanol, pentanol, hexanol, cyclic alcohols (e.g., cyciohexanoi), aromatic alcohols (e.g., phenol), or any other suitable combination of an OH moiety with a second moiety;

Ketones: methyl methyl ketone (acetone), methyl ethyl ketone (butanone), propyl ethyl ketone (pentanone), ), or any other suitable combination of alkyl chains with =0;

Carboxylases: methanoate, ethanoate, propanote, butanoate, pentanoate, hexanoate, or any other suitable combination of aikyl chain with 00 ";

Carboxylic acids: methanoic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, or any other suitable combination of aiky l chain with OOH;

Ethers: methoxy, ethoxy, methylmethoxy, ethylmethoxy, or any other suitable combination of alkyl chains surrounding an O; Amides: metlianamide (CONH2), etbanaraide (CH2CONH2), propanamide ((CH2)2CONH2), alkaifamide ((CH2)nCONH2), n-methyl alkaifamide ((C&^CQNHCiT,), e-methyl alkannamide ((CH2)DNHCOCH3), n-alkyl alkannamide ((CH2)nCONH(CH2)mCH3), c- methyl alkannamide ((CH2)nNHCO(CH2)mCH3), etc.;

Primary amines: NH2, methylamine, etliylamine, cycfopropylaini e, etc.;

Secondary amines: aminomethvl (NHCH3), aminoethyl (NHCH2CH})9 methyl- atninomethyl (CH2NHCH3; aka methylamine-methane), alkyf -aminomethane ((CH2)nNHCH3), etc.;

Tertiary amines: dimethylamine (N(CH3)2), dimethylamine Ν(0¾)2), methyl-ethyl-amine

(NCH3CH2CH3), methaiie-dietliyiamrae (CH2 (CH2CH3)2; a a raethylamrae-di ethane), etc.;

Cvanos: methyl carbonitrile (CH2CN), ethyl carbonitrile ((CH^ CN), alkyf carbonitrile

((CH2)nCN), etc.

Thiols: methanethiol (CH2SH), ethanethiol ((CH2)2SH), alkan ethiol ((CH2)nSH), etc

Sulfides: dimethyl sulfide (C¾SC¾), methyl-ethyl sulfide (CH2SCH2CH3), alkyf -alkyf1 sulfide ((CH2)nS(CH2)m-iCH3), etc.;

Sulfoxides: dimethyl sulfoxide (CH2SOCH3), methyl-ethyl sulfoxide i fSOi ! U Π ; ί. alkyf- alkyr sulfoxide uCH . i SOiCM.. ) ( Ή . etc;

Sulfone: dimethyl sulfone (CH2SQ2CH3; aka methyi-sulfone-methyl), methyl-ethyl sulfone

(CH2SO2CH2CH3; aka methyi-suffone-etliyi), alkyf -alkyf" sulfone ((CH2)nS02 (CH2)m. 1CH3; aka alkyf -suifone- alkyf1), R S02Ry (wherein Rx and Ry are independently selected from any of the moieties pro vided in this list or combinations thereof!, etc.;

Sulfinic acids: S(¾H, methyl sulfinic acid (CH2S02H), ethyl sulfide acid ((CH2)2S02H), alkyf sulfinic acid ((CTr^nSCMI), etc;

Phosphates: OP; () ·{ ()! 1 · .. methyl phosphate ·: < Π >ΟΡ! Ο κ θί ! !.> ;·. ethyl phosphate

ί ί ( 'ϋ ') ·ί)Ι;'ί O H O! i b S. alkyf phosphate { { CI ί.>)··ϋΡ·: O H Oi i M etc

In various embodiments, the above listed moieties are attached at the R!-R6 positions in any suitable conformation. In some embodiments, the above listed functional groups are combined to produce the substituents depicted in compounds B1-B76 of Ta ble 1. In other embodiments, additional compounds, not depicted in Table l or described herein by name or formula, are formed by combination of formula I and the functional groups described herein. In some embodiments, substituents not depicted in Table 1 or explicitly listed herein, are within the scope of the present invention, and may be appended formula I to yield compositions within the scope of the present invention.

Formula I is provided herein as an exemplary scaffold of the general class of compounds provided herein. While this scaffold, with any combination of the substitue ts depicted or described herein (e.g., explicitly or through combination of functional groups), is within the scope of embodiments of the invention, the present invention is not limited to such compounds. Compounds comprising substitutions and/or addition/deletion of substituents that produce functional equivalents and/or improved functionality (e.g., enhanced therapeutic effect, enhanced bioavailability, improved human tolerance, reduced side effects, etc.) are also within the scope of embodiments of the present invention. For example, in some embodiments, compounds of the present invention comprise a general formula of formula Π:

Figure imgf000026_0001

In other embodiments, compositions are limited to compounds defined by a subset of formulas I and/or II. For example, in some embodiments, compounds are limited to those with at least one heterocycle at R1 and/or R2. In certain embodiments, Y is limited to OR ', wherein R7 is not H.

In some embodiments, compounds are limited to those without an OH at the Y position. Other exemplary embodiments comprise a heterocycle at the A position. Compounds and

compositions may also caontain additional limitation on the scope of suitable compounds.

In some embodiments, the present invention provides compositions and methods for prevention and/or treatment of leukemia (e.g. MLL -related leukemia and other acute leukemias). In some embodiments, the present invention provides compositions and method for the inhibition of the protein-protein interaction between meni and MLL fusion proteins and/or menin and MLL wild type proteins (both MLL 1 and MLL2). In some embodiments, compositions and methods inhibit the interaction that is important for the oncogenic (e.g. leukemogenic) potential of MLL fusions. In some embodiments, the present invention provides small molecule inhibitors of interactions between menin and MLL fusion proteins and/or menin and MLL wild type proteins (both MLL ! and MLL2). In some embodiments, compositions and methods reverse (e.g. inhibit, decrease, abolish, etc.) the oncogenic (e.g. leukemogenic) potential of MLL fusion proteins, MLL-PTDs (Partial Tandem Duplications) and MLL wild type. In some embodiments, compositions find utility in targeted therapies (e.g. anti-leukemia agents). In some embodiments, compounds block menin-MLL interactions.

In some embodiments, the present invention provides compositions which inhibit the interaction between MLL (e.g. MLL fusion proteins and MLL wild type) and menin. In some embodiments, any compounds, small molecules (e.g. pharmaceuticals, drags, drag-like molecules, etc.), macromolecules (e.g. peptides, nucleic acids, etc.) and/or macromolecular complexes which inhibit the MLL-menin interaction find utility in the present invention. In some embodiments, the present invention provides small molecule compounds which inhibit MLL-menin and MLL fusion protein-menin interactions. In some embodiments, compositions of the present invention decrease the affinity of menin forMLL fusion proteins and/or MLL (e.g. MLL wild type protein) for menin. In some embodiments, compositions of the present invention disrupt bonding (e.g. hydrogen bonding, ionic bonding, covalent bonding, etc.), molecular interactions (e.g. hydrophobic interactions, electrostatic interactions, van der Waals interactions, etc.), shape recognition, and/or molecular recognition between MLL (e.g. MLL fusion proteins or MLL wild type protein) and menin. However, an understanding of the mechanisms of action is not required to practice the invention and the invention is not limited to any particular mechanism of action.

In some embodiments, compounds are provided that exhibit a threshold level of inhibition the MLL-menin interaction (e.g., as determined by a suitable assay (e.g., fluorescence polarization competition experiments)). In some embodiments, compounds exhibit an effectiveness (e.g., in vitro activity) in inhibiting the menin-MLL interaction, as measured by ICso value, of less than ΙΟΟμΜ (e.g., <lnM... lOnM... lOOnM... Ι μΜ... 10μΜ...50μΜ). In some embodiments, compounds have IC5.3 values of less than ΙΟμΜ, less that Ι μΜ, less than ! OOnM, less than 10 nM, etc. (e.g., as determined by fluorescence polarization competition assay).

The present invention provides any small molecules or classes of small molecules which disrupt, target, or inhibit MLL/menin and MLL fusion protein/menin interactions; and/or treat/prevent leukemia. In some embodiments, small molecules are effective in inhibiting the interaction of MLL- fusion proteins with menin or MIX wild type protein with raenin, in particular embodiments, the present invention provides a class of small molecules comprising the general structure of formula I. In some embodiments, small molecules of the present invention inhibit the interaction of MLL (e.g. MLL-fusion proteins or MLL wild type, both MLL! and MLL2) with menin. In some embodiments, small molecules of the present invention inhibit the oncogenic (e.g. leukemogenic) effects of MLL-fusion proteins, and/or MLL-menin and MLL fusion protein-nienin interactions. In some embodiments, small molecules of the present invention treat and/or prevent leukemia (e.g. MLL-dependant leukemias, MLL-related ieukemias, or other leukemias with and without high level of HOX genes expression etc.),

In some embodiments, the present invention provides administration of compositions of the present invention to subjects (e.g. leukemia patients) to treat or prevent disease (e.g. cancer, leukemia, MLL-related leukemia, etc.). In some embodiments, the present invention provides administration of compositions for the treatment or prevention of leukemia (e.g. acute leukemias, chronic ieukemias, lymphoblastic leukemias, lymphocytic leukemias, myeloid leukemias, myelogenous leukemias, Acute lymphoblastic leukemia (ALL), Chronic lymphocytic leukemia (CLL), Acute myelogenous leukemia (AML), Chronic myelogenous leulcemia (CML), Hairy cell leukemia (HCL), T-celi prolymphocyte leukemia (T-PLL), Large granular lymphocytic leukemia, MLL -positive ieukemias, MLL-induced lukemias, ieukemias with MLL

rearrangements, MLL-PTD leukemias, etc.).

In some embodiments, any of the compounds described herein are co-administered or used in combination with a known therapeutic agent (e.g., methotrexate, 6-mercaptopurine, antibody therapies, etc.). In some embodiments, a compound of the present invention is coadministered with another therapeutic agent effective in treating one or more leukemias.

In some embodiments, a compound of the present invention is co-administered with one or more therapeutic agents approved for the treatment of Acute Lymphoblastic Leukemia (ALL), for example: ABITREXATE (Methotrexate), ADRIAMYCIN PFS (Doxorubicin

Hydrochloride), ADRIAMYCIN RDF (Doxorubicin Hydrochloride), ARRANON (Nelarabme), Asparaginase Erwinia chrysanthemi, CERUBIDINE (Daunorubicin Hydrochloride), CLAFEN (Cyclophosphamide), CLOFARABINE, CLOFAREX (Clofarabine), CLOLAR (Clofarabine), Cyclophosphamide, Cytarabine, CYTOSAR-U (Cytarabine), CYTOXAN (Cyclophosphamide), Dasatinib, Daunorubicin Hydrochloride, Doxorubicin Hydrochloride, Erwinaze (Asparaginase Eiwinia Chrysa themi), FOLEX (Methotrexate), FOLEX PFS (Methotrexate), GLEEVEC (Imatinib Mesylate), ICLUSIG (Ponatinib Hydrochloride), Imatinib Mesylate, MARQIBO (Vincristine Sulfate Liposome), Methotrexate, METHOTREXATE EPF (Methorexate), MEXA'T'E (Methotrexate), MEXATE-AQ (Methotrexate), Nelarabine, NEOSAR

(Cyclophosphamide), ONCASPAR (Pegaspargase), Pegaspargase, Ponatinib Hydrochloride, RUBID OMYCIN (Daunorubicin Hydrochloride), SPRYCEL (Dasatimb), TARABINE PFS (Cytarabine), VINCASAR PFS (Vincristine Sulfate), Vincristine Sulfate, etc.

In some embodiments, a compound of the present invention is co-administered with one or more therapeutic agents approved for the treatment of Acute Myeloid Leukemia ( AML), for example: ADRIAMYCIN PFS (Doxorubicin Hydrochloride), ADRIAMYCIN RDF

(Doxorubicin Hydrochloride), Arsenic Tri oxide, CERUB1DJNE (Daunorubicin Hydrochloride), CLAFEN (Cyclophosphamide), Cyclophosphamide, Cytarabine, C-YTOSAR-U (Cytarabine), CYTOXAN (Cyclophosphamide), Daunorubicin Hydrochloride, Doxorubicin Hydrochloride, NEOSAR (Cyclophosphamide), RUBIDOMYCIN (Daunorubicin Hydrochloride), TARABINE PFS (Cytarabine), TRISENOX (Arsenic Trioxide), VINCASAR PFS (Vincristine Sulfate), Vincristine Sulfate, etc.

In some embodiments, a compound of the present invention is co-administered with one or more therapeutic agents approved for the treatment of Chronic Lymphocytic Leukemia (CLL), for example: Alemtuzumab, AMBOCHLORIN (Chlorambuc l), AMBOCLORIN

(Chlorambucil), ARZERRA (Ofatumumab), Bendamustine Hydrochioride, CAMPATH

(Alemtuzumab), CHLORAMBUCTLCLAFEN (Cyclophosphamide), Cyclophosphamide, CYTOXAN (Cyclophosphamide), FLUDARA. (Fludarabine Phosphate), Fludarabine Phosphate, LEUKERAN (Chlorambucil), LINFOLIZTN (Chlorambucil), NEOSAR (Cyclophosphamide), Ofatumumab, TREANDA (Bendamustine Hydrochloride), etc.

In some embodiments, a compound of the present invention is co-administered with one or more therapeutic agents approved for the treatment of Chronic Myelogenous Leukemia (CML), for example: BOSULIF (Bosutinib), Bosutinib, CLAFE (Cyclophosphamide), Cyclophosphamide, Cytarabine, CYTOSAR-U (Cytarabine), CYTOXAN (Cyclophosphamide), Dasatimb, GLEEVEC (Imatinib Mesylate), ICLUSIG (Ponatinib Hydrochloride), Imatinib Mesylate, NEOSAR (Cyclophosphamide), Niiotinib, Omacetaxme Mepesuccinate, Ponatinib Hydrochloride, SPRYCEL (Dasatinib), SYNRIBO (Omacetaxine Mepesuccinate), TARABINE PFS (Cytarabine), TASIGNA (Nilotinib), etc.

In some embodiments, a compound of the present invention is co-administered with one or more therapeutic agents approved for the treatment of Meningeal Leukemia, for example: CYTARABINE, CYTOSAR-U (Cytarabine), TARABINE PFS (Cytarabine), etc.

In some embodiments, the compositions of the present invention are provided as pharmaceutical and/or therapeutic compositions. The pharmaceutical and/or therapeutic compositions of the present invention can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.

Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers; aqueous, powder, or oily bases; thickeners; and the like can be necessary or desirable. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. Compositions and formulations for parenteral, intrathecal or intraventricular administration can include sterile aqueous solutions that can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Pharmaceutical and/or therapeutic compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self emulsifying solids and self emulsifying semisolids.

The pharmaceutical and/or therapeutic formulations of the present invention, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical/nutriceutical industries. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipieiit(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid earners or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present invention can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention can also be formulated as suspensions in aqueous, non aqueous, oil-based, or mixed media. Suspensions can further contain substances that increase the viscosity of the suspension including, for example, sodium earhoxymethylcellulose, sorbitol and/or dextran. The suspension can also contain stabilizers. In one embodiment of the present invention the pharmaceutical compositions can be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product.

Dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well .known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect, and the practical level of therapeutic effect obtainable. Generally, it is advisable to follow well-known pharmacological principles for administrating chemotherapeutic agents (e.g., it is generally advisable to not change dosages by more than 50% at time and no more than every 3-4 agent half-lives). For compositions that have relatively little or no dose-related toxicity considerations, and where maximum efficacy is desired, doses in excess of the average required dose are not uncommon. This approach to dosing is commonly referred to as the "maximal dose" strategy. In certain embodiments, the compounds are administered to a subject at a dose of about 0.01 mg kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are coadministered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. Dosing may be once per day or multiple times per day for one or more consecutive days.

In some embodiments, compounds and compositions of the present invention are prepared using any suitable synthesis and manufacturing techniques. In certain embodiments, compounds are prepared according to the following general methods. Tn various embodiments, compounds of type 1.3 can be prepared according to Scheme 1 below, starting from an appropriate 4-methanol substituted piperidine, addition with a 1,3- dihalosubstituted propane gives intermediate 1.2A which upon treatment with base, such as potassium carbonate or sodium hydride, in an aprotic solvent, such dimethyiformamide, and a heteroaryl or aryl phenol or amine gives examples of type 1.3. Alternatively, reaction of 1 .1 with epichlorohydrin derivatives provides intermediate 1.2B which upon treatment with base and a phenol or amine gives examples of type 1.3.

Figure imgf000032_0001

Alternatively, compounds may be prepared according to Scheme 2 starting from an appropriate amino ketone 2.1, double alk lation as before gives ketone 2.3, which upon treatment with an appropriate R" Grignard reagent or organolithiu reagent provides tertiary carbinols of type 2.4A. SCHEME 2

Figure imgf000033_0001

In another embodiment for R" substitution selected from alkyl, alkenyl, cvcioalkyl, or cycloalkeiiyl the Grignard reagent may optionally be prepared from an appropriate bromide precursor to give 2.5 which upon treatment with 2.3 give examples of type 2.4B. Furthermore, optional reduction of 2..4B using hydrogen and a heterogeneous catalyst, such as palladium on carbon, gives additional examples of type 2.4C.

Alternatively, in some embodiments, compounds are prepared according to Scheme 3. Starting from 4-cyanopiperidine hydrochloride 3.1 benzyl protection gives intermediate 3.2. Addition of Grignard or organo lithium R2. gives ketone 3.3, Subsequent addition of an appropriate R1 group, followed by deprotection using hydrogenolysss conditions gives 3.5. Final two-step alkylation using the previously described conditions (Scheme 1 , e.g. 1A or IB) provides examples of type 3.7 (Method A) or alternatively alkylation using previously prepared bromide intermediate 3.6 can accomplish formation of examples 3.7. SCHEME 3

Figure imgf000034_0001

In another embodiment, compounds are prepared according to Scheme 4 wherein intermediate 3.3 (prepared according to Scheme 3) is first deprotected to give aminoketone 4.1. Alkylation as previously described (Schemes 1 and 3) provides penultimate ketone 4.2, which upon subsequent treatment with organometalhc reagent derived from R1 gives example compounds 4.3.

SCHEME 4 alkylation

Figure imgf000034_0002
Method A or Method B

Scheme 3

3.3 4.1

Figure imgf000034_0003

4.2 4.3 Alternatively, certain R3 modifications are performed according to the general route outlined in Scheme 5 wherein the penultimate nitrile 5.1 is further modified to give examples 5.2A and 5.2B via basic hydrolysis. Reduction of nitrile 5, 1 using Raney-Nickel and hydrogen gives example benzyl amine 5.3, which is subsequently functio alized with acid and sulfonyl chlorides to give amide 5.4A and sulfonamide 5.413, respectively.

Figure imgf000035_0001

5.4B

In some embodiments, compounds of type 6.1 , 6.2, 6.3 A, and 6.3B are obtained as outlined in Scheme 6. Imide 6.1, obtained using methods from Schemes 1-4, is treated with hydrazine to provide examples of type 6,2. Aromatic amine 6.2 is further functionalized to giv amides and sulfonamides 6.3A and 6.3B, respectively. SCHEME 6

Figure imgf000036_0001

Figure imgf000036_0002

6.3A

In another aspect, penultimate bromide 7.1, obtained using methods described from Schemes 1 -4, are treated with Palladium (II) based cross-coupling conditions to prepare biaryl examples of type 7.2. Alternatively, preparation of azide 7,3 from 7.1 , and a subsequent copper azide-alkyrse cycloaddition leads to 1,2,3-triazole examples of type 7.4.

SCHEME 7

Figure imgf000036_0003

7.3 eOH 7.4

K2C03 In another embodiment, compounds are prepared according to Scheme 8 wherein hydroxy! examples of type 8, 1 is treated with strong acid in the presence of sodium azide. The solvolysis reaction provides azide intermediate 8,2, which upon reduction provides example 8.3. In another aspect, example amine 8.3 is treated with an alkylating agent or an aldehyde or bis aldehyde under reducing conditions using for example, sodium borohydride, to give examples 8.4A and 8.4B.

SCHEME 8

Figure imgf000037_0001

8.4B The above synthesis schemes are exemplary. Copounds are not limited to those produced through, or capable of being produced through such methods.

EXPERIMENTAL

As used herein, the term "EtOAc" means ethyl acetate, "DCM" means dichloromethane, "DIPEA" means N,N-diisopropylethylamine, "DMF" means N,N-dimetbylforaiamide,

"DTBAD" means di-fcri-butyl azodicarboxylate, "HATU" means 2-(7-aza- 1 H-benzotriazole- 1 - yl)-l, l,3,3-tetramethyluroniurn hexafluorophosphate, "LCMS" means liquid chromatography/mass spectrometry, "MeOH" means methanol, "[M+H] " means the protonated mass of the free base of the compound, "M. p." means melting point, "NMR" means nuclear magnetic resonance, "Rt" means retention time (in minutes), "THF" means tetrahydrofuran.

Microwave assisted reactions were performed in a single-mode reactor: EmrysfM Optimizer microwave reactor (Personal Chemistry A.B., currently Biotage).

Hydrogenation reactions were performed in a continuous flow hydrogenator H-CUBE® from ThalesNano Nanotechnology Inc. or using a Parr hydrogenation shaker apparatus.

Analytical thin layer chromatography was performed on Analtech silica gel GF 250 micron plates using reagent grade solvents. Normal phase flash silica gel-based column chromatography was performed using ready-to-eonnect cartridges from ISCO, on irregular silica gel, particle size 15-40 μηι on a Combi- flash Companion chromatography system from ISCO.

Low resolution mass spectra were obtained on an Agilent 1200 series 6130 mass spectrometer. High resolution mass spectra were recorded on a Waters Q-TOF API-US.

Analytical HPLC was pertonned on an HP 1100 with UV detection at 214 and 254 nm along with ELSD detection, LC/MS (J-Sphere80-C18, 3.0 x 50 mm, 4.1 min gradient,

5%[0.05%TFA/CH3CN]:95%[0.05%TFA/H2O] to 100%[0.05%TFA CH3CN]. Preparative RP- HPLC purification was performed on a custom HPl 100 automated purification system with collection triggered by mass detection or using a Gilson Inc. preparative UV-based system using a Phenonienex Luna CI 8 column (50 x 30 mm I.D., 5 μιη) with an acetonitrile (unmodified)- water (0.1% TFA) custom gradient.

For LC-MS-characterization of the compounds of the present invention, the following methods were used.

Method 1 : The HPLC measurement was performed using an Agilent 1200 system comprising a binary pump with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a SQ mass spectrometer and Polymer Labs ELSD. The MS detector was configured with an ES ionization source. Nitrogen was used as the nebulizer gas. The source temperature was maintained at 350 °C. Data acquisition was performed with Agilent Chemstation software. Reversed phase HPLC was carried out on a Kinetex C I 8 column (2,6 μ,ηι, 2.1 x 30 μχη) from Phenomenex, with a flow rate of 1.5 raL/min, at 45 °C. The gradient conditions used are: 93% A (water + 0.1% TFA), 7% B (acetonitrile), to 95% B in 1.1 minutes, returning to initial conditions at 1.1 1 minutes. Injection volume 1 μΙ_. Low-resolution mass spectra (single quadruple MSD detector) were acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage was 3.0 kV and the fragmentor voltage was 100V.

Method 2: Using method 1 instrument and column conditions. The gradient conditions used are: 93% A (water + 0.1% TFA), 7% B (acetonitrile), to 95% B in 2.0 minutes, returning to initial conditions at 2, 1 1 minutes. Injection volume 1 μ3_,. Low-resolution mass spectra (single quadruple MSD detector) were acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage was 3.0 kV and the fragmentor voltage was I00V.

Chiral purification of racemic mixtures was readily accomplished using a supercritical fluid chromatography (SFC) instrument from Thai Scientific Instruments. Chiral analytical and semi-prep SFC purification columns were from Chiral Technologies.

Ή NMR spectra were recorded either on a Broker DPX-400 or on a Bruker A.V-500 spectrometer with standard pulse sequences, operating at 400 MHz and 500 MHz respectively. Chemical shifts (δ) are reported in parts per million (ppm) downfieid from tetramethylsilane (TMS), which was used as internal standard,

Example 1

Preparation of intermediate (l-(3-(4-bromophenoxy)propyl)piperidin-4'

Figure imgf000039_0001

Step 1. To a DMF solution (40 mL) of 4-benzoylpiperdine hydrobromide (2.70 g, 10 mmol) and K2CO3 (6.9 g, 50 mmol) was added 1 -bromo-3 -chloropropane (1.55 g, 10 mmol). The reaction progress was monitored by LC-MS and upon completion of the reaction (~2 h) the mixture was poured onto EtOAc (60 mL) and water (25 mL). The organic layer was removed and the aqueous phase extracted with EtOAc (2x40 mL), The organic layers were combined, washed sequentially with aq. LiCl and brine, and then dried over Na2S04 and concentrated to dryness under reduced pressure to afford (l-(3-chloropropyl)piperidin-4-yl)diphenylmethano] (3.0 g, 86%).

Step 2. The crude chloride (0.5 g, 1.45 mmol) from step 1 was dissolved in CH3CN (12 mL) with K2CO3 (270 mg, 2.81 mml) and treated with excess 4-bromophenol (775 nig, 4.35 mmol). The mixture was allowed to stir overnight at rt. The reaction was poured into H20 and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine, dried over Na2S04, and evaporated to give the crude bromide. Purification over silica gel

(EtOAc/'hexanes) using automated normal phase chromatography provided title bromide as a clear viscous oil (550 mg, 79%): LC-MS (>98%) m/z ----- 480.3 [M+H]. Example 2

Preparaiioi! of 4-(3-(4-(hy propoxy)beiizonitrile (Bl)

Figure imgf000040_0001

Step 1. 4-Benzoylpiperdine hydrobromide (2.70 g, 10 mmol) was combined with K2C03 (6.9 g, 50 mmol) in DMF (-40 mL), followed by l-bromo-3-chloropropane (1.55 g, 10 mmol). The reaction progress was monitored by LC-MS and upon completion of the reaction (~2 h) 4- cyanophenol (1.3 g, 1 lmmol) was added and the reaction allowed to stir overnight. The mixture was poured onto water and extracted with ethyl acetate, washed with brine and dried over Na2S04. The volatiles were removed under reduced pressure and the crude mixture purified on silica gel (0-100% EtOAc in hexanes) to give 2.71g (78% yield over 2 steps) of4-(3-(4- benzoylpiperidin- 1 -yl)propoxy)benzonitrile: LC-MS (>98%) m/z = 349.2 [M+H].

Step 2. 4-(3-(4-Benzoylpiperidin- 1 -yl)propoxy)benzonitrile (0.5 g, 1.4 mmol) was dissolved in dry THF (-15 mL), and a solution of phenylmagnesium bromide (0.9 mL, 2M, 1.8 mmol) was added and the reaction stirred for 6 h. The reaction was quenched (sat. NH4CI) and extracted into EtOAc (2x). The organic layers were dried over N ?S0 and the volatiles removed under reduced pressure. The crude residue was purified on silica gel (EtOAc/hexanes) to give 417 mg (70% yield) of title compound Example B l : !H NMR (4G0MHz, CDCI3) δ 7.58 (2H, d, ./ S.X Hz), 7.50 (4H, d, ./ 7.6 ;·. 7.30 (4H, q, ./ 8 :·. 7.20 (2H, t, ./ 7.2 Hz), 6.94 (2H, d, ,/ 8.8 Hz), 4.06 (2H, i, ./ 6 Hz), 3.07 (2H, d, J=l 1.2 Hz), 2.59 (2H, t, ./ " Hz), 2.53-2.46 ( 1H, m), 2.14- 2.01 (4H, m), 1.66- 1.55 (4H, m), LC-MS (>98%) m/z = 427.0 [M+H]; HRMS = 427.2386

[M+H], 100% calculated for C28H31N2O2, 427.2386. Example 3

Preparation of 4-(3-(4-(cyclopentyl(hydroxy)(phenyl)methyl)piperidin- y1)propoxy)benzonitrile (Bl 1)

Figure imgf000041_0001

Step 1. 4-(3-(4-Benzoylpiperidin- 1 -yl)propoxy)benzonirrile. 4-Benzoylpiperdine hydrobromide (2.70 g, 10 mmol) was combined with K2CO3 (6.9 g, 50 mmol) in DMF (-40 mL), followed by l -bromo-3-chloropropane (1.55g, 10 mmol). The reaction progress was monitored by LC-MS and upon completion of the reaction (~2 h) 4-cyanophenoi (1.3 g, 1 mmol) was added and the reaction allowed to stir overnight. The mixture was poured onto water and extracted with ethyl acetate, washed with brine (2x) and dried over ¾S0 . The volatiles were removed under reduced pressure and the crude mixture purified on silica gel (0-100% EtOAc in hexane) to give 2.71g (78% yield over 2 steps) of the title intermediate compound: LC-MS (>98%) m/z = 349.2 [M+H].

Step 2. 4-(3-(4-Benzoylpiperidin- l-yr)propoxy)benzonitri3e ( 1.4 g, 4 mmol) was dissolved in dry THF (-25 mL), heated to 60° C and a solution of cyclopentylmagnesium chloride (4 mL, 2M) was added and the reaction stirred for 1 h. The reaction was quenched (sat. NH4CI) and extracted into EtOAc (2x). The organic layers were dried over Na2S04 and the volatiles removed under reduced pressure. The crude residue was purified on silica gel (0-4% MeOH in CH2C12). The combined fractions were further purified by reverse phase

chromatography to give 1 17 mg (7% yield) of analytically pure title compound: Ή NMR (400 MHz, CDC¾) δ 7.54 (2H, d, J=8.8 Hz), 7.3? (2H, d, J=7.6 Hz), 7.31 (2H, t, J=7.6 Hz), 7.22 (1H, t, J=7. Hz), 6.89 (2H, d, J=8.8 Hz), 4.02 (2H, t, J=6 Hz), 3.12-3.00 (2H, m), 2.74-2.62 (3H, m), 2.09-1.95 (4H, m), 1.80-1.60 (4H, m), 1.58-1.40 (7H, m), 1.25-1.24 (1H, m), 1.11 -1.09 (1H, m); LC-MS (>98%) m z = 419.3 [M+H] ; HRMS = 419.2701 [M+H], 100%, calculated for C27H35N2O2, 419.2699.

Example 4

Preparation of 4-(3-(4-(amino(cyclopentyl)(phenyl)methyl)piperidin-

Figure imgf000042_0001

Step 1 . A CHCI3 (4.78 mL, 0.25 M) solution of 4-(3-(4- (cyclopentyl(hydroxy)(phenyl)methyl)piperidm- 1 -ylipropoxy ibenzonitrile (0.5 g, 1.19 mmol) and sodium azide (1.16 g, 17.9 mmol) was cooled to 0 °C. To the solution H2S04 was added dropwise (0.28 mL, 9.3 mmol). The mixture was allowed to warm to rt over 4h with stirring, then re-cooled to 0 °C and treated with NH4OH till pH was basic. The biphasic solution was extracted with DCM (3 ) and the organic layers combined and dried over MgS04.

Concentration under reduced pressure and drying in vacuo afforded a crude oil. Purification by flash chromatography (DCM, MeOH, NH4OH) afforded 4-(3-(4~

(azido(cyclopentyl)(phenyl)methyl)piperidin-l -yi)propoxy)benzonitrile (45 mg, 10%): LC-MS (>98%) m/z = 444.3 [M+H].

Step 2. 4-(3-(4-(azido(cyclopentyl)(phenyi)methyl)piperidin- 1 -yi)propoxy)benzonitriie (30 mg, 0.07 mmol) was dissolved in degassed EtOH (0.5 mL) and Pd/C (2.7 mg) added in one portion. Reaction was placed under a balloon of H? gas and allowed to stir for 4h while stirring at rt. The reaction was filtered over Celite and rinsed with MeOH. The filtrate was concentrated to afford an oil RP-HPLC preparative purification afforded the title compound 4-(3-(4- (cyclopentyl(hydroxy)¾>henyl)methyl)piperidin- 1 -yl)propoxy)bertzonitrile as a TFA salt. The mixture was treated with a StratoSpheer SPE MP- carbonate resin to give title compound as a free base (5.6 mg, 20%): Ή MR (400 MHz, CDC13) δ 7.54 (2H, d, .7-6.0 Hz), 7.43 (2H, d, J=7.2 Hz), 7.31 (2H, t, J=7.2 Hz), 7.22 (1H, t, J=l .2 Hz), 6.91 (2H, d, J=6.0 Hz), 4.02 (2H, t, J=8.4 Hz), 3.05-2,96 (2H, tn), 2.62 (1H, m), 2.47 (br s, 2H), 1.96-1.89 (4H, m), 1.73 (1H, m), 1.62-1.40 (9H, tn), 1.29-1.24 (2H, m), 1.13-1.05 (2H, m); LC-MS (>98%) m/z - 418.0 [M+H],

Example 5

Preparation of (l-(3-(4-(lH-l,2,3-triazol-l-yl)phenoxy)propyl)piperidin-4-

Figure imgf000043_0001

Step 1. Bromide mierinediaie ( l-(3-(4-bromophenoxy)propyl)piperidm-4- yl)diphenylmethanol (Al) ( 100 mg, 0.21 mmoi) was dissolved in EtQfLwater (2: 1, 3 mL) and treated with Na s (34 nig, 0.53 snniol), Cul (5 nig), and sodioum ascorbate (2.5 mg). The mixture was heated in a sealed tube for lh at 100 °C. The reaction was cooled to rt and poured onto EtOAc (10 mL). The organic phase was washed with brine, dried over Na^SC , and concentrated to dryness. RP-HPLC purification afforded the desired azide (45 mg, 46%): LC- MS (>98%) m/z - 443.1 [M+H] .

Step 2. Azide from step 1 (40 mg, 0.09 mmoi), eth nyltrimethylsilane (1 1 mg, 0.1 1 mrnol), K2CO3 (1 mg, 0.11 mmol), CUSO4 (1.5 rag), and sodium ascorbate (1.0 mg) were stirred overnight in MeOH:H20 (1:1, 10 mL). The mixture was poured onto H20, extracted with EtOAc (2x10 mL) and the organic layers combined and washed with brine. Concentration in vacuo and RP-HPLC purification afforded the title example triazoie (22 mg, 52%): LC-MS (>98%) m/z = 469.1 [M+H].

Example 6

enyl(l-(3-(4-(pyridm-4-yl)phenoxy)propyl)piperidin-4-yl)methanol (B35)

Figure imgf000043_0002
Bromide intermediate (l -(3-(4-bTomophenoxy)propyl)piperidin-4-yl)diphenylmethano] (Al) (75 mg, 0.15 mmoi), PdfdppfiCi? ( 15 mg), CsC03 ( 150 mg), and pyridm-4-ylboronic acid (30 mg) was placed under an argon atmosphere in a microwave vial. Degassed THF (3 niL) and 0.1 mL of water was added via syringe and the mixture heated for 30 min. at 90 °C in a Biotage microwave reactor. The reaction was partitioned between EtOAc (10 mL) and water (3 mL) and the organic phase isolated. The organic phase was subsequently washed with brine, dried over Na2S04, and concentrated to dryness. Purification by RP-HPLC afforded the title compound (30 mg, 41%): LC-MS (>98%) m/z = 479.1 [M+H] .

Example 7

Characterization of exemplary compounds

The compounds in Table 1 were synthesized with methods identical or analogous to those described herein. The Synthetic Example indicated in Table I refers to the compound identified above and corresponding synthetic method described therein. The requisite starling materials were commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis. 'The mass spectrometry data were obtained using either General LC- MS Method 1 or General LC-MS Method 2 as described above. LC-MS [M+H]+ means the protonated mass of the free base of the compound.

TABLE 1. Exemplary compounds

Figure imgf000045_0001

44

Figure imgf000046_0001
Figure imgf000047_0001

Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001

Figure imgf000054_0001

53

Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001

Example 8

Assays for assessing Menin-MLL inhibition

Fluorescence Polarization Assay. Assays effecti ve in monitoring the inhibition of the MLL binding to menin were developed during experiments performed during the development of embodiments of the present invention. A fluorescein-labeled 12-amino acid peptide derived from MLL conta ining the high affinity menin binding motif was produced (Yokoyania et al., Cell., 2005.123(2): p. 207-18., herein incorporated by reference in its entirety). Upon binding of the peptide (1.7 kDa) to the much larger menin (67 kDa), the rotational correlation time of the fluorophore (peptide labeled with fluorescein at N-terminus) changes significantly, resulting in a substantial increase in the measured fluorescence polarization and fluorescence anisotropy (excitation at 500 nni, emission at 525 run). The fluorescence polarization (FP) assay was utilized to determine the ¾ for the binding of menin and the MLL peptide using a serial dilution of menin and 50 nM f!uorescein-labe!ed MLL peptide. The titration curve demonstrates nanomolar affinity (Kj =56 nM) for the menin-MLL interaction.

The effectiveness of compounds (IC50 values) in inhibiting the menin-MLL interaction was determined in the FP competition experiments. Compounds that inhibit the interaction decrease the fluorescence anisotropy which is being used as a read-out for compound screening and for IC50 determination. For validation of the FP assay, a control competition experiment with unlabeled MLL peptide (no fluorescein attached) was performed. The competitive displacement of the fluorescein-labeled MLL peptide from menin by unlabeled MLL peptide was monitored. Using this assay, the IC50 value for the MLL peptide with menin: IC50 -0.23 uM. In some embodiments of the present invention, the same competition FP assay is used for screening compounds targeting menin and inhibiting the menin-MLL interaction.

Biological activity of menin-MLL inhibitors is demonstrated in Example 9. The IC50 values shown were measured using the above fluorescence polarization (FP) assay.

Example 9

In vitro Activity of Representative Menin-MLL inhibitors

Example Example IC50 (M)

Bl 1.67E-05 B40 1.74E-05

B2 1.4QE-05 B41 1.15E-06

B3 5.2QE-05 B42 9.56E-06

B4 9.8QE-05 B43 9.48E-07

B5 9.6QE-05 B44 4.5QE-05

B6 2.65E-05 B45 2.10E-05

B7 1.53E-05 B46 1.00E-04

B8 1.12E-05 B47 4.00E-05

B9 7.87E-05 B48 3.10E-05

BIO 2.90E-05 B49 7.08E-05

Bll 8.83E-07 B50 4.00E-05

B12 1.68E-06 B51 1.50E-05

B13 7.75E-05 B52 5.50E-05

B14 5.80E-05 B53 3.16E-05

B15 7.60E-06 B54 5.3QE-06

B16 8.6QE-05 B55 5.3QE-06

B17 5.70E-07 B56 4.2QE-06

B18 1.13E-06 B57 7.50E-05

B19 3.36E-07 B58 7.09E-07

B20 4.12E-07 B59 1.13E-05

B21 4.05E-06 B60 3.07E-07

B22 4.00E-06 B61 8.94E-06 B23 3.10E-05 B62 7.43E-07

B24 1.43E-05 B63 2.8QE-05

B25 4.00E-05 B64 4.05E-06

B26 3.95E-06 B65 4.37E-07

B27 1.39E-05 B66 1.97E-07

B28 1.31E-05 B67 1.15E-07

B29 8.30E-06 B68 1.10E-06

B30 4.00E-05 B69 2.42E-07

B31 1.40E-06 B70 2.26E-07

B32 2.08E-06 B71 8.00E-08

B33 5.85E-05 B72 1.11E-06

B34 1.39E-05 B73 2.59E-07

B35 3.06E-05 B74 2.95E-07

B36 2.26E-05 B75 2.25E-07

B37 2.50E-05

B76 (NC) 2.50-04

B38 2.07E-05

B39 8.3QE-05

REFERENCES

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984-93.

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51 -7.

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Claims

What is claimed is:
1 . A composition comprising a compound having the structure of formula T:
Figure imgf000067_0001
wherein Y is independently selected from OH, OR' , N¾, NHR' , or NR'¾ '°;
wherein R' selected from Cj -6-alkyl, monohalo-Ci-e-alkyl, polyhalo-Ci-6-alkyl, (C1-4- alkyloxy)-Ci-6~alkyl, (Ci-4-dialkylaniino)-C1.6-alkyl, CM-( C3-6-cycioaikyl), Ci-4-(Cs-6- beteroaryi), Ci-rlCs-e-aryl), C -OH, CM-NH2, and C1-4-CN;
wherein R7a and R7B are selected from Ci-e-alkyl, monohalo-Cj-6-alkyl, polyhalo-Cj-g- alkyl, (C -alky1oxy)-Ci-6-alkyl, (Ci-4-dialky{amino)-C1-6-a1kyl, Ci..4-( Cs-e-cycloalkyJ), C -(CS- 6-lieteroaryl), C].4-(C;..6~aryi), Cj.-4-OH, Ci- -NH2, and C1 -4-CN, or may form a ring between R'a and R?B with C3.7 carbons; wherein R 1 is aryl or heteroaryi and substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxyi, Ci-3-alkyi, Ci-3~alkyloxy, monohaio-Ci-3- alkyl, polyhalo-Ci-3-alkyl, and sulfonyl-Ci-3-alkyl;
wherein R" is selected from heteroaryi, heterocycle, carbocycie containing a C3..3 ring size, or acyclic Ci-e-alkyl;
wherein is substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxyi, Cj -3-aSkyl, -s-alkyloxy, monolialo-Ci _3-alkyl, polyhalo-Ci-3-aIkyl, and sulfonyl-C-i -3-aikyl ;
wherein A is a 1 ,4-disubstituted aryl or heteroaryi ring substituted with X and R:' and may contain a third group R6 independently selected from cyano, halo, hydroxyi, Ci-j-alkyl, Cj.j- alkyloxy, monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, sulfonyl-Cj-3-alkyl and sulfonamide;
wherein X is O, NH, or NR¾; wherein when X is NR.8, R8 may be independently selected from Ci-3-alkyl, Cj-3-alkyloxy, monohalo-C i-3-alkyl, polyhalo-C i-3-alkyl, and sulfonyl-Ci-3-alkyf wherein R3 is CN, S02NH2, S02NR9aR9b, CONR9aR9b, S02CH3, OCF3, CF3, CL CH3, CH2CN, CH2NH2, CH2NHC(0)R10, CH2NH8O2Ri0, N02, 4-pyridyL 3-pyridyL C(0)R, 1.2.3· triazole, OCH3; wherein R9a and R9omay be independently selected from hydrogen, Cj- -alkyl, or polyhalo-Ci -j-alkyl, or may form a ring between R9a and R9b with C3.7 carbons; wherein R,0 is Ci_. 3-alkyl; or polyhafo-Ci.3-alkyf;
wherein R'* is hydrogen, or Ci-3-alkyl; and
wherein R"1 is hydrogen, OH, or Ci..3-alkyl.
2. The composition of claim 1 , wherein one or both of R1 and R" are phenyl.
3. The composition of claim 2, wherein R1 is phenyl.
4. The composition of claim i, wherein Y is OH. 5. The composition of claim 1 , wherein A is a disubstituted phenyl group.
6. The composition of claim 5, wherein A is al ,4-disubstituted phenyl group.
7. The composition of claim 6, wherein A is a phenyl group connected to the rest of the scaffold at the 1 position and comprising a substituent of 30 or fewer atoms at the 4 position.
8. The composition of clai 6, wherein said phenyl has a substituent of 20 or fewer atoms at the 4 position. 9. The composition of claim 8, wherein said substituent at the 4 position comprises a heteroaryl.
10. The composition of claim 8, wherein said substituent at the 4 position comprises 5 or fewer atoms.
1 1. The composition of claim 10, wherein said substituent at the 4 position selected from the list consisting of CN, CI, Br, CF3, OCF3.
12. The composition of claim 10, wherei R 6 is a halogen.
13. The composition of claim 1, wherein X is O.
14. The composition of claim 1 , wherein one or both of R4 and are H. 15. The composition of claim 14, wherein R4 is H.
16. The composition of claim 15, wherein both R4 and RD are H.
17. The composition of claim 1, wherein the compound is selected from compounds B 1 -B76
18. A method for the treatment of a disease or condition comprising administering a composition of one of claims 1 or 17 to a subject suffering from said disease or condition.
19. The method of claim 18, wherein said disease or condition comprises a leukemia or other hematologic malignancies, solid tumor cancer, or diabetes.
20. The method of claim 19, wherein said leukemia comprises AML or ALL.
21. A method of inhibiting the interaction of MLL or MLL fusion protein and menin comprising administering composition of one of claims 1 or 17 to a sample comprising MLL or MLL fusion protein and menin.
A composition comprising a compound having the structure of formula 11:
Figure imgf000070_0001
wherein R '¾ and R 73 are independently selected from H, Cj .6-alk.yl, monohalo-Ci-e-alkyl, polyhalo-Ci-6-alkyl, (Cj-4-alkyloxy)-Ci-6-alkyl, (CM-dialkylaminoJ-Ci-e-alkyl, Ct- -( Cs-e- cyeloaJky!), CM-(Cs-6-heteroaryl), Cj -WCs-e-aryl), C -OH, C1 - H2, and C1..4-C , or may form a ring between R 78 and R ?b with C3-7 carbons;
wherein R1 is aryl or heteroarvl and substituted with 0, 1, 2, or 3 groups each
independently selected from cyano, halo, hydroxy!, Ci-3-alkyi, d-3-alkyloxy, monob.alo-C1.3- alky!, polyhalo-Ci-3-aJkyl, and suif0nyl-Cj.3-a.ikyl;
wherein R2 is selected from heteroaryl, heterocycle, carbocycle containing a Qs-s ring size, or acyclic Ci-6-alkyl;
wherein R2 is substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxy.!, Ci-3-alkyl, Ci-3-alkyloxy, monohalo-Ci-3-alkyi, polyhalo-Ci-3-alkyi, and suifonyl-C] -3-alkyl;
wherein A is a 1,4-disubstituted aryl or heteroarvl ring substituted with X and R3 and may contain a third group R° independently selected from cyano, halo, hydroxy!, d-3-alkyi, C1.3- alkyloxy, monohalo-Ci-3-a!kyl, polyhalo-Ci-3-a!kyl, sulfonyl-Ci-3-alkyl and sulfonamide;
wherein X is O, NH, or NR"; wherein when X is NR8, R* may be independently selected from Ci-3-alkyl, Ci-3-alkyloxy, nionohalo- -3-alkyl, polyhalo- -3-alkyl, and sulfonyl-Ci-3-alkyi wherein R3 is CN, SO.-M h. S02NR9aR9b, CONR.9aR9b, SO2CH3, (XT .. CF3, CI, CH3, CH2CN, α¾Ν1¾, CH2NHC(0)R10, CT-feNHSOzR10, N02, 4-pyridyl, 3-pyridyl, C(0)R, 1,2,3- triazole, OCH3; wherem R9a and Ry,J may be independently selected from hydrogen, d-3-alkyl, or polyhaio-Ci-3-alkyi, or may form a ring between R9d and R9b with C3-7 carbons: wherein R'° is Cj - 3-alkyl; or polyhaio-Cj.-3-alkyi;
wherein R4 is hydrogen, or C] -3-alkyl; and
wherein Rs is hydrogen, OH, or Cj -3-alkyl.
23. The composition of claim 22, wherem one or both of R1 and R2 are phenyl. 24 The composition of claim 23, wherein R is phenyl.
The composition of claim 22, wherein A is a disubstituted phenyl group.
26. The composition of claim 25, wherein A is al ,4-disubstituted phenyl group.
27. The composition of claim 2.6, wherem A. is a phenyl group connected to the rest of the scaffold at the 1 position and comprising a substituent of 30 or fewer atoms at the 4 position.
28. The composition of claim 27, wherein said phenyl has a substituent of 20 or fewer atoms at the 4 position.
29. The composition of claim 28, wherein said substituent at the 4 position comprises a heteroaryl.
30. The composition of claim 28, wherein said substituent at the 4 position comprises 5 or fewer atoms. 31. The composition of claim 30, wherem said substituent at the 4 position selected from the list consisting of CN, CI, Br, CF , OCF3.
32. The composition of claim 30, wherein R6 is a halogen. 33. The composition of claim 22, wherein X is O.
34. The composition of claim 22, wherem one or both of R4 and R5 are H.
35. The composition of claim 34, wherein R4 is H.
36 The composition of claim 35, wherein both R" and R5 are II.
37. A method for the treatment of a disease or condition comprising administering a composition of 2.2 to a subject suffering from said disease or condition. 38. The method of claim 37, wherein said disease or condition comprises a leukemia or other hematologic malignancy,solid tumor cancer, or diabetes.
39. The method of claim 38, wherein said leukemia comprises AML or ALL. 40. A method of inhibiting the interaction of MLL or MLL fusion protein and menin comprising administering composition of claim 22 to a sample comprising MLL or MLL fusion protein and menin.
41. A composition comprising e of formula I:
Figure imgf000072_0001
wherein A. is heteroaryl ring;
wherein X is O, H, or NR.8; wherein when X is NR8, Rd may be independently selected from Ci-3-alkyL C] -3-alkyloxy, monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, and sulfonyl-Ci -3-alkyi; wherein R3 is CN, S02NH2, S02NR9aR9b, CONR9aR9b, S02CH3, OCF3, CF3, CI, CJ¾, CH2CN, CH2NH2, ( '! i - 1 iC 'i O iR ". CH2NHS(32R10, NO .. 4-pyridyl, 3-pyridyl, C(0)R, 1 ,2,3- triazole, OCH3; wherein Rya and R9,J may be independently selected from hydrogen, d-j-alkyl, or polyhaio-Ci-3-alkyI, or may form a ring between R9° and R9b with C3-7 carbons: wherein R'° is C]_ 3-alkyl; or polyhalo-Ci..3-alkyl;
wherein R6 is selected from H, cyano, halo, hydroxy!, Ci-3-a3kyl, Ci-3-alkyloxy, monohalo-Ci-3-alkyl, polyhalo-Ci-3-alkyl, sulfonyl-Ci-3-alkyl and sulfonamide;
wherein Y is independently selected from OH, OR'', NH2, NHR7, or MR7aR7b; wherein R ? selected from C i .e-alky], monohalo-Ci-e-alkyl, poiyhalo-C-i-e-alkyl, (Ci_ -alkyIoxy)-C i-e-alkyl,
Figure imgf000073_0001
Ci-4-( Cs-e-cycloalkyl), Cw-(Cs-tf- heteroaryi), Ci^-iCs-e-aryl), C1 -4-OH, C14-MH2, and C1-4-CN; wherem R'S and R ?b are selected from C aJkyl, monohalo-C-i-e-alkyl, polyhalo-
C i-e-alkyl,
Figure imgf000073_0002
(Ci _4-dialkylamino)-Ci_6-alkyI, C M-( C'3_6-cycloalkyl), C 1-4- (Cs-c-heteroaryl), Ci4-(C5-6-aryl), Ci-4-OH, O-4-NH2, and CM-CN, or may form a ring between R ' a and R ' 0 with C3-7 carbons; wherein R 1 is aryl or heteroaryl and substituted with 0, 1 , 2, or 3 groups each
independently selected from cyano, halo, hydroxy!, Ci-3-alkyl, Cj -3-alky!oxy, monohaio-Ci-3- alky], polyhalo-Ci-3-alkyl, and sulfonyl-Ci-3-alkyl;
wherein R" is seiected from heteroaryl, heterocycle, carbocycle containing a€}.$ ring size, or acyclic C ,-.- ;iii-. i;
wherein R2 is substituted with 0, 1 , 2, or 3 groups each independently selected from cyano, halo, hydroxy!, Ci-j-alkyl, Ci-3-alkyloxy, monohalo-Cj -3-alkyl, polyhalo-Ci -3-alkyl, and sulfonyl-Ci-3-alkyl;
wherein R4 is hydrogen, or Cj .3-alkyl; and
wherein RJ is hydrogen, OH, or C-i-3-alky3.
42. The composition of claim 41 , wherein one or both of R1 and R7' are pheny l.
43. The composition of claim 42, wherein R1 is phenyl. 44. The composition of claim 41 , wherein Y is OH.
45. The composition of claim 41, wherein A is a pyridine.
46. The composition of claim 45, wherem A. is connected to X at its 3 position and R3 at is 6 position.
47. The composition of claim 41 , wherein RJ is a halogen.
48. The composition of claim 41 , wherein X is O. 49. The composition of claim 41, wherein one or both of R4 and R5 are H.
50. The composition of claim 49, wherein R"* is H.
51. The composition of claim 50, wherein both R" and R5 are H,
52. The composition of claim 41, wherein the compound is selected from compounds B37, B61, and 1364
53. A method for the treatment of a disease or condition comprising administering a composition of one of claims 41 or 52 to a subject suffering from said disease or condition.
54. The method of claim 53, wherein said disease or condition comprises a leukemia, hematologic malignancy, solid tumor cancer, or diabetes. 55. The method of claim 54, wherein said leukemia comprises AML or ALL.
56. A method of inhibiting the interaction of MLL or MLL fusion protein and menin comprising administering composition of one of claims 41 or 52 to a sample comprising MLL or MLL fusion protein and menin.
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WO2017192543A1 (en) * 2016-05-02 2017-11-09 Regents Of The University Of Michigan Piperidines as menin inhibitors
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