Tricyclic methylene derivatives and related uses

Abstract

Described herein are compounds of Formula 1-0: and their pharmaceutically acceptable salts, solvates, and stereoisomers thereof, as well as their uses (e.g., as menin inhibitors).

Description

Attorney Docket No. APG-701WOTRICYCLIC METHYLENE DERIVATIVES AND RELATED USESRELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 736,376, filed December 19, 2024, the entire contents of which are hereby incorporated by reference for all purposes.BACKGROUND

[0002] Menin is a protein encoded by the MEN1 tumor suppressor gene, which is mutated in both hereditary and sporadic endocrine tumors. This protein regulates cellular processes such as cell proliferation, DNA repair, and transcription. Menin normally interacts with various transcription factors and cofactors to form macromolecular complexes, influencing the expression of HOX genes critical for cell differentiation and growth.

[0003] Mixed-lineage leukemia (MLL), a proto-oncogene, can form chimeric fusion proteins due to chromosomal translocations, which are implicated in various human leukemias. These fusion proteins often retain menin-binding ability, essential for their leukemogenic activity. Aberrant interactions between menin and MLL fusion proteins result in the dysregulation of target genes, particularly HOX genes like HOXA9, contributing to the development and maintenance of leukemia.

[0004] Targeting and disrupting the menin-MLL interaction has emerged as a promising strategy for developing novel anticancer therapies. Inhibiting this interaction can reverse inappropriate gene expression, abrogate leukemic properties of transformed cells, and represents an effective therapeutic approach for leukemia characterized by MLL translocations. Ongoing research aims to find small molecules capable of inhibiting menin-MLL binding, providing new avenues for treating cancers rooted in these molecular pathways.SUMMARY

[0005] In some aspects, the present disclosure provides a compound of Formula 1-0:1IPTS / 2OO243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables in Formula 1-0 is described herein.

[0006] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.

[0007] In some aspects, the present disclosure provides methods of binding menin in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

[0008] In some aspects, the present disclosure provides uses of a compound described herein in the manufacture of a medicament for binding menin in a subject or biological sample.

[0009] In some aspects, the present disclosure provides compounds described herein for use in binding menin in a subject or biological sample.

[0010] In some aspects, the present disclosure provides methods of inhibiting menin in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

[0011] In some aspects, the present disclosure provides uses of a compound described herein in the manufacture of a medicament for inhibiting menin in a subject or biological sample.

[0012] In some aspects, the present disclosure provides compounds described herein for use in inhibiting menin in a subject or biological sample.

[0013] In some aspects, the present disclosure provides methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a compound described herein.

[0014] In some aspects, the present disclosure provides uses of a compound described herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0015] In some aspects, the present disclosure provides compounds described herein for use in treating or preventing a disease or disorder in a subject in need thereof.IPTS / 200243831.1Attorney Docket No. APG-701WO

[0016] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0017] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0019] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIGs. 1A-1D depict the effects of the indicated compounds on MV4;11 Xenograft genes.

[0021] FIGs. 2A-2D depict the anti-tumor activities of the indicated compounds.DETAILED DESCRIPTION

[0022] Without wishing to be bound by theory, the present disclosure relates to compounds that may show activity in inhibiting menin, and pharmaceutical compositions comprising such compounds. The present disclosure further relates to methods of inhibiting menin in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein. The present disclosure also relates to methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a compound described herein.3IPTS / 2OO243831.1Attorney Docket No. APG-701WOCompounds of the Present Disclosure

[0023] In some aspects, the present disclosure provides a compound of Formula 1-0:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RA1, when present, is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or 3- to 10- membered heterocycloalkyl;RA2, when present, is H or -C(=O)-(C2-Ce alkenyl), wherein the -C(=O)-(C2-Ce alkenyl) is optionally substituted with one or more halogen, cyano, -OH, or -NH2;R1is H, halogen, or -O-(Ci-Ce alkyl), wherein the -O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2;R2is H or halogen;R3is H or halogen;R4is halogen;RN1is H or Ci-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2; orIPTS / 200243831.1Attorney Docket No. APG-701WORN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6- membered heteroaryl or a 4- to 6-membered heterocycle, wherein the heteroaryl or heterocycle is optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo;RN3is H or Ci-C6alkyl;R° is Ci-C6alkyl; and n is 1, 2, or 3.

[0024] In some aspects, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RA1, when present, is Ci-Ce alkyl optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or 3- to 10-membered heterocyclo alkyl;RA2, when present, is -C(=O)-(C2-Ce alkenyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2;R1is H, halogen, or -O-(Ci-Ce alkyl), wherein the -O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2;R2is H or halogen;R3is H or halogen;R4is halogen;RN1is H or Ci-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2;RN3is H or Ci-C6alkyl;5IPTS / 200243831.1Attorney Docket No. APG-701WOR° is Ci-C6alkyl; and n is 1, 2, or 3.

[0025] In some embodiments, when A isthen R1and R2are not both H.

[0026] In some embodiments, when A isthen R1and R2are not both H.

[0027] In some embodiments, whenthen R1and R2are not both H.

[0028] In some embodiments, whenthen R1and R2are not both H.

[0029] In some embodiments, when A isthen RN1is not, , then R1and R2are not both H.

[0031] In some embodiments, when A is6IPTS / 200243831.1Attorney Docket No. APG-701WO

[0032] It is understood that, for a compound of the present disclosure, variables A, RA1, R^, R1, R2, R3, R4, RN1, RN2, RN3, R°, and n can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables A, RA1, RA2, R1, R2, R3, R4, RN1, RN2, RN3, R°, and n can be combined, where applicable, with any group described herein for one or more of the remainder of variables A, RA1, RA2, R1, R2, R3, R4, RN1, RN2, RN3, R°, and n.Variables A, RA1and RA2

[0033] In some embodiments, A is H. In some embodiments, A is. In some embodiments, A isIn some embodiments, A isIn some embodiments, A issome embodiments,In some embodiments,In some embodiments,some embodiments,IPTS / 200243831.1Attorney Docket No. APG-701WO

[0037] In some embodiments, RA1, when present, is H.

[0038] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0039] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, - OH, -NH2, -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), n- butoxy (C4), z-butoxy (C4), s-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)), -N(Ci- C6alkyl)2(e.g., -N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)), or 3- to 10- membered heterocycloalkyl.

[0040] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), orIPTS / 200243831.1Attorney Docket No. APG-701WO hexyl (Ce)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, - O-(Ci-Ce alkyl) e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)), -N(Ci-Ce alkyl)2 (e.g., -N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)), or 3- to 10- membered heterocycloalkyl.

[0041] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one halogen (e.g., -F, -Cl, -Br, or -I).

[0042] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one cyano.

[0043] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one -OH.

[0044] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one -NH2.

[0045] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0046] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one -N(Ci-Ce alkyl)2 (e.g., -N(Ci alkyl)(Ci-Ce alkyl), - N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0047] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one 3- to 10-membered heterocycloalkyl.

[0048] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one azetidinyl.9IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0049] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), 77-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one piperidinyl.

[0050] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) substituted with at least one morpholinyl.

[0051] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I) or -OH.

[0052] In some embodiments, RA1, when present, is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I) or -OH.

[0053] In some embodiments, RA1, when present, is methyl.

[0054] In some embodiments, RA1, when present, is methyl optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I) or -OH.

[0055] In some embodiments, RA1, when present, is methyl substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I) or -OH.

[0056] In some embodiments, RA1, when present, is methyl optionally substituted with one or more fluoro or -OH.

[0057] In some embodiments, RA1, when present, is methyl substituted with one or more fluoro or -OH.

[0058] In some embodiments, RA1, when present, is -CH3, -CHF2, -CH2CH3, -CH(CH3)2, or - CH2CH2OH.

[0059] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) (e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)).

[0060] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) (e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, or -NH2.

[0061] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) (e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, or -NH2.10IPTS / 200243831.1Attorney Docket No. APG-701WO

[0062] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) (e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)) substituted with at least one halogen e.g., -F, -Cl, -Br, or -I).

[0063] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)) substituted with at least one cyano.

[0064] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) (e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)) substituted with at least one -OH.

[0065] In some embodiments, RA2, when present, is -C(=O)-(C2-Ce alkenyl) (e.g., -C(=O)-(C2 alkenyl), -C(=O)-(C3alkenyl), -C(=O)-(C4alkenyl), -C(=O)-(C5alkenyl), or -C(=O)-(C6alkenyl)) substituted with at least one -NH2.

[0066] In some embodiments, RA2, when present, is -C(=O)-(C2 alkenyl).Variables R1, R2, R3, and R4

[0067] In some embodiments, R1is H.

[0068] In some embodiments, R1is halogen (e.g., -F, -Cl, -Br, or -I).

[0069] In some embodiments, R1is fluoro.

[0070] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0071] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)), or -NH2.

[0072] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, - O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)), or -NH2.

[0073] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with at least one halogen (e.g., -F, -Cl, -Br, or -I).11IPTS / 200243831.1Attorney Docket No. APG-701WO

[0074] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with at least one cyano.

[0075] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with at least one -OH.

[0076] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with at least one -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0077] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with at least one -NH2.

[0078] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more -OH or -O-(Ci-Ce alkyl) (e.g. , methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0079] In some embodiments, R1is -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) substituted with one or more -OH or -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0080] In some embodiments, R1is -O-(Ci-C3 alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), or z-propoxy (C3)) optionally substituted with one or more -OH or -O-(Ci-C3 alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), or z-propoxy (C3)).

[0081] In some embodiments, R1is -O-(Ci-C3 alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), or z-propoxy (C3)) substituted with one or more -OH or -O-(Ci-C3 alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), or z-propoxy (C3)).

[0082] In some embodiments, R1is -O-(C2-C3 alkyl) (e.g., ethoxy (C2), propoxy (C3), or i- propoxy (C3)) substituted with one or more -OH or -O-(Ci alkyl).

[0083] In some embodiments, R1is -O-CH2CH3, -O-CH2CH2-OH, -O-CH2CH2-OCH3, or -O- CH(CH3)2.12IPTS / 200243831.1Attorney Docket No. APG-701WO

[0084] In some embodiments, R2is H.

[0085] In some embodiments, R2is halogen {e.g., -F, -Cl, -Br, or -I).

[0086] In some embodiments, R2is fluoro.

[0087] In some embodiments, R1is H, and R2is not H.

[0088] In some embodiments, R2is H, and R1is not H.

[0089] In some embodiments, R3is H.

[0090] In some embodiments, R3is halogen {e.g., -F, -Cl, -Br, or -I).

[0091] In some embodiments, R3is fluoro.

[0092] In some embodiments, R4is halogen {e.g., -F, -Cl, -Br, or -I).

[0093] In some embodiments, R4is fluoro.

[0094] In some embodiments, R3is H and R4is fluoro.

[0095] In some embodiments, R3and R4are each fluoro.Variables RN1, RN2, RN3, R°, and n.

[0096] In some embodiments, RN1is H.

[0097] In some embodiments, RN1is Ci-Ce alkyl {e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)).

[0098] In some embodiments, RN1is -CH3. In some embodiments, RN1is -CH2CH3.

[0099] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)).

[0100] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) {e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) optionally substituted with one or more halogen {e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, - O-(Ci-Ce alkyl) {e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)), or -N(Ci-Ce alkyl)2 {e.g., -N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0101] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) {e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with one or more halogen {e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, -O-(Ci-Ce alkyl) {e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), / -butoxy (C4), pentoxy (C5), or hexoxy (Ce)), or -N(Ci-Ce alkyl)2 {e.g., - N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).13IPTS / 200243831.1Attorney Docket No. APG-701WO

[0102] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) (e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with at least one halogen e.g., -F, -Cl, -Br, or -I).

[0103] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with at least one cyano.

[0104] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) (e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with at least one -OH.

[0105] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) (e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with at least one -NH2.

[0106] In some embodiments, RN2is -C(=O)-(Ci-Ce alkyl) (e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with at least one -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), i- propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (Cs), or hexoxy (Ce)).

[0107] In some embodiments, RN2is -C(=O)-(Ci-C6alkyl) (e.g., -C(=O)-(Ci alkyl), -C(=O)- (C2alkyl), -C(=O)-(C3alkyl), -C(=O)-(C4alkyl), -C(=O)-(C5alkyl), or -C(=O)-(C6alkyl)) substituted with at least one -N(Ci-Ce alkyl)2(e.g., -N(Ci alkyl)(Ci-Ce alkyl), -N(C2alkyl)(Ci- C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), - N(C6alkyl)(Ci-C6alkyl)).

[0108] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(C6alkyl)).

[0109] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, -O-(Ct-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), z-butoxy (C4), pentoxy (Cs), or hexoxy (Ce)), or -N(CI-C6alkyl)2(e.g., -N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci- C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0110] In some embodiments, RN2is -C(=O)-O-(Ci-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or -14IPTS / 200243831.1Attorney Docket No. APG-701WOC(=O)-O-(Ce alkyl)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, - OH, -NH2, -O-(Ci-Ce alkyl) e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), n- butoxy (C4), z-butoxy (C4), s-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)), or - N(CI-C6alkyl)2(e.g., -N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0111] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) substituted with at least one halogen (e.g., -F, -Cl, -Br, or -I).

[0112] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) substituted with at least one cyano.

[0113] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) substituted with at least one -OH.

[0114] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) substituted with at least one -NH2.

[0115] In some embodiments, RN2is -C(=O)-O-(Ct-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) substituted with at least one -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0116] In some embodiments, RN2is -C(=O)-O-(Ci-Ce alkyl) (e.g., -C(=O)-O-(Ci alkyl), - C(=O)-O-(C2alkyl), -C(=O)-O-(C3alkyl), -C(=O)-O-(C4alkyl), -C(=O)-O-(C5alkyl), or - C(=O)-O-(Ce alkyl)) substituted with at least one -N(Ci-Ce alkyl)2 (e.g., -N(Ci alkyl)(Ci-Ce alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0117] In some embodiments, RN2is -S(=O)2-(Ci-C6alkyl) (e.g., -S(=O)2-(Ct alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)).

[0118] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, - O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), Fbutoxy (C4), pentoxy (C5), or hexoxy (Ce)), or -N(Ci-Ce alkyl)215IPTS / 200243831.1Attorney Docket No. APG-701WO(e.g., -N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0119] In some embodiments, RN2is -S(=0)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=0)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)), or -N(Ci-Ce alkyl)2(e.g., - N(Ci alkyl)(Ci-C6alkyl), -N(C2alkyl)(Ci-C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), -N(C6alkyl)(Ci-C6alkyl)).

[0120] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with at least one halogen (e.g., -F, -Cl, -Br, or -I).

[0121] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with at least one cyano.

[0122] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with at least one -OH.

[0123] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with at least one -NH2.

[0124] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with at least one halogen (e.g., -F, -Cl, -Br, or -I), cyano, -OH, -NH2, -O-(Ci-Ce alkyl) (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), 5-butoxy (C4), z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)).

[0125] In some embodiments, RN2is -S(=O)2-(Ci-Ce alkyl) (e.g., -S(=O)2-(Ci alkyl), -S(=O)2- (C2alkyl), -S(=O)2-(C3alkyl), -S(=O)2-(C4alkyl), -S(=O)2-(C5alkyl), or -S(=O)2-(C6alkyl)) substituted with at least one -N(Ci-Ce alkyl)2(e.g., -N(Ci alkyl)(Ci-Ce alkyl), -N(C2alkyl)(Ci- C6alkyl), -N(C3alkyl)(Ci-C6alkyl), -N(C4alkyl)(Ci-C6alkyl), -N(C5alkyl)(Ci-C6alkyl), - N(C6alkyl)(Ci-C6alkyl)).

[0126] In some embodiments, RN2is -S(=O)2-CH3, -C(=O)-CH3, or -C(=O)-OCH3.

[0127] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl (e.g., azetyl (4-membered), oxetyl (4-membered),16IPTS / 200243831.1Attorney Docket No. APG-701WO thietyl (4-membered), imidazolyl (5-membered), thiazolyl (5-membered), isoxazolyl (5- membered), pyridyl (6-membered), pyridazinyl (6-membered), or pyrimidinyl (6-membered)).

[0128] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl (e.g., azetyl (4-membered), oxetyl (4-membered), thietyl (4-membered), imidazolyl (5-membered), thiazolyl (5-membered), isoxazolyl (5- membered), pyridyl (6-membered), pyridazinyl (6-membered), or pyrimidinyl (6-membered)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (Ce)), or oxo.

[0129] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl e.g., azetyl (4-membered), oxetyl (4-membered), thietyl (4-membered), imidazolyl (5-membered), thiazolyl (5-membered), isoxazolyl (5- membered), pyridyl (6-membered), pyridazinyl (6-membered), or pyrimidinyl (6-membered)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)), or oxo.

[0130] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl (e.g., azetyl (4-membered), oxetyl (4-membered), thietyl (4-membered), imidazolyl (5-membered), thiazolyl (5-membered), isoxazolyl (5- membered), pyridyl (6-membered), pyridazinyl (6-membered), or pyrimidinyl (6-membered)) substituted with at least one halogen (e.g., -F, -Cl, -Br, or -I).

[0131] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl (e.g., azetyl (4-membered), oxetyl (4-membered), thietyl (4-membered), imidazolyl (5-membered), thiazolyl (5-membered), isoxazolyl (5- membered), pyridyl (6-membered), pyridazinyl (6-membered), or pyrimidinyl (6-membered)) substituted with at least one Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)).

[0132] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl (e.g., azetyl (4-membered), oxetyl (4-membered), thietyl (4-membered), imidazolyl (5-membered), thiazolyl (5-membered), isoxazolyl (5- membered), pyridyl (6-membered), pyridazinyl (6-membered), or pyrimidinyl (6-membered)) substituted with at least one oxo.

[0133] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a imidazolyl.17IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0134] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a imidazolyl, optionally substituted with one or more Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0135] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a imidazolyl, substituted with at least one Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0136] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a imidazolyl, substituted with a C3 alkyl (e.g., zz-propyl (C3) or z-propyl (C3)).

[0137] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form.

[0138] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl e.g., thietanyl (4-membered), azetidinyl (4- membered), oxetanyl (4-membered), oxazolidinyl (5-membered), isothiazolidinyl (5- membered), imidazolidinyl (5-membered), morpholinyl (6-membered), piperazinyl (6- membered), or piperidinyl (6-membered)).

[0139] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl (e.g., thietanyl (4-membered), azetidinyl (4- membered), oxetanyl (4-membered), oxazolidinyl (5-membered), isothiazolidinyl (5- membered), imidazolidinyl (5-membered), morpholinyl (6-membered), piperazinyl (6- membered), or piperidinyl (6-membered)) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)), or oxo.

[0140] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl (e.g., thietanyl (4-membered), azetidinyl (4- membered), oxetanyl (4-membered), oxazolidinyl (5-membered), isothiazolidinyl (5- membered), imidazolidinyl (5-membered), morpholinyl (6-membered), piperazinyl (6- membered), or piperidinyl (6-membered)) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I), Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), 5-butyl (C4), Fbutyl (C4), pentyl (C5), or hexyl (Ce)), or oxo.18IPTS / 200243831.1Attorney Docket No. APG-701WO

[0141] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl (e.g., thietanyl (4-membered), azetidinyl (4- membered), oxetanyl (4-membered), oxazolidinyl (5-membered), isothiazolidinyl (5- membered), imidazolidinyl (5-membered), morpholinyl (6-membered), piperazinyl (6- membered), or piperidinyl (6-membered)) substituted with at least one halogen (e.g., -F, -Cl, - Br, or -I).

[0142] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl (e.g., thietanyl (4-membered), azetidinyl (4- membered), oxetanyl (4-membered), oxazolidinyl (5-membered), isothiazolidinyl (5- membered), imidazolidinyl (5-membered), morpholinyl (6-membered), piperazinyl (6- membered), or piperidinyl (6-membered)) substituted with at least one Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0143] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl (e.g., thietanyl (4-membered), azetidinyl (4- membered), oxetanyl (4-membered), oxazolidinyl (5-membered), isothiazolidinyl (5- membered), imidazolidinyl (5-membered), morpholinyl (6-membered), piperazinyl (6- membered), or piperidinyl (6-membered)) substituted with at least one oxo.

[0144] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl.

[0145] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl optionally substituted with one or more Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0146] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl substituted with at least one Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0147] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl substituted with at least one methyl (Ci).

[0148] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl optionally substituted with one or more oxo.

[0149] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl substituted with at least one oxo.19IPTS / 200243831.1Attorney Docket No. APG-701WO

[0150] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a oxazolidinyl substituted with at least one Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)) and at least one oxo.

[0151] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form.

[0152] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a isothiazolidinyl.

[0153] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a isothiazolidinyl optionally substituted with one or more oxo.

[0154] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form a isothiazolidinyl substituted with at least one oxo.

[0155] In some embodiments, RN1and RN2, together with the nitrogen to which they are attached, form.

[0156] In some embodiments, RN3is H.

[0157] In some embodiments, RN3is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0158] In some embodiments, R° is Ci-Ce alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), i- propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Ce)).

[0159] In some embodiments, R° is -CH3.

[0160] In some embodiments, n is 1.

[0161] In some embodiments, n is 2.

[0162] In some embodiments, n is 3.Exemplary Embodiments of the Compounds

[0163] In some embodiments, the compound is of Formula I’-O:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R1, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0164] In some embodiments, the compound is of Formula I:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RA1, when present, is Ci-Ce alkyl optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or 3- to 10-membered heterocycloalkyl;RA2, when present, is -C(=O)-(C2-Ce alkenyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2;RN1is H or Ci-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2; and variables R1, R2, R3, R4, RN3, R°, and n are described herein.

[0165] In some embodiments, the compound is of Formula I’:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R1, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0166] In some embodiments, the compound is of Formula 1-0-i:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: ring V is a 4- to 6-membered heteroaryl or a 4- to 6-membered heterocyclyl, wherein the heteroaryl or heterocycle is optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo; and variables A, R1, R2, R3, R4, RN3, R°, and n are described herein.

[0167] In some embodiments, the compound is of Formula I’-O-i:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R1, R2, R3, R4, RN3, R°, ring V, and n are described herein.

[0168] In some embodiments, the compound is of Formula 1-0-ii:22IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RN1is H or CI-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2; and variables A, R1, R2, R3, R4, RN3, R°, and n are described herein.

[0169] In some embodiments, the compound is of Formula I’-O-ii:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R1, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0170] In some embodiments, the compound is of Formula I-i:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R1, R2, R3, R4, and RN2are described herein.

[0171] In some embodiments, the compound is of Formula I’-i:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R1, R2, R3, R4, and RN2are described herein.

[0172] In some embodiments, the compound is of Formula 1-1’:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RO1is Ci-C6alkyl optionally substituted with one or more halogen, cyano, -OH, -O- (Ct-C6alkyl), or -NH2; and variables RA1, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0173] In some embodiments, the compound is of Formula 1-1:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:24IPTS / 200243831.1Attorney Docket No. APG-701WORO1is Ci-C6alkyl optionally substituted with one or more halogen, cyano, -OH, -O- (Ct-C6alkyl), or -NH2; and variables RA1, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0174] In some embodiments, RO1is Ci-Ce alkyl.

[0175] In some embodiments, RO1is Ci-Ce alkyl optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2.

[0176] In some embodiments, RO1is Ci-Ce alkyl substituted with one or more halogen, cyano, -OH, -O-(Ci-C6alkyl), or -NH2.

[0177] In some embodiments, RO1is Ci-Ce alkyl at least one halogen.

[0178] In some embodiments, RO1is Ci-Ce alkyl at least one cyano.

[0179] In some embodiments, RO1is Ci-Ce alkyl at least one -OH.

[0180] In some embodiments, RO1is Ci-Ce alkyl at least one -O-(Ci-Ce alkyl).

[0181] In some embodiments, RO1is Ci-Ce alkyl at least one -NH2.

[0182] In some embodiments, RO1is -CH2CH3, -CH2CH2-OH, -CH2CH2-OCH3, or -CH(CH3)2.

[0183] In some embodiments, RO1is -CH2CH3.

[0184] In some embodiments, RO1is Ci-Ce alkyl substituted with at least one halogen.

[0185] In some embodiments, RO1is Ci-Ce alkyl substituted with at least one cyano.

[0186] In some embodiments, RO1is Ci-Ce alkyl substituted with at least one -OH.

[0187] In some embodiments, RO1is Ci-Ce alkyl substituted with at least one -O-(Ci-Ce alkyl).

[0188] In some embodiments, RO1is Ci-Ce alkyl substituted with at least one -NH2.

[0189] In some embodiments, the compound is of Formula I’-l:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, R2, R3, R4, RN1, RN2, RN3, R°, RO1, and n are described herein.

[0190] In some embodiments, the compound is of Formula I-l-a, I-l-b, or I-l-c:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA1, R2, R3, R4, RN1, RN2, RN3, R°, RO1, and n are described herein.

[0191] In some embodiments, the compound is of Formula I’-l-a , I’-l-b, or I’-l-c:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA1, R2, R3, R4, RN1, RN2, RN3, R°, RO1, and n are described herein.

[0192] In some embodiments, the compound is of Formula I-l-a-i or I-l-b-i:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA1, R2, R3, R4, RN2, and RO1are described herein.

[0193] In some embodiments, the compound is of Formula I’-l-a-i or I’-l-b-i:27IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA1, R2, R3, R4, RN2, and RO1are described herein.

[0194] In some embodiments, the compound is of Formula I-l-a-ii, I-l-b-ii, or I-l-c-ii:IPTS / 200243831.1Attorney Docket No. APG-701WO or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RNais Ci-C6alkyl; and variables RA1, R2, R3, R4, RN2, and RO1are described herein.

[0195] In some embodiments, RNais -CH3. In some embodiments, RNais -CH2CH3.

[0196] In some embodiments, the compound is of Formula I’-l-a-ii or I’-l-b-ii, or I’-l-c-ii:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA1, R2, R3, R4, RNa, RN2, and RO1are described herein.

[0197] In some embodiments, the compound is of Formula I-1-a-iii, I-l-b-iii, or I-l-c-iii:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: ring V is a 4- to 6-membered heteroaryl optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo; and variables RA1, R2, R3, R4, and RO1are described herein.

[0198] In some embodiments, ring V is a 4- to 6-membered heteroaryl optionally substituted with one or more halogen.

[0199] In some embodiments, ring V is a 4- to 6-membered heteroaryl optionally substituted with one or more Ci-Ce alkyl.

[0200] In some embodiments, ring V is a 4- to 6-membered heteroaryl (e.g., imidazolyl) substituted with at least one Ci-Ce alkyl (e.g., -CH(CHs)2).

[0201] In some embodiments, ring V is ==J .

[0202] In some embodiments, the compound is of Formula I’-l-a-iii, I’-l-b-iii, or I’-l-c-iii:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA1, R2, R3, R4, RO1, and ring V are described herein.

[0203] In some embodiments, the compound of is of Formula 1-2:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R1is halogen; and variables RA2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0204] In some embodiments, the compound is of Formula I’-2IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, RA2, R1, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0205] In some embodiments, the compound is of Formula I-2-a or I-2-b:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R1, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0206] In some embodiments, the compound is of Formula I’-2-a or I’-2-b:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R1, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0207] In some embodiments, the compound is of Formula I-2-a-i or I-2-b-i:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R1, R3, R4, and RN2are described herein.

[0208] In some embodiments, the compound is of Formula I’-2-a-i or I’-2-b-i:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R1, R3, R4, and RN2are described herein.

[0209] In some embodiments, the compound of is of Formula 1-3:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:and variables RA2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0210] In some embodiments, the compound of is of Formula I’-3:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables A, RA2, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.34IPTS / 200243831.1Attorney Docket No. APG-701WO

[0211] In some embodiments, the compound is of Formula I-3-a, I-3-b, I-3-c, I-3-d, I-3-e, orIPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0212] In some embodiments, the compound is of Formula I’-3-a, I’-3-b, I’-3-c, I’-3-d, I’-3- e, or I’-3-f:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R2, R3, R4, RN1, RN2, RN3, R°, and n are described herein.

[0213] In some embodiments, the compound is of Formula I-3-a-i, I-3-b-i, I-3-c-i, I-3-d-i, I-3-e-i, or I-3-f-i:37IPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4ais halogen; and variables RA2, R2, R3, R4, RN1, and RN2are described herein.

[0214] In some embodiments, R4ais fluoro.

[0215] In some embodiments, the compound is of Formula I’-3-a-i, I’-3-b-i, I’-3-c-I, I’-3-d- i, I’-3-e-i, or I’-3-f-i:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2,R2, R3, R4a, RN1, and RN2are described herein.

[0216] In some embodiments, the compound is of Formula I-3-a-ii, I-3-b-ii, I-3-c-ii, I-3-d-ii,I-3-e-ii, or I-3-f-ii:-ii),40IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4ais halogen;41IPTS / 2OO243831.1Attorney Docket No. APG-701WO ring V is a 4- to 6-membered heterocyclyl optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo; and variables RA2, R2, and R3are described herein.

[0217] In some embodiments, ring V is a 4- to 6-membered heterocyclyl optionally substituted with one or more oxo.

[0218] In some embodiments, ring V is a 4- to 6-membered heterocyclyl optionally substituted with one or more Ci-Ce alkyl.

[0219] In some embodiments, ring V is a 4- to 6-membered heterocyclyl (e.g., oxazolidinyl or isothiazolidinyl) substituted with at least one oxo.

[0220] In some embodiments, ring V is a 4- to 6-membered heterocyclyl (e.g., oxazolidinyl or isothiazolidinyl) substituted with at least one Ci-Ce alkyl (e.g., -CH3).

[0221] In some embodiments, ring

[0222] In some embodiments, the compound is of Formula I’-3-a-ii, I’-3-b-ii, I’-3-c-ii, I’-3- d-ii, I’-3-e-ii, or I’-3-f-ii:IPTS / 200243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein variables RA2, R2, R3, R4a, and ring V are described herein.

[0223] In some embodiments, the compound is selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0224] In some embodiments, the compound is selected from the compounds in Tables 1-3.

[0225] In some embodiments, the compound is selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts thereof.IPTS / 200243831.1Attorney Docket No. APG-701WO

[0226] In some embodiments, the compound is selected from the compounds in Tables 1-3 and solvates thereof.

[0227] In some embodiments, the compound is selected from the compounds in Tables 1-3 and stereoisomers thereof.

[0228] In some embodiments, the compound is selected from the compounds in Tables 1 and 2 and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0229] In some embodiments, the compound is selected from the compounds in Tables 1 and 2.

[0230] In some embodiments, the compound is selected from the compounds in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0231] In some embodiments, the compound is selected from the compounds in Tables 1 and 2 and solvates thereof.

[0232] In some embodiments, the compound is selected from the compounds in Tables 1 and 2 and stereoisomers thereof.

[0233] In some embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0234] In some embodiments, the compound is selected from the compounds in Table 1.

[0235] In some embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0236] In some embodiments, the compound is selected from the compounds in Table 1 and solvates thereof.

[0237] In some embodiments, the compound is selected from the compounds in Table 1 and stereoisomers thereof.

[0238] In some embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0239] In some embodiments, the compound is selected from the compounds in Table 2.

[0240] In some embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts thereof.

[0241] In some embodiments, the compound is selected from the compounds in Table 2 and solvates thereof.

[0242] In some embodiments, the compound is selected from the compounds in Table 2 and stereoisomers thereof.

[0243] In some embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.44IPTS / 200243831.1Attorney Docket No. APG-701WO

[0244] In some embodiments, the compound is selected from the compounds in Table 3.

[0245] In some embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts thereof.

[0246] In some embodiments, the compound is selected from the compounds in Table 3 and solvates thereof.

[0247] In some embodiments, the compound is selected from the compounds in Table 3 and stereoisomers thereof.

[0248] Without wishing to be bound by theory, one or more compounds of the present disclosure may be inhibitors of menin, e.g., reversible (e.g., non-covalent) inhibitors of menin or irreversible (e.g., covalent) inhibitors of menin.

[0249] In some embodiments, the compound is an inhibitor of menin.

[0250] In some embodiments, the compound is a reversible (e.g., non-covalent) inhibitor of menin.

[0251] In some embodiments, the compound is an irreversible (e.g., covalent) inhibitor of menin.

[0252] In some embodiments, the compound of Formula I is a reversible (e.g., non-covalent) inhibitor of menin, wherein A is

[0253] In some embodiments, the compound of Formula I is a reversible (e.g., non-covalent) inhibitor of menin, wherein A is. In some embodiments, the compound of FormulaI is a reversible (e.g., non-covalent) inhibitor of menin, wherein A is. In some embodiments, the compound of Formula I is a reversible (e.g., non-covalent) inhibitor of menin, whereinIPTS / 200243831.1Attorney Docket No. APG-701WO

[0254] In some embodiments, the compound of Formula I is an irreversible (e.g., covalent) inhibitor of menin, wherein A is

[0255] In some embodiments, the compound of Formula I is an irreversible (e.g., covalent) inhibitor of menin, whereinsome embodiments, the compound ofFormula I is an irreversible (e.g., covalent) inhibitor of menin, whereinsome embodiments, the compound of Formula I is an irreversible (e.g., covalent) inhibitor of menin, whereinIn some embodiments, the compound of Formula I is an irreversible (e.g., covalent) inhibitor of menin, whereinsome embodiments, the compound of Formula I is an irreversible e.g., covalent) inhibitor of menin, wherein A isIPTS / 200243831.1Attorney Docket No. APG-701WO. In some embodiments, the compound of Formula I is an irreversible (e.g., covalent) inhibitor of menin, wherein

[0256] In some embodiments, the compound of the present disclosure s a reversible (e.g., non- covalent) inhibitor of menin. In some embodiments, the compound of the present disclosure is an irreversible (e.g., covalent) inhibitor of menin.

[0257] In some embodiments, the compound of the present disclosure is a reversible (e.g., non-covalent) inhibitor of menin.

[0258] In some embodiments, the compound of the present disclosure is an irreversible (e.g., covalent) inhibitor of menin.IPTS / 200243831.1Attorney Docket No. APG-701WOTable 1IPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOTable 250IPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOTable 3IPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WO61IPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WOIPTS / 200243831.1Attorney Docket No. APG-701WO

[0259] Without wishing to be bound by theory, the compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known menin inhibitors. For example, the compounds of the present disclosure may display improved menin- inhibition activity to wild-type and mutant menin, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and / or AUC), and / or less interaction with other cellular targets and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.

[0260] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0261] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0262] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0263] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0264] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0265] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0266] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0267] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0268] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula I is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula I. In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof). In some embodiments, the compound is a18F labeled compound.64IPTS / 200243831.1Attorney Docket No. APG-701WOIn some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof. In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0269] It is understood that the18F,1231,1241,1251,1291,1311,1351,32S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,1241,1251,1291,1311,1351,3S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0270] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,1231,1241,1251,1291,131I,1351,32S,34S,35S, and36S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0271] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0272] The various functional groups and substituents making up the compounds of the Formula I are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less.

[0273] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.65IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0274] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0275] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0276] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0277] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0278] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0279] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem.66IPTS / 200243831.1Attorney Docket No. APG-701WO1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0280] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0281] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0282] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0283] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0284] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.67IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0285] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0286] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0287] The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess menin-inhibitory activity.

[0288] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0289] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a 68IPTS / 2OO243831.1Attorney Docket No. APG-701WO substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0290] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0291] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0292] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non- stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0293] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.

[0294] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0295] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically 69IPTS / 200243831.1Attorney Docket No. APG-701WO or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0296] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess menin-inhibitory activity.

[0297] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess menin-inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0298] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0299] ketoeno1enolate

[0300] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula I that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogencontaining heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see70IPTS / 200243831.1Attorney Docket No. APG-701WO for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0301] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein.Methods of Synthesis

[0302] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0303] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0304] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0305] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0306] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0307] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0308] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0309] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any71IPTS / 2OO243831.1Attorney Docket No. APG-701WO convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0310] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0311] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0312] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.72IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0313] Once a compound of Formula I has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula I into another compound of Formula I; and / or (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0314] The resultant compounds of Formula I can be isolated and purified using techniques well known in the art.

[0315] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0316] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0317] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0318] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0319] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which 73IPTS / 2OO243831.1Attorney Docket No. APG-701WO kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance - wherever necessary or useful - in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply - whenever necessary or useful - synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0320] General routes for the preparation of a compound of the application are described in Schemes 1 and 2 herein.Scheme 1IPTS / 2OO243831.1Attorney Docket No. APG-701WOScheme 2Biological Assays

[0321] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0322] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.75IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0323] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0324] In some embodiments, the biological assay is described in the Examples herein.

[0325] In some embodiments, the biological assay is described in Candoni, A. and Coppola, G. Hematol. Rep. 2024, 16, 244-254, incorporated herein by reference.

[0326] In some embodiments, the biological assay is a menin binding affinity assay.

[0327] In some embodiments, the biological assay is a cell growth inhibition assay.

[0328] In some embodiments, the biological assay is a competitive binding assay.

[0329] In some embodiments, the biological assay is a fluorescence polarization (FP) competitive binding assay.

[0330] In some embodiments, the activity is measured by fluorescence polarization (FP).

[0331] In some embodiments, the biological assay is a cell proliferation assay.

[0332] In some embodiments, the activity is measured by cell viability.

[0333] In some embodiments, the cell is a cancer cell.

[0334] In some embodiments, the cell is a leukemia cell.

[0335] In some embodiments the cell is a MV4;11 cell.

[0336] In some embodiments, the cell is a MOEM13 cell.

[0337] In some embodiments, the cell is a HE60 cell.Pharmaceutical Compositions

[0338] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0339] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0340] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release 76IPTS / 200243831.1Attorney Docket No. APG-701WO formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0341] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0342] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P-cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulfated P-cyclodextrin (S-P-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y-cyclodextrin, and trimethyl-y- cyclodextrin, and mixtures thereof.

[0343] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0344] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0345] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as77IPTS / 2OO243831.1Attorney Docket No. APG-701WO propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0346] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0347] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0348] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and e-aminocaproic acid, and mixtures thereof.

[0349] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0350] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with 78IPTS / 2OO243831.1Attorney Docket No. APG-701WO excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0351] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0352] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0353] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring, and / or preservative agents.

[0354] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a menin-related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0355] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a menin-related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0356] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of79IPTS / 2OO243831.1Attorney Docket No. APG-701WO the animal or patient and the route of administration, according to well-known principles of medicine.Methods of Use

[0357] In some aspects, provided herein are methods of binding menin in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

[0358] In some aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for binding menin in a subject or biological sample.

[0359] In some aspects, provided herein are compounds described herein for use in binding menin in a subject or biological sample.

[0360] In some aspects, provided herein are methods of inhibiting menin comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

[0361] In some aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for inhibiting menin in a subject or biological sample.

[0362] In some aspects, provided herein are compounds described herein for use in inhibiting menin in a subject or biological sample.

[0363] In some aspects, provided herein are methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a compound described herein.

[0364] In some aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0365] In some aspects, provided herein are compounds described herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0366] In some embodiments, the subject is a mammal.

[0367] In some embodiments, the subject is a human.

[0368] In some embodiments, the disease or disorder is associated with menin activity.

[0369] In some embodiments, the disease or disorder is described in Candoni, A. and Coppola, G. Hematol. Rep. 2024, 16, 244-254, incorporated herein by reference.

[0370] In some embodiments, the disease or disorder is cancer.

[0371] In some embodiments, the cancer is selected from the Table A:80IPTS / 200243831.1Attorney Docket No. APG-701WOTable A81IPTS / 2OO243831.1Attorney Docket No. APG-701WO82IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0372] In some embodiments, the cancer is a solid tumor.

[0373] In some embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B.Table B

[0374] In some embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0375] In some embodiments, the hematological cancer is myelodysplastic syndrome.83IPTS / 200243831.1Attorney Docket No. APG-701WO

[0376] In some embodiments, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL) . In some embodiments, the leukemia is NPMlc mutant acute myelogenous leukemia. In some embodiments, the leukemia is MLL-r acute myelogenous leukemia. In some embodiments, the leukemia is MLL-r acute lymphocytic leukemia. In some embodiments the cancer is NUT- midline carcinoma. In some embodiments the cancer is multiple myeloma. In some embodiments the cancer is a lung cancer such as small cell lung cancer (SCLC) . In some embodiments the cancer is a neuroblastoma. In some embodiments the cancer is Burkitt's lymphoma. In some embodiments the cancer is cervical cancer. In some embodiments the cancer is esophageal cancer. In some embodiments the cancer is ovarian cancer. In some embodiments the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is Ewing’s sarcoma.

[0377] In some embodiments, the cancer is mixed-lineage leukemia.

[0378] In some embodiments, the cancer is KMT2A-rearranged acute myeloid leukemia.

[0379] In some embodiments, the cancer is NPM1 -mutated acute myeloid leukemia.

[0380] In some embodiments, the present disclosure provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.

[0381] In some embodiments, the present disclosure provides a method of treating infectious and noninfectious inflammatory events and autoimmune and other inflammatory diseases by administration of an effective amount of a present compound to a mammal, in particular a human in need of such treatment. Examples of autoimmune and inflammatory diseases, disorders, and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, skin sunbum, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic 84IPTS / 200243831.1Attorney Docket No. APG-701WO obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, Type I diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituatarism, Guillain-Barre syndrome, Behcet's disease, scleracierma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0382] In some embodiments, the present disclosure provides a method of treating systemic inflammatory response syndromes, such as LPS-induced endotoxic shock and / or bacteria- induced sepsis by administration of an effective amount of a compound described herein to a mammal, in particular a human in need of such treatment.

[0383] In some embodiments, the present disclosure provides a method for treating viral infections and diseases. Examples of viral infections and diseases treated using the compounds and methods described herein include episome-based DNA viruses including, but not limited to, human papillomavirus, Herpesvirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and hepatitis C virus.

[0384] In some embodiments, the present disclosure provides therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and / or apoptosis in vivo in diseases mentioned above, in particular cancer, inflammatory disease, and / or viral disease is provided by administering a therapeutically effective amount of a compound described herein to a subject in need of such therapy.

[0385] In some embodiments, the present disclosure provides a method of regulating endogenous or heterologous promoter activity by contacting a cell with a compound described herein.Routes of Administration

[0386] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the85IPTS / 200243831.1Attorney Docket No. APG-701WO simultaneous, sequential or separate administration of the individual components of the treatment.

[0387] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the compound of Formula I with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0388] In the instances where the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0389] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination for use in the treatment of a disease in which menin activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0390] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier.

[0391] In addition to its use in therapeutic medicine, compounds of Formula I and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of modulators of menin activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents.86IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0392] In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant disclosure, any of the alternate embodiments of macromolecules of the present disclosure described herein also apply.

[0393] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0394] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.Definitions

[0395] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0396] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. For example, while various options for variables are described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables.

[0397] As used herein, “alkyl”, “Ci, C2, C3, C4, C5 or Ce alkyl” or “Ci-Ce alkyl” is intended to include Ci, C2, C3, C4, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or Ce branched saturated aliphatic hydrocarbon groups. For example, CrC6alkyl is intends to include CpC2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for87IPTS / 2OO243831.1Attorney Docket No. APG-701WO straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0398] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0399] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g. , C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0400] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0401] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one 88IPTS / 200243831.1Attorney Docket No. APG-701WO triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- Ce” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or G, chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6alkenylene linker is intended to include C2, C3, C4, C5 and G, alkenylene linker groups.

[0402] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0403] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl- 1 ,2,3,6-tetrahydropyridinyl.

[0404] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be nonaromatic.89IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0405] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.s1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, 1- oxaspiro [4.5] decanyl, 1 -azaspiro [4.5] decanyl, 3'H- spiro [cyclohexane- 1 , l'-isobenzofuran] -yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4, 5, 6, 7- tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H- cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic e.g., 4, 5,6,7- tetrahydrobenzo [c] isoxazolyl).

[0406] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocycloalkyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

[0407] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl.90IPTS / 200243831.1Attorney Docket No. APG-701WO

[0408] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.s1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (z.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (z.e., N— >0 and S(O)P, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, the heteroaryl is thiophenyl. In some embodiments, the heteroaryl benzothiophenyl.

[0409] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0410] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).91IPTS / 200243831.1Attorney Docket No. APG-701WO

[0411] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (z.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0412] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0413] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0414] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O’.

[0415] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0416] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0417] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, 92IPTS / 200243831.1Attorney Docket No. APG-701WO thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0418] As used herein, the term “alkoxy” or “alkoxy!” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0419] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0420] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0421] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial93IPTS / 200243831.1Attorney Docket No. APG-701WO so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0422] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0423] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’ s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’ s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art

[0424] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0425] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description 94IPTS / 2OO243831.1Attorney Docket No. APG-701WO of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0426] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0427] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0428] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0429] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a 95IPTS / 2OO243831.1Attorney Docket No. APG-701WO condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0430] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0431] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0432] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0433] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0434] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.96IPTS / 2OO243831.1Attorney Docket No. APG-701WOOne skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0435] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0436] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0437] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0438] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for 97IPTS / 2OO243831.1Attorney Docket No. APG-701WO chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0439] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0440] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat or ameliorate an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0441] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD50 (the dose lethal to 50 % of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.98IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0442] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0443] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0444] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by99IPTS / 2OO243831.1Attorney Docket No. APG-701WO including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.

[0445] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0446] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0447] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0448] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.100IPTS / 200243831.1Attorney Docket No. APG-701WO

[0449] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0450] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0451] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[0452] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0453] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.101IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0454] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxy maleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0455] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0456] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0457] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.102IPTS / 200243831.1Attorney Docket No. APG-701WO

[0458] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

[0459] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.

[0460] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0461] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0462] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.103IPTS / 200243831.1Attorney Docket No. APG-701WO

[0463] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0464] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.List of Exemplary Embodiments

[0465] The invention is further described by the following non-limiting exemplary embodiments:Embodiment 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:RA1, when present, is Ci-Ce alkyl optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or 3- to 10-membered heterocycloalkyl;RA2, when present, is -C(=O)-(C2-Ce alkenyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2;R1is H, halogen, or -O-(Ci-Ce alkyl), wherein the -O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2;R2is H or halogen;104IPTS / 200243831.1Attorney Docket No. APG-701WOR3is H or halogen;R4is halogen;RN1is H or CI-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ct-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ct-C6alkyl), -C(=O)-O-(Ct-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2,;RN3is H or Ci-C6alkyl;R° is Ci-C6alkyl; and n is 1, 2, or 3.Embodiment 2. The compound of embodiment 1, wherein the compound is of Formula I’:or a pharmaceutically acceptable salt thereof.Embodiment 3. The compound of embodiment 1, wherein the compound is of Formula I- 1:or a pharmaceutically acceptable salt thereof, wherein:RO1is Ci-C6alkyl optionally substituted with one or more halogen, cyano, -OH, -O- (Ct-C6alkyl), or -NH2.105IPTS / 2OO243831.1Attorney Docket No. APG-701WOEmbodiment 4. The compound of embodiment 1 or 3, wherein the compound is ofFormula I’-l:or a pharmaceutically acceptable salt thereof.Embodiment 5. The compound of embodiment 1, wherein the compound is of Formula 1-2or a pharmaceutically acceptable salt thereof, wherein:R1is halogen.Embodiment 6. The compound of embodiment 1 or 5, wherein the compound is ofFormula I’-2or a pharmaceutically acceptable salt thereof.Embodiment 7. The compound of any one of embodiments 1-6, wherein R1is H.106IPTS / 2OO243831.1Attorney Docket No. APG-701WOEmbodiment 8. The compound of any one of embodiments 1-6, wherein R1is halogen.Embodiment 9. The compound of embodiment 8, wherein R1is fluoro.Embodiment 10. The compound of any one of embodiments 1-6, wherein R1is -O-(Ci-Ce alkyl), wherein the -O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ct-C6alkyl), or -NH2.Embodiment 11. The compound of embodiment 10, wherein R1is -O-CH2CH3, -O-CH2CH2-OH, -O-CH2CH2-OCH3, or -O-CH(CH3)2.Embodiment 12. The compound of any one of embodiments 1-11, wherein R2is H.Embodiment 13. The compound of any one of embodiments 1-11, wherein R2is halogen.Embodiment 14. The compound of embodiment 13, wherein R2is fluoro.Embodiment 15. The compound of any one of embodiments 1-14, wherein R3is H.Embodiment 16. The compound of any one of embodiments 1-14, wherein R3is halogen.Embodiment 17. The compound of embodiment 16, wherein R3is fluoro.Embodiment 18. The compound of any one of embodiments 1-14, wherein R4is fluoro.Embodiment 19. The compound of any one of embodiments 1-18, wherein RN1is H.Embodiment 20. The compound of any one of embodiments 1-18, wherein RN1is Ci-Ce alkyl.Embodiment 21. The compound of embodiment 20, wherein RN1is -CH3.Embodiment 22. The compound of any one of embodiments 1-21, wherein RN2is -C(=O)-(Ci-Ce alkyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2.Embodiment 23. The compound of embodiment 22, wherein RN2is -C(=O)-CH3.Embodiment 24. The compound of any one of embodiments 1-21, wherein RN2is -C(=O)-O-(Ci-Ce alkyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2.Embodiment 25. The compound of embodiment 24, wherein RN2is -C(=O)-OCH3.Embodiment 26. The compound of any one of embodiments 1-21, wherein RN2is -S(=O)2-(Ci-Ce alkyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2.Embodiment 27. The compound of embodiment 26, wherein RN2is -S(=O)2-CH3.Embodiment 28. The compound of any one of embodiments 1-27, wherein RN3is H.Embodiment 29. The compound of any one of embodiments 1-27, wherein RN3is Ci-Ce alkyl.Embodiment 30. The compound of any one of embodiments 1-29, wherein R° is -CH3.Embodiment 31. The compound of any one of embodiments 1-30, wherein n is 1.Embodiment 32. The compound of any one of embodiments 1-30, wherein n is 2.Embodiment 33. The compound of any one of embodiments 1-30, wherein n is 3.Embodiment 34. A compound selected from the compounds in Tables 1 and 2 and pharmaceutically acceptable salts thereof.107IPTS / 200243831.1Attorney Docket No. APG-701WOEmbodiment 35. A pharmaceutical composition comprising the compound of any one of embodiments 1-34, and a pharmaceutically acceptable excipient.Embodiment 36. A method of inhibiting menin in a subject or biological sample comprising administering the compound of any one of embodiments 1-34 to the subject or contacting the biological sample with the compound of any one of embodiments 1-34.Embodiment 37. Use of the compound of any one of embodiments 1-34 in the manufacture of a medicament for inhibiting menin in a subject or biological sample.Embodiment 38. The compound of any one of embodiments 1-34 for use in inhibiting menin in a subject or biological sample.Embodiment 39. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 1-34 or pharmaceutical composition of embodiment 35.Embodiment 40. Use of the compound of any one of embodiments 1-34 in the manufacture of a medicament for treating or preventing a disease or disorder.Embodiment 41. The compound of any one of embodiments 1-34 or pharmaceutical composition of embodiment 35 for use in treating or preventing a disease or disorder.Embodiment 42. The method, use, or compound of any one of embodiments 39-41, wherein the disease or disorder is associated with menin activity.Embodiment 43. The method, use, or compound of any one of embodiments 39-42, wherein the disease or disorder is cancer.Embodiment 44. The method, use, or compound of embodiment 43, wherein the cancer is leukemia.Embodiment 45. The method, use, or compound of embodiment 43 or embodiment 44, wherein the cancer is mixed-lineage leukemia.EXAMPLES

[0466] For exemplary purpose, neutral compounds of Formula I are synthesized and tested in the examples. It is understood that the neutral compounds of Formula I may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt).Abbreviations:108IPTS / 200243831.1Attorney Docket No. APG-701WOBoc tert-butoxycarbonylDCE 1,2-dichloroethaneDCM dichloromethaneDIBALH diisobutylaluminum hydrideDIEA N,N-diisopropylethylamineDMF dimethylformamideDMPU N,N’ -dimethylpropyleneureaDMSO dimethylsulfoxide dtbpf l,l’-bis(di-tert-butylphosphino)ferroceneESI-MS electrospray ionization mass spectrometryEtOAc ethyl acetateHATU hexafluorophosphate azabenzotriazole tetramethyl uraniumHPLC high-performance liquid chromatographyHz HertzLHMDS lithium bis(trimethylsilyl)amideMeOH methanolNMR nuclear magnetic resonanceQDa quadrupole daltonRT room temperatureRt retention timeTHF tetrahydrofuranTLC thin-layer chromatographyUPLC ultra performance liquid chromatographySynthetic Routes and ProceduresExample 1. Synthesis of Intermediate 3pyr ne(1R,2S)-2- 0°C to RT 0°C to RTI Intermediate 3 aminoc Intermediate 1 ntermediate 2 y clopentanol hydrochloride

[0467] Triethylamine (4.46 mL, 31.98 mmol) was added to a solution of (lR,2S)-2- aminocyclopentanol hydrochloride (2.2 g, 15.99 mmol) in MeOH (22 mL). The solution was109IPTS / 200243831.1Attorney Docket No. APG-701WO cooled to 0°C then B0C2O (3.84 g, 17.59 mmol) was added and the reaction was allowed to warm to RT. After overnight, the solvent was removed, H2O and EtOAc were added and stirred until the solid disappeared then the aqueous layer was extracted three time with EtOAc, concentrated and purified by column chromatography (use DCM / EtOAc gradient) to produce 3.27 g of Intermediate 1.

[0468] A solution of Intermediate 1 (3.27 g, 16.25 mmol) in 15 mL of CH3CN was added to a solution, at -35°C, of thionyl chloride (2.5 mL) in dry CH3CN (25 mL). Next, pyridine (6.64 mL) was slowly added and the reaction was allowed to slowly warm to RT. After overnight, the solvent was removed; water and EtOAc were added and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted three more times with EtOAc, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (DCM / EtOAc gradient) to produce 2.74g of Intermediate 2.

[0469] Intermediate 2 (2.74 g, 11.08 mmol) was dissolved in CH3CN (18 mL) and H2O (18 mL) and cooled to 0°C. RUCI3.3H2O (11 mg) was added followed by addition of NaKU (4.74 g, 22.16 mmol) in portions. The mixture was stirred at RT for 2 hours. After the reaction was complete, the aqueous layer was extracted three times with diethyl ether, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (DCM / EtOAc gradient) to produce 2.76 g of Intermediate 3 as a white solid.2H NMR (400 MHz, Chloroform-^ / ) 6 5.16 (ddt, J = 5.7, 4.9, 1.2 Hz, 1H), 4.60 - 4.51 (m, 1H), 2.26 - 2.14 (m, 1H), 2.08 - 1.92 (m, 3H), 1.90 - 1.75 (m, 2H), 1.55 (s, 9H).Example 2. Synthesis of Intermediate 5Intermediate 4 Intermediate 5

[0470] Sodium ethoxide (16 mL, 48.99 mmol of 21% wt in ethanol) was added to a solution of 2-(3,5-difluorophenyl)acetonitrile (5g, 32.66 mmol) in MeOH (125 mL) and stirred briefly. To this solution was added l-benzylpiperidin-4-one (6.18 g, 32.66 mmol) and reaction was refluxed. After overnight, the solvent was removed, water and EtOAc were added and separated. The aqueous layer was extracted two more times with EtOAc, dried over Na2SO4, filtered and concentrated and the crude was purified by column chromatography (using a110IPTS / 2OO243831.1Attorney Docket No. APG-701WO gradient of dichloromethane and Ethyl acetate) to give Intermediate 4 (1.92 g). ESI-MS [M + H]+= 324.91, Rt(UPLC / QDa) = 2.85 min.

[0471] Intermediate 4 (1.92 g, 5.919 mmol) was redissolved in MeOH (8 mL) and NaBfE (0.675 g, 17.76 mmol) was slowly added. After overnight, the reaction was checked by TLC (if the reaction was not complete, more NaBfE was added). After complete conversion of Intermediate 4 to Intermediate 5, 8 mL of water was added and the reaction was concentrated then more H2O and EtOAc were added and separated. The aqueous layer was extracted three times with EtOAc, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (DCM / EtOAc gradient) to produce Intermediate 5 (1.68g) as an oil. ESI-MS [M + H]+= 326.96, Rt(UPLC / QDa) = 3.03 min.Example 3. Chiral synthesis of Intermediate 61) 18-Crown-6Intermediate 5 Intermediate 6 Intermediate 74:1 ratio of Intermediate 6:lntermediate 7

[0472] Intermediate 5 (1.68 g, 5.14 mmol), DMPU (1.83 mL, 15.41 mmol), and Intermediate 3 (4.05 g, 15.41 mmol) were added to a dry round-bottom flask. Then, the flask was covered with a kimwipe and dried in a desiccator under vacuum for 1-2 days. After the drying step, the flask was removed from the desiccator and quickly capped with a septum. The system was vacuumed and protected under nitrogen atmosphere. The contents in the flask were then dissolved completely with 45 mL of dry THF. The solution was then briefly vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). The reaction was cooled to 0 °C, LHMDS (IM in THF, 15.4 mL, 15.41 mmol) was added slowly, and the reaction was allowed to warm to room temperature and stirred overnight. After overnight, a solution of concentrated H2SO4 (0.6 mL, 11.31 mmol) in H2O (10 mL) was added (Note: pH of solution should be 6 - 7), and the solution was vigorously stirred overnight. Then, the reaction mixture was slowly quenched and basified with saturated NaHCCL, extracted with ethyl acetate three times. The combined organic solvent was dried over Na2SO4, filtered, and 111IPTS / 2OO243831.1Attorney Docket No. APG-701WO concentrated. The residue was purified by column chromatography to give the mixture of diastereomers in a ratio of 4:1 as a yellow solid (1.56 g, 60 %). A 0.6 g sample of the mixture of diastereomers was taken and separated by reverse phase preparative HPLC to give the enantiopure title Intermediate 6 (0.525 g, 72%) as a salt of trifluoro acetic acid (S7 was discarded). Data for Intermediate 6:2H NMR (400 MHz, Methanol-^) 87.50 - 7.41 (m, 5H), 7.12 (d, J = 8.2 Hz, 2H), 7.05 - 6.95 (m, 1H), 4.24 (s, 2H), 3.78 (q, J = 6.5 Hz, 1H), 3.55 - 3.45 (m, 2H), 3.08 - 2.96 (m, 2H), 2.76 (q, J = 7.8 Hz, 1H), 2.41 (t, J = 12.4 Hz, 1H), 2.21 (dt, J= 14.3, 2.9 Hz, 1H), 2.17 - 2.09 (m, 1H), 1.95 (d, J = 14.6 Hz, 1H), 1.87 - 1.76 (m, 1H), 1.74 - 1.58 (m, 3H), 1.57 - 1.44 (m, 2H), 1.42 - 1.33 (m, 1H), 1.30 (s, 9H). ESI-MS [M + H]+= 510.33, Rt(UPLC / QDa) = 3.88 min.Example 4. Synthesis of Intermediate 9

[0473] Intermediate 6 (0.525 g, 1.03 mmol) was dissolved in DCM (2 mL), and then CF3CO2H (6 mL) was added. After 15 minutes, the reaction was complete, and the solvent was removed in vacuo to produce Intermediate 8 that was used without purification. At 0°C, dimethyl dicarbonate (173 mg, 1.29 mmol) was added to a solution of Intermediate 8 and Et?N (0.6 mL, 4.31 mmol) in DCM (10 mL). After 2 hours, the reaction was concentrated and purified by column chromatography to produce Intermediate 9 (190 mg).1H NMR (400 MHz, Ch loro form- ) 6 7.32 - 7.20 (m, 5H), 7.04 (d, J = 9.1 Hz, 2H), 6.78 (tt, J = 8.5, 2.2 Hz, 1H), 4.34 (d, J = 5.7 Hz, 1H), 3.89 - 3.78 (m, 1H), 3.52 (s, 2H), 3.45 (s, 2H), 2.96 - 2.86 (m, 2H), 2.73 (s, 1H), 2.10 - 1.83 (m, 6H), 1.71 - 1.54 (m, 4H), 1.39 (td, J = 12.2, 3.7 Hz, 1H), 1.31 - 1.13 (m, 2H). ESLMS [M + H]+= 468.28, Rt(UPLC / QDa) = 3.24 min.112IPTS / 2OO243831.1Attorney Docket No. APG-701WOExample 5. Synthesis of Intermediate 11

[0474] At 0°C, diisobutylaluminium hydride (25% in toluene, 0.924 mL, 1.63 mmol) was slowly added to a solution of Intermediate 9 (190 mg, 0.406 mmol) in toluene (4 mL). After 1 hour at 0°C consumption of Intermediate 9 was checked, if consumed completely (or, if not completely consumed more DIBALH was added and stirred for an additional 30 minutes at 0°C), the reaction was allowed to warm to room temperature for 15 minutes, and then the reaction was slowly quenched with 2M NaOH. The quenched reaction was diluted with ethyl acetate, brine, and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated, and vacuumed to remove the residual solvent to produce a mixture of Intermediate 10 and Intermediate 11. This crude product was redissolved in methanol then treated with NaBH4 (31 mg, 0.812 mmol). After overnight the reaction was quenched with 2M NaOH, diluted with ethyl acetate, brine, and then extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and vacuumed to remove the residual solvent to produce crude Intermediate 11 (169 mg) that was used without further purification.1H NMR (400 MHz, Methanol-^) 8 7.34 - 7.22 (m, 5H), 7.09 - 7.01 (m, 2H), 6.82 (tt, J = 8.8, 2.2 Hz, 1H), 4.08 (q, J = 7.1 Hz, 1H), 3.54 (s, 3H), 3.48 (s, 2H), 3.26 - 3.09 (m, 2H), 2.99 - 2.87 (m, 2H), 2.36 (q, J = 8.6 Hz, 1H), 2.06 - 1.85 (m, 4H), 1.84 - 1.72 (m, 1H), 1.64 - 1.16 (m, 8H). ESI-MS [M + H]+= 472.14, Rt(UPLC / QDa) = 2.96 min.113IPTS / 2OO243831.1Attorney Docket No. APG-701WOExample 6. Synthesis of Intermediate 14Intermediate 11 Intermediate 12Intermediate 13 Intermediate 14

[0475] Intermediate 11 (1.9 g, 4.03 mmol) was dissolved in MeOH (100 mL). To this solution was added Na2SO4 (3g) followed by formaldehyde (0.327 mL, 37% in water) and stirred. After stirring for 3 hours, NaBH4 (306 mg, 8.06 mmol) was added slowly to the reaction. After 2 hours the reaction was determined to be complete by UPLC / QDa then the reaction was concentrated by rotovap and the residue was quenched with 2M NaOH, diluted with ethyl acetate, brine, and then extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and vacuumed to remove the residual solvent to produce crude Intermediate 12 (1.9 g) that was used without further purification. ESLMS [M + H]+= 486.30, Rt (UPLC / QDa) = 1.72 min.

[0476] At 0°C, acetic anhydride (0.389 mL, 4.12 mmol) was added to a solution of Intermediate 12 (1.0 g, 2.06 mmol) and Et?N (1.14 mL, 8.24 mmol) in DCM (50 mL). After 2 hours, the reaction was concentrated and purified by preparative-HPLC to produce Intermediate 13 (quantitative yield). ESLMS [M + H]+= 528.29, Rt(UPLC / QDa) = 3.32 min.

[0477] Intermediate 13 was dissolved in MeOH (30 mL), vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). To this solution, Pd / C (250 mg, 10% wt) was added and the suspension was vacuumed and then put under hydrogen atmosphere and this purge was repeated 2 more times. After overnight under hydrogen atmosphere, the reaction was filtered through celite, concentrated, and vacuumed to remove114IPTS / 2OO243831.1Attorney Docket No. APG-701WO the residual solvent to produce Intermediate 14 (1.2 g, quantitative yield) that was used without further purification. ESI-MS [M + H]+= 438.32, Rt(UPLC / QDa) = 2.21 min.Example 7. Synthesis of Intermediate 18

[0478] Potassium carbonate (1.85 g, 13.28 mmol) was added to a solution of 2-bromo-5- iodophenol (2.0 g, 6.69 mmol) dissolved in DMF (8 mL). After stirring for 5 minutes, iodoethane (0.807 mL, 10.03 mmol) was added to the reaction. After overnight, the reaction was determined to be complete by TLC and the reaction was quenched with a saturated aqueous solution of NaHCCh and extracted three times with ethyl acetate. The combined organic layers were washed with water then brine, concentrated and purified by column chromatography to produce pure Intermediate 15 (2.11 g).2H NMR (400 MHz, Chloroform-7) 6 7.24 (d, J = 8.2 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.09 (q, 7 = 7.0 Hz, 2H), 1.48 (t, 7 = 7.0 Hz, 3H).

[0479] A solution of Intermediate 15 (1.5 g, 4.588 mmol), 6,6-dimethoxy-2- azaspiro[3.3]heptane (1.08 g, 6.88 mmol), L-proline (528 mg, 4.588 mmol), K2CO3 (2.53 g, 18.352 mmol), and Cui (437 mg, 2.294 mmol), dissolved in DMSO was vacuumed for 10 minutes then put under nitrogen atmosphere and briefly vacuumed once more and put under nitrogen atmosphere and the reaction was heated to 90°C. After overnight, the reaction was cooled to RT, quenched with water and extracted three times ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCCL, water then brine, concentrated and purified by column chromatography to produce pure Intermediate 16 (1.24 g). ESLMS [M + H]+= 355.90, 357.86, Rt(UPLC / QDa) = 7.60 min.

[0480] Intermediate 16 (1.084 g, 3.045 mmol), l-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.27 g, 6.090 mmol), and potassium carbonate (1.68 g, 12.18 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL) then vacuumed for three minutes then put under nitrogen atmosphere. To this solution, Pd(dtbpf)Ch (496 mg, 0.761115IPTS / 2OO243831.1Attorney Docket No. APG-701WO mmol) was quickly added and the solution was again vacuumed then put under nitrogen atmosphere three times and the reaction was refluxed. After overnight, the reaction was cooled, diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with saturated aqueous NaHCCL, water then brine, concentrated and purified by column chromatography to produce pure Intermediate 17 (1.26 g).2H NMR (400 MHz, Chloroform-^) 6 7.79 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 6.10 (dd, J = 8.4, 2.2 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 4H), 3.18 (s, 6H), 2.40 (s, 4H), 1.47 (t, J = 6.9 Hz, 3H). ESI-MS [M + H]+= 358.03, Rt (UPLC / QDa) = 4.63 min.

[0481] Intermediate 17 (432 mg, 1.211 mmol) was first dissolved in trifluoroacetic acid (1 mL) then water (0.05 mL) and dichloromethane (10 mL) were added and the reaction stirred at room temperature. After one hour, the reaction was determined to be complete by UPLC / Qda and the solvent was removed and vacuumed to remove the residual solvent to produce Intermediate 18 (quantitative yield) that was used immediately without further purification. ESI-MS [M + H]+= 311.96, Rt(UPLC / QDa) = 3.63 min.Example 8. Synthesis of methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH-pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound Al)Molecular Weight: 732.92Intermediate 14 Compound A1

[0482] Intermediate 14 (530 mg, 1.211 mmol) and Intermediate 18 (crude, 1.211 mmol) were dissolved in 1,2-dichloroethane (10 mL) followed by the addition of triethylamine (0.674 mL, 4.844 mmol) and the reaction was stirred at room temperature. After 30 minutes, sodium triacetoxyborohydride (1.02 g, 4.844 mmol) was added and the reaction stirred. After four hours, the reaction was determined to be complete by UPLC / Qda. To quench the residual Intermediate 18, 1 -methylpiperazine (121 mg, 1.211 mmol) was added and the reaction stirred overnight. After overnight, the solvent was removed and the residue was re-dissolved in 116IPTS / 2OO243831.1Attorney Docket No. APG-701WO acetomitrile (20 mL) and sodium hydroxide (20 mL, 4M in water) was added and the reaction stirred for an additional five hours. The above solution was then extracted with ethyl acetate three times, washed with brine, dried over sodium sulfate, filtered through celite and concentrated. The crude product was re-dissolved in acetonitrile: water (1:1), acidified with formic acid, and purified by preparative HPLC, using a gradient of (acetonitrile and water containing 0.01% of formic acid) to produce pure methyl ((lS,2R)-2-((S)-l-(3,5- difluorophenyl)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH-pyrazol-3-yl)phenyl)-2- azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N-methylacetamido)ethyl)cyclopentyl)carbamate (Compound Al) (436 mg) as a white powder.2H NMR (400 MHz, Methanol-^) 8 7.58 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.32 - 7.19 (m, 2H), 6.88 (tt, J= 8.6, 2.1 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 6.14 - 6.05 (m, 2H), 4.57 (s, 3H), 4.11 (s, 1H), 4.09 - 3.98 (m, 3H), 3.93 - 3.86 (m, 4H), 3.78 (s, 2H), 3.57 (s, 3H), 3.24 - 3.06 (m, 3H), 2.96 (s, 3H), 2.64 (q, J = 8.1 Hz, 1H), 2.53 - 2.41 (m, 2H), 2.25 - 1.99 (m, 8H), 1.92 - 1.78 (m, 2H), 1.64 - 1.45 (m, 4H), 1.42 (t, J = 7.0 Hz, 3H), 1.39 - 1.22 (m, 3H). ESI-MS [M + H]+= 733.32, Rt(UPLC / QDa) = 4.45 min.Example 9. Synthesis of Intermediate 20MeOH, Pd / C (10%), H2(g), 1 atm, overnightIntermediate 20

[0483] At 0°C, methanesulfonyl chloride (0.239 mL, 3.09 mmol) was added to a solution of Intermediate 12 (500 mg, 1.03 mmol) and Et?N (0.573 mL, 4.12 mmol) in DCM (25 mL).117IPTS / 2OO243831.1Attorney Docket No. APG-701WOAfter 2 hours, the reaction was concentrated and purified by preparative-HPLC to produce Intermediate 19 (quantitative yield). ESI-MS [M + H]+= 564.25, Rt(UPLC / QDa) = 3.40 min.

[0484] Intermediate 19 was dissolved in MeOH (15 mL), vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). To this solution, Pd / C (250 mg, 10% wt) was added and the suspension was vacuumed and then put under hydrogen atmosphere and this purge was repeated 2 more times. After overnight under hydrogen atmosphere, the reaction was filtered through celite, concentrated, and vacuumed to remove the residual solvent to produce Intermediate 20 (quantitative yield) that was used without further purification. ESI-MS [M + H]+= 474.24, Rt(UPLC / QDa) = 2.56 min.Example 10. Synthesis of methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3-ethoxy- 4-(l-methyl-lH-pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound A2); methyl ((lS,2R)-2-((S)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH-pyrazol-3-yl)phenyl)-2- azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound A5); methyl ((lS,2R)-2-((S)-l-(l-(2-(5-ethoxy-2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-2- azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound Bl); methyl ((S)-2- (l-(2-(5-ethoxy-2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-2-azaspiro[3.3]heptan- 6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound B2); and methyl ((lS,2R)-2-((S)-l-(l-(2-(5-ethoxy-2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound B3)

[0485] Compounds A2, A5, Bl, B2, and B3 were produced according to similar procedures as described for Compound Al.118IPTS / 200243831.1Attorney Docket No. APG-701WOMolecular Weight: 768.97Intermediate 20 Compound A2

[0486] Methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH- pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound A2): ’H NMR (400 MHz, Methanol-^) 6 7.59 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 10.4 Hz, 2H), 6.93 (t, J = 8.8 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 6.13 - 6.07 (m, 2H), 4.56 (s, 5H), 4.11 - 3.97 (m, 3H), 3.95 - 3.76 (m, 8H), 3.61 (s, 3H), 2.95 (s, 3H), 2.74 (s, 3H), 2.65 - 2.51 (m, 4H), 2.39 - 2.24 (m, 3H), 2.10 (d, J= 11.4 Hz, 1H), 2.00 - 1.81 (m, 3H), 1.63 - 1.46 (m, 3H), 1.42 (t, J = 7.0 Hz, 3H), 1.39 - 1.25 (m, 3H). ESI-MS [M + H]+= 769.24, Rt(UPLC / QDa) = 4.68 min.

[0487] Methyl (( 1 S,2R)-2-((S)- 1 -( 1 -(2-(3-ethoxy-4-( 1 -methyl- lH-pyrazol-3-yl)phenyl)-2- azaspiro [3.3] heptan-6-yl)piperidin-4-yl)- 1 - (3-fluorophenyl)-2- (N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound A5): ’H NMR (400 MHz, Methanol-^) 8 7.59 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.48 - 7.38 (m, 3H), 7.12 - 7.03 (m, 1H), 6.65 (d, J = 2.3 Hz, 1H), 6.15 - 6.04 (m, 2H), 4.57 (s, 4H), 4.11 - 3.96 (m, 3H), 3.93 (s, 2H), 3.88 (s, 3H), 3.86 - 3.77 (m, 3H), 3.64 (s, 3H), 3.57 - 3.47 (m, 1H), 3.46 - 3.38 (m, 1H), 2.95 (s, 3H), 2.74 - 2.47 (m, 8H), 2.45 - 2.34 (m, 2H), 2.23 - 1.81 (m, 5H), 1.57 - 1.46 (m, 2H), 1.42 (t, J = 6.9 Hz, 3H), 1.38 - 1.26 (m, 2H). ESI-MS [M + H]+= 751.31, Rt (UPLC / QDa) = 4.64 min.119IPTS / 200243831.1Attorney Docket No. APG-701WO

[0488] Methyl ((lS,2R)-2-((S)-l-(l-(2-(5-ethoxy-2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound Bl): ESI-MS [M + H]+= 771.32, found: Rt(UPLC / QDa) = 4.73 min.

[0489] Methyl ((S)-2-(l-(2-(5-ethoxy-2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-2- azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound B2): ESI-MS [M + H]+= 751.36, Rt(UPLC / QDa) = 4.82 min.

[0490] Methyl ((lS,2R)-2-((S)-l-(l-(2-(5-ethoxy-2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound B3): ESI-MS [M + H]+= 735.35, Rt (UPLC / QDa) = 4.46 min.120IPTS / 200243831.1Attorney Docket No. APG-701WOExample 11. Synthesis of Intermediate 23Intermediate 20 Intermediate 21Intermediate 22 Intermediate 23

[0491] Intermediate 21 was prepared according to the procedure described for Intermediate 12. ESI-MS [M + H]+= 468.84, Rt(UPLC / QDa) = 1.82 min.

[0492] At 0°C, dimethyl dicarbonate (611 mg, 4.555 mmol) was added to a solution of Intermediate 21 (1.42 g, 3.037 mmol) and Et?N (1.69 mL, 12.148 mmol) in DCM (50 mL). After 2 hours, the reaction was quenched with NaHCO3 and extracted with dichloromethane three times. The combined organic layers were concentrated and purified by column chromatography to produce Intermediate 22 (1.05 g). ESI-MS [M + H]+= 526.05, Rt(UPLC / QDa) = 1.69 min (5 min UPLC method run).

[0493] Intermediate 22 (1.05 g) was dissolved in MeOH (30 mL), vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). To this solution, Pd / C (250 mg, 10% wt) was added and the suspension was vacuumed and then put under hydrogen atmosphere and this purge was repeated 2 more times. After overnight under hydrogen atmosphere, the reaction was filtered through celite, concentrated, and vacuumed to remove the residual solvent to produce Intermediate 23 (0.864 g) that was used without further purification. ’ H NMR (400 MHz, Methanol-^) 8 7.45 - 7.31 (m, 3H), 7.06 - 6.94 (m, 1H), 4.70 - 4.49 (m, 1H), 4.16 - 3.91 (m, 3H), 3.77 - 3.68 (m, 3H), 3.63 - 3.55 (m, 3H), 3.29 - 3.20 (m, 1H), 2.96 - 2.67 (m, 5H), 2.61 (p, J = 7.7 Hz, 1H), 2.51 - 2.30 (m, 1H), 2.16 - 1.79 (m, 3H), 1.63 - 1.28 (m, 6H), 1.20 - 1.05 (m, 1H). ESI-MS [M + H]+= 436.01, Rt(UPLC / QDa) = 1.39 min (5 min UPLC method run).IPTS / 200243831.1Attorney Docket No. APG-701WOExample 12. Synthesis of methyl ((S)-2-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound A3)

[0494] Intermediate 23 (300 mg, 0.689 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane- 2-carboxylate (218 mg, 1.033 mmol) were dissolved in 1,2-dichloroethane (8 mL) followed by the addition of triethylamine (0.383 mL, 2.756 mmol) and the reaction was stirred at room temperature. After 30 minutes, sodium triacetoxyborohydride (582 mg, 2.756 mmol) was added and the reaction stirred. After two hours, the reaction was determined to be complete by UPLC / Qda. The reaction was concentrated and purified by preparative HPLC to produce Intermediate 24. ESLMS [M + H]+= 631.46, Rt(UPLC / QDa) = 3.98 min.

[0495] Intermediate 24 was dissolved in trifluoroacetic acid (3 mL) and after stirring for 10 minutes it was determined, by UPLC / QDa, that the Boc protecting group had been completely removed. Dichloromethane (10 mL) and then the solvent was removed, and vacuumed to remove the residual solvent to produce Intermediate 25 that was used without further purification. ESLMS [M + H]+= 531.87, Rt(UPLC / QDa) = 1.62 min.

[0496] Intermediate 25 (crude, 0.689 mmol), Intermediate 26 (283 mg, 0.758 mmol), and potassium carbonate (380 mg, 2.756 mmol) were dissolved in DMSO (2 mL) and heated to 90°C. After 30 minutes, the reaction was determined to be complete; consequently it was122IPTS / 2OO243831.1Attorney Docket No. APG-701WO diluted with water / acetonitrile (1:1), acidified with trifluoracetic acid and purified by preparative HPLC to produce Intermediate 27. ESI-MS [M + H]+= 885.91, Rt(UPLC / QDa) = 4.51 min.

[0497] The isolated Intermediate 27 was dissolved in trifluoroacetic acid (3 mL) and after stirring for 10 minutes it was determined, by UPLC / QDa, that the Boc protecting group had been removed completely and this reaction was diluted with DCM and concentrated the redissolved in acetonitrile / water (1:1), frozen, and lyophilized to produce Intermediate 28 (393 mg, after 4-steps) as a white powder. ESI-MS [M + H]+= 785.73, Rt(UPLC / QDa) = 3.70 min.

[0498] Methyl ((S)-2-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)- 2-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound A3): Acrylic acid (18 mg, 0.255 mmol) was dissolved in dry DMF (2 mL) followed by the addition of DIEA (0.190 mL, 1.12 mmol) then HATU (107 mg, 0.280 mmol) and the reaction briefly stirred. Immediately, this solution was quickly added to a solution of Intermediate 28 (200 mg, 0.255 mmol) in DMF (0.5 mL) and the reaction stirred. After five minutes, as determined by UPLC / QDa, the reaction was complete. The reaction was diluted with water / acetonitrile (1:1), acidified with trifluoracetic acid and purified by preparative HPLC to produce Compound A3 (136 mg) as a white powder.1H NMR (400 MHz, Methanol-^) 87.53 - 7.30 (m, 5H), 7.08 - 6.99 (m, 1H), 6.67 - 6.56 (m, 1H), 6.38 - 6.21 (m, 2H), 5.77 - 5.71 (m, 1H), 4.51 (d, J = 14.9 Hz, 1H), 4.23 - 3.96 (m, 7H), 3.74 (s, 3H), 3.68 - 3.35 (m, 9H), 3.23 (dd, J = 9.6, 2.1 Hz, 1H), 2.90 - 2.76 (m, 4H), 2.73 - 2.57 (m, 4H), 2.47 - 2.33 (m, 3H), 2.25 (d, J = 14.4 Hz, 1H), 2.08 - 1.98 (m, 1H), 1.93 - 1.16 (m, 12H). ESI-MS [M + H]+= 839.46, Rt (UPLC / QDa) = 4.37 min.Example 13. Synthesis of methyl ((S)-2-(l-(2-(4-(((R)-4-acryloyl-l,4-oxazepan-6- yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-123IPTS / 2OO243831.1Attorney Docket No. APG-701WO fluorophenyl)-2-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound A4)

[0499] Intermediate 25 (480 mg, 0.906 mmol) and Intermediate 29 (376 mg, 0.997 mmol) were dissolved in DMSO (3 mL) followed by the addition of DIEA (0.457 mL, 3.624 mmol) and sodium bicarbonate (304 mg, 3.624 mmol) and the reaction was heated to 90°C. After 30 minutes, the reaction was determined to be complete; consequently it was diluted with water / acetonitrile (1:1), acidified with trifluoracetic acid and purified by preparative HPLC to produce Intermediate 30. The isolated Intermediate 30 was dissolved in trifluoroacetic acid (3 mL) and after stirring for 10 minutes it was determined, by UPLC / QDa, that the Boc protecting group had been removed completely. This reaction was diluted with DCM, concentrated then re-dissolved in acetonitrile / water (1:1), frozen, and lyophilized to produce Intermediate 31 (462 mg) as a white powder.

[0500] Methyl ((S)-2-(l-(2-(4-(((R)-4-acryloyl-l,4-oxazepan-6-yl)sulfonyl)-2-fluorophenyl)- 2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound A4): Acrylic acid (20.8 pL, 0.3033 mmol) was dissolved in dry DMF (2 mL) followed by the addition of DIEA (206 pL, 1.213 mmol) then HATU (138 mg, 0.364 mmol) and the reaction briefly stirred and cooled to 0°C. Immediately, this solution was quickly added to a solution, at 0°C, of Intermediate 31 (239 mg, 0.3033 mmol) in DMF (0.5 mL) and the reaction stirred. After five minutes, as determined by UPLC / QDa, the reaction was complete. The reaction was diluted with water / acetonitrile (1:1), acidified with trifluoracetic acid and purified by preparative HPLC to produce Compound A4 as a white powder.1H NMR (400 MHz, Methanol-^) 87.58 - 7.31 (m, 5H), 7.09 - 7.00 (m, 1H), 6.76 - 6.58 (m, 2H), 6.23 (dd, J = 16.7, 1.9 Hz, 1H), 5.75124IPTS / 2OO243831.1Attorney Docket No. APG-701WO(td, J = 10.4, 1.9 Hz, 1H), 4.40 - 3.96 (m, 9H), 3.90 (dt, J = 12.1, 3.3 Hz, 1H), 3.85 - 3.35 (m, 14H), 3.25 - 3.14 (m, 1H), 2.89 - 2.77 (m, 4H), 2.74 - 2.58 (m, 4H), 2.46 - 2.33 (m, 3H), 2.25 (d, J = 14.5 Hz, 1H), 2.03 (d, J = 14.0 Hz, 1H), 1.95 - 1.83 (m, 1H), 1.74 - 1.31 (m, 7H). ESIMS [M + H]+= 842.48, Rt(UPLC / QDa) = 4.38 min.Example 14. Synthesis of Methyl ((lS,2R)-2-((S)-l-(l-(2-(4-bromo-3-ethoxyphenyl)-2- azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3,5-difluorophenyl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Intermediate 33)Intermediate 14

[0501] Intermediate 33 was produced using the same synthetic sequence used to obtain Compound Al. ESI-MS [M + 1]+ = 731.35, 733.32, Rt (UPLC / QDa) = 4.64 min.Example 15. Synthesis of methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3-ethoxy-4-(lH-pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound Cl)Molecular Weight: 961.21Molecular Weight: 731.72 Intermediate 35Intermediate 33Molecular Weight: 718.89Compound C1125IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0502] Intermediate 33 (50 mg, 0.0683 mmol), Intermediate 34 (60 mg, 0.137 mmol), and potassium carbonate (38 mg, 0.273 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL) then vacuumed for three minutes then put under nitrogen atmosphere. To this solution, Pd(dtbpf)C12 (11.1 mg, 0.0171 mmol) was quickly added and the solution was again vacuumed then put under nitrogen atmosphere three times and the reaction was refluxed. After overnight, the reaction was cooled, diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with saturated aqueous NaHCCh, water then brine, concentrated and purified by column chromatography to produce pure Intermediate 35. Crude Intermediate 35 was then treated with neat trifluoroacetic acid. After two hours, the reaction was determined to be complete by UPLC / Qda and the solvent was removed and the crude product was re-dissolved in acetonitrile: water (1:1), acidified with formic acid, and purified by preparative HPLC, using a gradient of (acetonitrile and water containing 0.01% of formic acid) to produce pure Compound Cl (46 mg) as a white powder. ESLMS [M + 1]+= 719.37, [M + 2]+= 360.25, Rt(UPLC / QDa) = 3.81 min.Example 16. Synthesis of methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3-ethoxy- 4-(l-(2-methoxyethyl)-lH-pyrazoL3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4- yl)-2-(N-methylacetamido)ethyl)cyclopentyl)carbamate (Compound C2)Molecular Weight: 776.97Compound C2

[0503] According to the same procedure used to obtain Intermediate 35, crude Compound C2 was obtained and was re-dissolved in acetonitrile: water (1:1), acidified with formic acid, and purified by preparative HPLC, using a gradient of (acetonitrile and water containing 0.01% of formic acid) to produce pure Compound C2 (52 mg) as a white powder. ESLMS [M + 1]+= 777.39, [M + 2]+= 389.36, Rt(UPLC / QDa) = 4.16 min.126IPTS / 2OO243831.1Attorney Docket No. APG-701WOExample 17. Synthesis of methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3- ethoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound C3)Intermediate 33 Compound C3

[0504] Intermediate 33 ( 20 mg, 0.0273 mmol) was dissolved in MeOH (2 mL), vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). To this solution, Pd / C (20 mg, 10% wt) was added and the suspension was vacuumed and then put under hydrogen atmosphere and this purge was repeated 2 more times. After two hours under hydrogen atmosphere, the reaction was filtered through celite, concentrated, re-dissolved in acetonitrile: water (1:1), acidified with formic acid, and purified by preparative HPLC, using a gradient of (acetonitrile and water containing 0.01% of formic acid) to produce pure Compound C3 (12 mg) as a white powder. ESI-MS [M + 1]+= 653.44, [M + 2]+= 327.26, Rt(UPLC / QDa) = 4.37 min.Example 18. Synthesis of 3-(2-ethoxy-4-fluorophenyl)-5-methyl-l,2,4-oxadiazole (Intermediate 38)Intermediate 36 Intermediate 37 Intermediate 38

[0505] Triethylamine (0.381 mL, 2.741 mmol) was added to a solution of Intermediate 36 (152 mg, 0.914 mmol) and hydroxylamine hydrochloride salt (190 mg, 2.741 mmol) dissolved in ethanol (1 mL) and the mixture was heated to 70 °C. After overnight, ethanol was evaporated off and the mixture was quenched with aqueous NH4CI, extracted three times with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated to produce crude Intermediate 37 which was used without further purification. ESLMS [M + H]+= 199.09, Rt(UPLC / QDa) = 0.575 min. Intermediate 37 was dissolved in acetic anhydride (2 mL) and heated under 140°C until 37 was consumed. Then the mixture was cooled, diluted with H2O and carefully quenched127IPTS / 2OO243831.1Attorney Docket No. APG-701WO with ammonia. The mixture was extracted three times with ethyl acetate, washed with brine, dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography to give Intermediate 38 as off-white solid (141 mg). ESI-MS [M + H]+= 223.41, Rt(UPLC / QDa) = 4.05 min.Example 19. Synthesis of 3-(4-(6,6-dimethoxy-2-azaspiro[3.3]heptan-2-yl)-2- ethoxyphenyl)-5-methyl-l,2,4-oxadiazole (intermediate 39)Intermediate 38 Intermediate 39

[0506] 6,6-dimethoxy-2-azaspiro[3.3]heptane (178 mg, 1.134 mmol) and K2CO3 (260 mg, 1.89 mmol) were added to the solution of Intermediate 38 (84 mg, 0.378 mmol) in DMSO (1.5 mL). The mixture was heated to 110°C. After overnight, the mixture was cooed to rt, quenched with NH4CI (aq), extracted three times with ethyl acetate, washed with brine, dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography to give Intermediate 39 as off-white solid (89 mg). ESI-MS [M + H]+= 360.16, Rt(UPLC / QDa) = 4.72 min.Example 20. Synthesis of 2-(3-ethoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-2- azaspiro[3.3]heptan-6-one (intermediate 40)Intermediate 39 Intermediate 40

[0507] Intermediate 40 was obtained according to the same procedure described for intermediate 17. ESI-MS [M + H]+= 314.09, Rt(UPLC / QDa) = 3.53 min.Example 21. Synthesis of methyl ((lS,2R)-2-((S)-l-(3,5-difluorophenyl)-l-(l-(2-(3- ethoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound C4)IPTS / 2OO243831.1Attorney Docket No. APG-701WOMolecular Weight: 734.89Compound C4

[0508] According to the same procedure described to obtain Compound Al, pure Compound C4 was produced using Intermediate 40. ESLMS [M + 1]+= 735.48, Rt(UPLC / QDa) = 4.19 min.Example 22. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3- fluorophenyl)-2-(2-isopropyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate(Intermediate 41) and methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-isopropyLlH- imidazol-l-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (Intermediate 42)Intermediate 20 Intermediate 41 Intermediate 42

[0509] At 0 °C, ammonium acetate (1.702 g, 22.075 mmol), glyoxal (4.25 mL, 40% in water, 22.075 mmol), and isobutyraldehyde (4.04 mL, 44.15 mmol) were added to a solution of Intermediate 20 (2.0 g, 4.415 mmol) in methanol (120 mL). After stirring at 0 °C for 30 minutes the reaction was removed from the ice bath and allowed to stir at room temperature for 1 hour then it was heated to reflux. After refluxing overnight, the reaction was concentrated and purified by reverse-phase combiflash to produce Intermediate 41 (972 mg) as an oil. ESLMS [M + H]+= 547.33, Rt(UPLC / QDa) = 1.39 min.

[0510] Intermediate 41 (706 mg) was dissolved in MeOH (30 mL), vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). To this solution, Pd / C (500 mg, 10% wt) was added and the suspension was vacuumed and then put under hydrogen atmosphere and this purge was repeated 2 more times. After overnight under hydrogen atmosphere, the reaction was filtered through celite, concentrated, and vacuumed to remove the residual solvent to produce Intermediate 42 (706 mg) that was used without further purification. ESLMS [M + H]+= 457.30, Rt(UPLC / QDa) = 1.11 min.129IPTS / 200243831.1Attorney Docket No. APG-701WOExample 23. Synthesis of methyl ((!S,2R)-2-((S)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH- pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2- isopropyl- IH-imidazol- l-yl)ethyl)cyclopentyl)carbamate (Compound C5)Compound C5

[0511] Starting with Intermediate 42 and following the procedure described to produce Compound Al, pure Compound C5 was produced. ESI-MS [M + 1]+= 752.47, [M + 2]+= 376.89, Rt(UPLC / QDa) = 2.88 min.Example 24. Synthesis of methyl ((lS,2R)-2-((S)-2-(N-ethylacetamido)-l-(3- fluorophenyl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (Intermediate 45)Intermediate 20 Intermediate 43Intermediate 44 Intermediate 45

[0512] Intermediate 45 was obtained following a similar synthetic sequence described for Intermediate 14. ESI-MS [M + H]+= 434.36, Rt(UPLC / QDa) = 2.85 min.130IPTS / 200243831.1Attorney Docket No. APG-701WOExample 25. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH- pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(N-ethylacetamido)-l- (3-fluorophenyl)ethyl)cyclopentyl)carbamate (Compound C6)Molecular Weight: 728.95Compound C6

[0513] Starting with Intermediate 45 and following the procedure described for Compound Al, pure Compound C6 was produced. ESI-MS [M + 1]+= 729.51, [M + 2]+= 365.37, Rt(UPLC / QDa) = 4.24 min.Example 26. Synthesis of Methyl ((S)-2-(3,5-difluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)-2-(piperidin-4-yl)ethyl)(methyl)carbamate (Intermediate 47)Intermediate 12 Intermediate 46 Intermediate 47

[0514] Intermediate 47 was prepared according to the procedure described for Intermediate23. ESI-MS [M + H]+= 454.28, Rt(UPLC / QDa) = 2.61 min.Example 27. Synthesis of methyl ((S)-2-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-2-(3,5-difluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C7)131IPTS / 200243831.1Attorney Docket No. APG-701WOCompound C7

[0515] Starting with Intermediate 47 and following the procedure described for Compound A3, pure Compound C7 was produced. ESI-MS [M + 1]+= 857.37, [M + 2]+= 429.38, Rt(UPLC / QDa) = 4.05 min.Example 28. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-l-(3,5-difluorophenyl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound C8)Molecular Weight: 841.00Compound C8

[0516] Starting with Intermediate 14 and following the procedure described for Compound A3, Compound C8 was produced. ESI-MS [M + 1]+= 841.27, [M + 2]+= 421.37, Rt(UPLC / QDa) = 3.84 min.Example 29. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-l-(3,5-difluorophenyl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound C9)132IPTS / 200243831.1Attorney Docket No. APG-701WOMolecular Weight: 877.05Compound C9

[0517] Starting with Intermediate 20 and following the procedure described for Compound A3, Compound C9 was produced. ESI-MS [M + 1]+= 877.34, [M + 2]+= 439.38, Rt(UPLC / QDa) = 3.88 min.Example 30. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(3-ethoxy-4-(l-methyl-lH- pyrazol-3-yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound CIO)Intermediate 49 Molecular Weight: 714.93Compound C10

[0518] Starting with Intermediate 49 and following the procedure described for Compound Al, pure Compound CIO was produced. ESI-MS [M + 1]+= 715.47, [M + 2]+= 358.37, Rt(UPLC / QDa) = 3.87 min.Example 31. Synthesis of methyl ((S)-2-(l-(2-(4-(((R)-4-acryloyl-l,4-oxazepan-6- yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,5- difluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C26)133IPTS / 200243831.1Attorney Docket No. APG-701WOMolecular Weight: 860.00Compound C26

[0519] Starting with Intermediate 47 and following the procedure described for Compound A3, pure Compound C26 was produced. ESI-MS [M + 1]+= 860.34, Rt(UPLC / QDa) = 4.00 min.Example 32. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylacetamido)ethyl)cyclopentyl)carbamate (Compound C12)Molecular Weight: 823.01Compound C12

[0520] Starting with Intermediate 49 and following the procedure described for Compound A3, pure Compound C12 was produced. ESI-MS [M + 1]+= 823.39, [M + 2]+= 412.39, Rt(UPLC / QDa) = 3.94 min.Example 33. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2-isopropyl-lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Compound C13)134IPTS / 200243831.1Attorney Docket No. APG-701WOIntermediate 42Molecular Weight: 860.08Compound C13

[0521] Starting with Intermediate 44 and following the procedure described for Compound A3, pure Compound C13 was produced. ESI-MS [M + 1]+= 860.42, [M + 2]+= 430.99, Rt(UPLC / QDa) = 2.92 min.Example 34. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate (Compound C 14)Intermediate 50 Molecular Weight: 824.99Compound C14

[0522] Starting with Intermediate 50 and following the procedure described for Compound A3, pure Compound C14 was produced. ESI-MS [M + 1]+= 824.37, [M + 2]+= 413.37, Rt(UPLC / QDa) = 4.26 min.Example 35. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(N- methylmethylsulfonamido)ethyl)cyclopentyl)carbamate (Compound C15)135IPTS / 200243831.1Attorney Docket No. APG-701WOCompound C15

[0523] Starting with Intermediate 51 and following the procedure described for Compound A3, pure Compound C15 was produced. ESI-MS [M + 1]+= 859.35, [M + 2]+= 430.41, Rt(UPLC / QDa) = 3.97 min.Example 36. Synthesis of methyl ((lS,2R)-2-((S)-2-(5,5-dimethyl-2-oxooxazolidin-3-yl)-l-(3-fluorophenyl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (Intermediate 53)

[0524] 2,2-dimethyloxirane (0.036 mL) was added to a solution of Intermediate 20 (200 mg, 0.441 mmol) dissolved in ethanol (2 mL) and the reaction heated to 100 °C. After overnight the solvent was removed to produce Intermediate 52 as a white solid that was used without further purification. Triphosgene (78 mg, 0.264 mmol) was added to a 0 °C solution of Intermediate 52 (crude) and triethylamine (0.245 mL, 1.764 mmol) dissolved in dichloromethane (4 mL). After 1 hour the reaction was complete. The solvent was removed and solid was purified by prep-HPLC to produce Intermediate 53 (102 mg) as a white solid. ESLMS [M + H]+= 462.30, Rt(UPLC / QDa) = 2.65 min.Example 37. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-2-(5,5-dimethyl-2-oxooxazolidin-3-yl)-l-(3- fluorophenyl)ethyl)cyclopentyl)carbamate (Compound C16)136IPTS / 2OO243831.1Attorney Docket No. APG-701WOIntermediate 53Molecular Weight: 865.05Compouond C16

[0525] Starting with Intermediate 53 and following the procedure described for Compound A3, pure Compound C16 was produced. ESI-MS [M + 1]+= 865.46, [M + 2]+= 433.44, Rt(UPLC / QDa) = 4.19 min.Example 38. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-2-(l,l- dioxidoisothiazolidin-2-yl)-l-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (Intermediate55) and methyl ((lS,2R)-2-((S)-2-(l,l-dioxidoisothiazolidin-2-yl)-l-(3-fluorophenyl)-l- (piperidin-4-yl)ethyl)cyclopentyl)carbamate (Intermediate 56)Intermediate 55 Intermediate 56

[0526] 3-chloropropane-l -sulfonyl chloride (0.201 mL, 1.652 mmol) was added, at 0 °C , to a solution of Intermediate 20 (500 mg, 1.101 mmol) and triethylamine (0.460 mL, 3.303 mmol) in dichloromethane (5 mL). After overnight at RT, the solvent was removed and produced crude Intermediate 54 that was used without further purification. Sodium hydride (132 mg, 3.303 mmol, 60% wt / wt in oil) was added, at 0 °C, to a solution of crude Intermediate 54 dissolved in THF (6 mL) then the reaction was heated to 55 °C. After 8 hours the reaction was quenched with methanol, the solvent removed and purified by prep-HPLC to produce Intermediate 55 (370 mg). ESI-MS [M + H]+= 558.27, Rt(UPLC / QDa) = 3.71 min.137IPTS / 200243831.1Attorney Docket No. APG-701WO

[0527] Intermediate 55 (370 mg) was dissolved in MeOH (5 mL), vacuumed and then put under a nitrogen atmosphere. (This purging was repeated two more times). To this solution, Pd / C (200 mg, 10% wt) was added and the suspension was vacuumed and then put under hydrogen atmosphere and this purge was repeated 2 more times. After overnight under hydrogen atmosphere, the reaction was filtered through celite, concentrated, and vacuumed to remove the residual solvent to produce Intermediate 56 (272 mg) that was used without further purification. ESI-MS [M + H]+= 468.25, Rt(UPLC / QDa) = 2.62 min.Example 39. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6- yl)piperidin-4-yl)-2-(l,l-dioxidoisothiazolidin-2-yl)-l-(3- fluorophenyl)ethyl)cyclopentyl)carbamate (Compound C17)Molecular Weight: 871.07Compound C17

[0528] Starting with Intermediate 56 and following the procedure described for Compound A3, pure Compound C17 was produced. ESI-MS [M + 1]+= 871.35, [M + 2]+= 436.39, Rt(UPLC / QDa) = 3.85 min.Example 40. Synthesis of methyl ((S)-2-(l-(2-(4-(((l-acryloylazetidin-3- yl)methyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3- fluorophenyl)-2-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C18)Intermediate 25 Molecular Weight: 794.00Compound C18138IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0529] Starting with Intermediate 57 and following the procedure described for Compound A4, pure Compound C18 was produced. ESI-MS [M + 1]+= 794.44, [M + 2]+= 397.91, Rt(UPLC / QDa) = 3.79 min.Example 41. Synthesis of methyl ((S)-2-(l-(2-(4-(((R)-4-acryloyl-l,4-oxazepan-6- yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2- ((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C19)Compound C19

[0530] Starting with Intermediate 58 and following the procedure described for Compound A4, pure Compound C19 was produced. ESI-MS [M + 1]+= 824.41, [M + 2]+= 412.93, Rt(UPLC / QDa) = 3.90 min.Example 42. Synthesis of methyl ((S)-2-(l-(2-(4-(((S)-l-acryloylazepan-3- yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2- ((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C20)Compound C20

[0531] Starting with Intermediate 59 and following the procedure described for Compound A4, pure Compound C20 was produced. ESI-MS [M + 1]+= 822.48, [M + 2]+= 411.93, Rt(UPLC / QDa) = 4.23 min.Example 43. Synthesis of methyl ((S)-2-(l-(2-(4-(((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-139IPTS / 200243831.1Attorney Docket No. APG-701WO yl)-2-(3-fluorophenyl)-2-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C21)Molecular Weight: 821.02Compound C21

[0532] Starting with Intermediate 60 and following the procedure described for Compound A4, pure Compound C21 was produced. ESI-MS [M + 1]+= 821.40, [M + 2]+= 411.41, Rt(UPLC / QDa) = 3.94 min.Example 44. Synthesis of methyl ((S)-2-(l-(2-(4-((l-acryloylazetidin-3- yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2- ((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate (Compound C22)Intermediate 61 Intermediate 25 Compound C22

[0533] Starting with Intermediate 61 and following the procedure described for Compound A4, pure Compound C22 was produced. ESI-MS [M + 1]+= 780.46, [M + 2]+= 390.89, Rt(UPLC / QDa) = 3.78 min.Example 45. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((R)-4-acryloyl-l,4-oxazepan-6-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(l,l-140IPTS / 200243831.1Attorney Docket No. APG-701WO dioxidoisothiazolidin-2-yl)-l-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (CompoundIntermediate 56Molecular Weight: 874.07Compound C23

[0534] Starting with Intermediate 56 and following the procedure described for Compound A3, pure Compound C23 was produced. ESI-MS [M + 1]+= 874.37, [M + 2]+= 437.88, Rt(UPLC / QDa) = 3.88 min.Example 46. Synthesis of methyl ((lS,2R)-2-((S)-l-(l-(2-(4-(((S)-l-acryloylazepan-3- yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(l,l- dioxidoisothiazolidin-2-yl)-l-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (Compound C24)Intermediate 56Molecular Weight: 874.07Compound C24

[0535] Starting with Intermediate 56 and following the procedure described for Compound A3, pure Compound C24 was produced. ESI-MS [M + 1]+= 854.43, [M + 2]+= 427.91, Rt(UPLC / QDa) = 3.99 min.Example 47. Synthesis of methyl ((S)-2-(l-(2-(4-(((S)-l-acryloylpyrrolidin-3-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-IPTS / 200243831.1Attorney Docket No. APG-701WO((lR,2S)-2-((methoxycarbonyl)ammo)cyclopentyl)ethyl)(methyl)carbamate (Compound

[0536] Starting with Intermediate 61 and following the procedure described for Compound A4, pure Compound C25 was produced. ESI-MS [M + 1]+= 812.38, [M + 2]+= 406.88, Rt(UPLC / QDa) = 3.99 min.Example 48. Menin binding affinity of exemplary compounds

[0537] A fluorescence polarization (FP) competitive binding assay was used to determine the binding affinities of representative menin inhibitors. A FAM labeled fluorescent probe was designed and synthesized based on a MLL1 peptide (FAM-MM2). Equilibrium dissociation constant (K ) value of FAM-MM2 to menin protein was determined from protein saturation experiments by monitoring the total fluorescence polarization of mixtures composed with the fluorescent probe at a fixed concentration and the protein with increasing concentrations up to full saturation. Serial dilutions of the protein were mixed with FAM-MM2 to a final volume of 200 pl in the assay buffer (PBS with 0.02% Bovine y-Globulin and 4% DMSO. 0.01% Triton X-100 was added right before assays). Final FAM-MM2 concentration was 2 nM. Plates were incubated at room temperature for 30 minutes with gentle shaking to assure equilibrium. FP values in millipolarization units (mP) were measured using the Infinite M-1000 plate reader (Tecan U.S., Research Triangle Park, NC) in Microfluor 1 96-well, black, v-bottom plates (Thermo Scientific, Waltham, MA) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. K / value of FAM-MM2, which was calculated by fitting the sigmoidal dose-dependent FP increases as a function of protein concentrations using Graphpad Prism 6.0 software (Graphpad Software, San Diego, CA), was determined as 1.4 nM.

[0538] The IC50 of representative Compounds of the Disclosure were determined in a competitive binding experiment. Mixtures of 5 pl of the tested compounds in DMSO and 195 pl of preincubated protein / probe complex solution in the assay buffer were added into assay plates which were incubated at room temperature for 30 minutes with gentle shaking. Final142IPTS / 2OO243831.1Attorney Docket No. APG-701WO concentration of the menin protein was 4 nM, and final probe concentration is 2 nM. Negative controls containing protein / probe complex only (equivalent to 0% inhibition), and positive controls containing only free probes (equivalent to 100% inhibition), were included in each assay plate. FP values were measured as described above. IC50 values were determined by nonlinear regression fitting of the competition curves. See Table I.

[0539] For IC50 values in Table B: “A” < 5 nM; 5 nM < “B” < 10 nM; 10 nM < “C” < 20 nM; 20 nM < “D” < 30 nM; 30 nM < “E” < 40 nM; 40 nM < “F” < 50 nM; 50 nM < “G” < 100 nM; and 100 nM < “H”.Table I143IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0542] Ref. Compound No. 3:Example 49. Cell growth inhibition activity of exemplary compounds

[0543] The effect of representative Compounds of the Disclosure on cell viability was determined in a 4-day proliferation assay. Cells were maintained in the appropriate culture medium with 10% FBS at 37°C and an atmosphere of 5% CO2.

[0544] Cells were seeded in 96-well flat bottom white plate (Corning COSTAR, Corning, NY, cat# 3903) at a density of 7,500 cells / well (MV411 cells) or 3,000 cells / well (MOLM13 and HL60 cells) in 100 pl of culture medium containing serial diluted compounds. After the addition of compounds, the cells were incubated at 37°C in an atmosphere of 5% CO2 for 4 days. Cell viability was determined using CellTiter-Glo cell Viability Assay Kit from Promega144IPTS / 200243831.1Attorney Docket No. APG-701WOCorporation. The readings were normalized to the DMSO-treated cells and the half maximal inhibitory concentration (IC50) was calculated by nonlinear regression (four parameters sigmoid fitted with variable slope, least squares fit, and no constraint) analysis using the GraphPad Prism 5 software (GraphPad Software, La Jolla, CA). See Table II.

[0545] For IC50 values in Table II: “A” < 5 nM; 5 nM < “B” < 10 nM; 10 nM < “C” < 20 nM; 20 nM < “D” < 30 nM; 30 nM < “E” < 40 nM; 40 nM < “F” < 50 nM; 50 nM < “G” < 100 nM; and 100 nM < “H”.Table II145IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0546] Ref. Compound Nos. 1, 2, and 3 of Table II are the same as Ref. Compound Nos. 1, 2, and 3, respectively, of Table I.Example 50. In vivo pharmacokinetics studies in dogs, cynomolgus monkeys, and rats

[0547] Test article preparation:

[0548] Blood sample collection and procedure: The blood was taken via jugular vein or other suitable vein, 1.0 mL / time point. Sample was placed in tubes containing K2-EDTA and stored on ice until centrifuged. The blood samples were centrifuged at 2200 g for 10 minutes at 2-8 °C within Ih after collected and stored frozen at approximately -80°C.

[0549] Sample preparation: An aliquot of 60 pL plasma sample was protein precipitated with 300 pL MeOH in which contains 10 ng / mL IS. The mixture was vortexed for 1 min. Then, samples treated with tube were centrifuged at 14000 rpm for 7 min; samples treated with 96 well plates were centrifuged at 4000 rpm for 10 min. 280 pL supernatant was transferred to 96 well plates. An aliquot of 10 pL supernatant was injected for LC-MS / MS analysis.

[0550] Calibration curve: 1-1000 ng / mL for drug in animal plasma samples.146IPTS / 2OO243831.1Attorney Docket No. APG-701WO

[0551] Sample analysis and data processing: The analytical results were confirmed using quality control samples for intra-assay variation. The accuracy of >66.7% of the quality control samples were confirmed to be between 80 - 120% of the known value(s).

[0552] Standard set of parameters including Area Under the Curve (AUC<o-t) and AUC(o-oo)), elimination half-life (T1 / 2), maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax) were calculated using noncompartmental analysis modules in FDA certified pharmacokinetic program Phoenix WinNonlin 7.0 or other version (Pharsight, USA) by the Study Director. Example results are summarized in Table III.Table III

[0553] Ref. Compound147IPTS / 2OO243831.1Attorney Docket No. APG-701WOExample 51. In vivo pharmacokinetics and pharmacodynamics and efficacy studies in an MV4;11 human AML xenograft model in mice

[0554] MV4;11 cells were grown in a suspension and collected in the log phase. A cell sample was mixed 1:1 with Trypan Blue (GIBCO, Invitrogen Corp.) and counted on a hemocytometer to determine the number of live / dead cells. Cells were washed twice with lx phosphate- buffered saline (PBS, GIBCO, Invitrogen Corp.) and resuspended in an ice-cold mixture of 1 : 1 PBS and Matrigel (BD Biosciences, Invitrogen Corp.) for a final Matrigel protein concentration of 5 mg / mL. MV4;11 cells were inoculated into female C.B-17 SCID mice at 5 x 106cells in 0.1 mL with Matrigel. Cells were injected by the subcutaneous route into the flank region of each mouse. The size of tumors growing in the mice was measured in two dimensions using calipers. Tumor volume (mm3) = (A x B2) / 2, where A and B are the tumor length and width (mm), respectively.

[0555] For pharmacokinetics and pharmacodynamics studies, mice bearing MV4;11 tumors of 150 mm3volume were administered with a vehicle or compound at designated mg / kg doses via oral gavage (QD) at lOml / kg in three consecutive days. At 3h or 24h time points the mice were euthanized with CO2. 250-300 uL of blood was collected by cardiac punctre and put into 1.5 mL microfuge tubes containing Heparin and placed on wet ice. Samples were centrifuged at 15,000 rpm for 10 min. A minimum of 100 uL of blood plasma was collected from the upper layer, leaving the blood cells behind in the microfuge tube. The plasma was transferred into a fresh 1.5 mL microfuge tube and frozen at -80°C for analysis. Tumors from each mouse were divided into two parts. One part was immediately frozen in liquid nitrogen, ground into fine powder and placed on dry ice and stored in -80°C for Western blot analysis. Another part was placed in tared 1.5mL microfuge tube, weighed, snap frozen in liquid nitrogen and stored at - 80°C for drug analysis.

[0556] Real-Time PCR: Total RNA was isolated from tumor samples for pharmacodynamic studies, using an RNeasy kit (QIAGEN) according to the manufacturer’ s protocol. The cDNA was generated using a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Real-time PCR amplifications of HOXA9, ME1S1, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) genes were carried out with primers specific for each gene, using TaqMan gene expression assays (Applied Biosystems). Relative quantification of each gene transcript was calculated by a comparative cycle threshold (Ct) method. The results were presented as relative expression to vehicle treatment after normalizing to an internal loading control GAPDH. The catalog numbers for primers of each genes are Hs00365956_ml148IPTS / 2OO243831.1Attorney Docket No. APG-701WO(H0XA9), Hs00180020_ml (MEISl), and Hs02786624_gl (GAPDH). Exemplary results are shown in FIGs. 1A-1D and Table IV.Table IV

[0557] Ref. Compound

[0558] Ref. Compound No. 5 of Table IV is the same as that of Table III.

[0559] For efficacy studies, before treatment, tumors were allowed to grow to 60-140 mm3in volume. Mice with tumors within the acceptable size range were randomized into treatment groups of seven mice per group. Treatment was administered daily at designated mg / kg dose by oral gavage (QD) at lOml / kg. During treatment, tumor volume and body weight were measured two or three times per week. After the treatment was stopped, tumor volume and body weight were measured at least once per week. Exemplary results are shown in FIGs. 2A- 2D.EQUIVALENTS

[0560] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which149IPTS / 2OO243831.1Attorney Docket No. APG-701WO this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0561] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.150IPTS / 2OO243831.1

Claims

Attorney Docket No. APG-701WOCLAIMS1. A compound of Formula 1-0:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RA1, when present, is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or 3- to 10- membered heterocycloalkyl;RA2, when present, is H or -C(=O)-(C2-Ce alkenyl), wherein the -C(=O)-(C2-Ce alkenyl) is optionally substituted with one or more halogen, cyano, -OH, or -NH2;R1is H, halogen, or -O-(Ci-Ce alkyl), wherein the -O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2;R2is H or halogen;R3is H or halogen;R4is halogen;RN1is H or Ci-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2; or151IPTS / 2OO243831.1Attorney Docket No. APG-701WORN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6- membered heteroaryl or a 4- to 6-membered heterocycle, wherein the heteroaryl or heterocycle is optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo;RN3is H or Ci-C6alkyl;R° is Ci-C6alkyl; and n is 1, 2, or 3.

2. The compound of claim 1, whereinare not both H; and / or3. The compound of claim 1, being of Formula I:152IPTS / 2OO243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt thereof, wherein:RA1, when present, is Ci-Ce alkyl optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or 3- to 10-membered heterocycloalkyl;RA2, when present, is -C(=O)-(C2-Ce alkenyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2;R1is H, halogen, or -O-(Ci-Ce alkyl), wherein the -O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2;R2is H or halogen;R3is H or halogen;R4is halogen;RN1is H or Ci-C6alkyl;RN2is -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl), wherein the -C(=O)-(Ci-C6alkyl), -C(=O)-O-(Ci-C6alkyl), or -S(=O)2-(Ci-C6alkyl) is optionally substituted with one or more halogen, cyano, -OH, -NH2, -O-(Ci-Ce alkyl), or -N(Ci- Ce alkyl)2,;RN3is H or Ci-C6alkyl;R° is Ci-Ce alkyl; and n is 1, 2, or 3.

4. The compound of claim 1 or 2, wherein the compound is of Formula I’-O:153IPTS / 2OO243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or 2, wherein the compound is of Formula 1-1:or a pharmaceutically acceptable salt thereof, wherein:RO1is Ci-Ce alkyl optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-C6alkyl), or -NH2.

6. The compound of claim 5, wherein the compound is of Formula I’-l:or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 or 2, wherein the compound is of Formula 1-3:154IPTS / 2OO243831.1Attorney Docket No. APG-701WOor a pharmaceutically acceptable salt thereof, wherein:

8. The compound of claim 7, wherein the compound is of Formula I’-3or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-8, wherein R1is H.

10. The compound of any one of claims 1-8, wherein R1is halogen.

11. The compound of claim 10, wherein R1is fluoro.

12. The compound of any one of claims 1-8, wherein R1is -O-(Ci-Ce alkyl), wherein the - O-(Ci-Ce alkyl) is optionally substituted with one or more halogen, cyano, -OH, -O-(Ci-Ce alkyl), or -NH2.155IPTS / 2OO243831.1Attorney Docket No. APG-701WO13. The compound of claim 12, wherein R1is -O-CH2CH3, -O-CH2CH2-OH, -O-CH2CH2- OCH3, or -O-CH(CH3)2.

14. The compound of any one of claims 1-13, wherein R2is H.

15. The compound of any one of claims 1-13, wherein R2is halogen.

16. The compound of claim 15, wherein R2is fluoro.

17. The compound of any one of claims 1-16, wherein R3is H.

18. The compound of any one of claims 1-16, wherein R3is halogen.

19. The compound of claim 18, wherein R3is fluoro.

20. The compound of any one of claims 1-19, wherein R4is fluoro.

21. The compound of any one of claims 1-20, wherein RN1is H.

22. The compound of any one of claims 1-20, wherein RN1is Ci-Ce alkyl.

23. The compound of claim 22, wherein RN1is -CH3 or -CH2CH3.

24. The compound of any one of claims 1-23, wherein RN2is -C(=O)-(Ci-Ce alkyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2.

25. The compound of claim 24, wherein RN2is -C(=O)-CH3.

26. The compound of any one of claims 1-23, wherein RN2is -C(=O)-O-(Ci-Ce alkyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2.

27. The compound of claim 26, wherein RN2is -C(=O)-OCH3.156IPTS / 2OO243831.1Attorney Docket No. APG-701WO28. The compound of any one of claims 1-23, wherein RN2is -S(=O)2-(Ci-Ce alkyl) optionally substituted with one or more halogen, cyano, -OH, or -NH2.

29. The compound of claim 28, wherein RN2is -S(=O)2-CHs.

30. The compound of any one of claims 1-20, wherein RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heteroaryl optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo.

31. The compound of claim 30, wherein the 4- to 6-membered heteroaryl is imidazolyl optionally substituted with one or more Ci-Ce alkyl.

32. The compound of any one of claims 1-20, wherein RN1and RN2, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl optionally substituted with one or more halogen, Ci-Ce alkyl, or oxo.

33. The compound of claim 32, wherein the 4- to 6-membered heterocyclyl is oxazolidinyl or isothiazolidinyl optionally substituted with one or more Ci-Ce alkyl or oxo.

34. The compound of any one of claims 1-33, wherein RN3is H.

35. The compound of any one of claims 1-33, wherein RN3is Ci-Ce alkyl.

36. The compound of any one of claims 1-35, wherein R° is -CH3.

37. The compound of any one of claims 1-36, wherein n is 1.

38. The compound of any one of claims 1-36, wherein n is 2.

39. The compound of any one of claims 1-36, wherein n is 3.

40. A compound selected from the compounds in Tables 1, 2, and 3 and pharmaceutically acceptable salts thereof.157IPTS / 2OO243831.1Attorney Docket No. APG-701WO41. A pharmaceutical composition comprising the compound of any one of claims 1-40, and a pharmaceutically acceptable excipient.

42. A method of inhibiting menin in a subject or biological sample comprising administering the compound of any one of claims 1-40 to the subject or contacting the biological sample with the compound of any one of claims 1-40.

43. Use of the compound of any one of claims 1-40 in the manufacture of a medicament for inhibiting menin in a subject or biological sample.

44. The compound of any one of claims 1-40 for use in inhibiting menin in a subject or biological sample.

45. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-40 or pharmaceutical composition of claim 41.

46. Use of the compound of any one of claims 1-40 in the manufacture of a medicament for treating or preventing a disease or disorder.

47. The compound of any one of claims 1-40 or pharmaceutical composition of claim 41 for use in treating or preventing a disease or disorder.

48. The method, use, or compound of any one of claims 45-47, wherein the disease or disorder is associated with menin activity.

49. The method, use, or compound of any one of claims 45-47, wherein the disease or disorder is cancer.

50. The method, use, or compound of claim 49, wherein the cancer is leukemia.

51. The method, use, or compound of claim 49 or 50, wherein the cancer is mixed-lineage leukemia.158IPTS / 2OO243831.1

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