Compounds for lysine acetyltransferase 6 (KAT6) inhibition and therapeutic applications thereof

Abstract

The present disclosure relates to compounds represented by one of structural formulas (I'), (I), (II), and (III) or a pharmaceutically acceptable salt thereof: Further disclosed are pharmaceutical compositions comprising the compounds and methods of treating a cancer, a genetic disorder, an epigenetic disorder, a neurodegenerative disorder, a hematological disorder, or an inflammatory disorder using the compounds or the pharmaceutical compositions.

Description

PATENT APPLICATION Docket No. POQ-00525METHODS AND COMPOUNDS FOR LYSINE ACETYLTRANSFERASE 6 (KAT6)INHIBITION AND THERAPEUTIC APPLICATIONS THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Patent Application No.: 63 / 753,751, filed February 4, 2025, and U. S. Provisional Patent Application No.:63 / 793,980, filed April 24, 2025. The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] The MYST family, comprising the largest family of Lysine Acetyltransferases (KATs), plays a crucial role in various biological functions such as gene regulation, DNA repair, cell-cycle regulation, and development. Dysregulation of MYST proteins is associated with cancer and autoimmune diseases. Accordingly, potent and selective inhibitors of KATs, and specifically KAT6A and KAT6B, are needed.SUMMARY OF THE INVENTION

[0003] In some embodiments, the present disclosure relates to a compound represented by structural formula (I’) or a pharmaceutically acceptable salt thereof:wherein:W is selected from the following moieties:POQ-00525- 2 -R5x2X3\' ^X1R I I R5a 2R35b R4, and 5-membered heteroaryl;A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further optionally substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;: I is a single or double bond;each x1, x2, x3, and x4is independently selected from N and CH, wherein 1, 2, or 0 of x1, x2, x3, and x4is N;Z is selected from O and NR7;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and the following moiety:M is selected from a bond, C1-3 alkylene, and NRM,RMIS H, C1-6 alkyl, or C(=O)O(C1-6alkyl);each t, u, and v, is independently 1 or 2;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;POQ-00525- 3 -R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, Ci-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-3 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-memberedPOQ-00525- 4 -heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C(=O)R28, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl optionally substituted with 1-3 C1-3 alkyl,wherein R28is C1-6 alkoxy or 4- to 12-membered heterocyclyl optionally substituted with C(=O)O(C1-6alkyl).

[0004] In some embodiments, the present disclosure relates to a compound represented by structural formula (II) or a pharmaceutically acceptable salt thereof:wherein:W* is selected from C6-12 aryl and 5- to 12-membered heteroaryl;Z* is O or NR7*;R1* is selected from C3-12 cycloalkyl and 4- to 12-membered heterocyclyl, whereinthe 4- to 12-membered heterocyclyl comprises at least one nitrogen atom andthe nitrogen atom is attached to the sulfur atom in structural formula (II); andR7* is selected from H and C1-6 alkyl;wherein each C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;each R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, C6-12 aryl(C1-3 alkyl)2, 4- to 12- membered heterocyclyl, 5- to 12-membered heteroaryl, and C1-6 haloalkyl, orPOQ-00525- 5 -one or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0005] In some embodiments, the present disclosure relates to a compound represented by structural formula (III) or a pharmaceutically acceptable salt thereof:u7O H N B VR2XO QwhereinB is 5- to 12-membered heteroaryl,each U5and U6is independently C or N, provided that if B is a 5-membered heteroaryl, then at least one of U5and U6is N;each U7and U8is independently CH or N;: I is a single or double bond;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;POQ-00525- 6 -R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C6-12 aryl, phenyl, 4- to 12- membered heterocyclyl, 5-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0006] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), and (III) or a compound selected from the compounds of Tables A, B, and 5) and a pharmaceutically acceptable excipient.POQ-00525- 7 -

[0007] In some embodiments, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), and (III) or a compound selected from the compounds of Tables A, B, and 5) or a pharmaceutical composition disclosed herein, wherein the disease or disorder is selected from a cancer, a genetic disorder, an epigenetic disorder, a neurodegenerative disorder, a hematological disorder, and an inflammatory disorder. In a specific aspect, the disease or disorder is a KAT6-mediated disease or disorder.

[0008] In some embodiments, the present disclosure relates to a compound disclosed herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), and (III) or a compound selected from the compounds of Tables A, B, and 5) or a pharmaceutical acceptable salt thereof for use in treating a KAT6-mediated disease or disorder such as cancer, a genetic disorder, an epigenetic disorder, a neurodegenerative disorder, a hematological disorder, and an inflammatory disorder.

[0009] In another embodiment, the present disclosure related to the use of (e.g., a compound represented by one of structural formulas (I’), (I), (II), and (III) or a compound selected from the compounds of Tables A, B, and 5) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a KAT6-mediated disease or disorder such as cancer, a genetic disorder, an epigenetic disorder, a neurodegenerative disorder, a hematological disorder, and an inflammatory disorder.DETAILED DESCRIPTION OF THE INVENTION

[0010] A description of example embodiments of the invention follows.

[0011] Acetylation of histone residues by MYST proteins is generally linked to transcriptional activation. However, MYST proteins can also contribute to transcriptional repression. Each member of the MYST family engages in essential biochemical interactions:

[0012] HB01: Initiates DNA replication via histone acetylation, promoting chromatin accessibility. Implicated in breast cancer and Acute Myeloid Leukemia (AML).

[0013] TIP60 (KAT5): Plays a pivotal role in transcription regulation and DNA damage repair. Acetylates proteins like p53, ATM, and c-Myc. Crucial for regulatory T-cell (Treg) biology, with implications in cancer.POQ-00525- 8 -

[0014] MOF: Involved in histone H4K16 acetylation, impacting various cellular functions and linked to cancer. Required for sustaining specific leukemia types.

[0015] KAT6B: Important in embryonic development, neural stem cell maintenance, and mutated in rare forms of leukemia.

[0016] KAT6A (MOZ): commonly amplified in various cancers.

[0017] KAT6 proteins function by forming a complex with BRPF1 / 2 / 3 (bromodomain-PHD finger protein), ING4 / 5 (inhibitor of growth 4 / 5) and MEAF6 (MYST / Esal -associated factor 6).

[0018] Cancer and MYST Family

[0019] Inhibitors of MYST family-mediated lysine acetylation are considered promising anti-neoplastic agents. MYST proteins, especially KAT6A(MOZ) and KAT6B, are oncogenes implicated in leukemia and other cancers. Inhibitors like WM-8014 and WM-1119 show promise in targeting MYST-catalyzed histone acetylation, suggesting therapeutic potential in cancer treatment.

[0020] Epigenetic Regulation and Diseases

[0021] Acetylation of histones by KATs, especially KAT6, plays a role in various diseases, including cancers, neurodegenerative disorders, and inflammatory conditions. Modulating gene expression through KAT6 inhibition presents a promising avenue for therapeutic intervention. KAT6 inhibitors are explored for treating certain cancers, hematological disorders, and epigenetic disorders associated with dysregulated histone acetylation.

[0022] Epigenetic Regulation of Hormone Related Signaling

[0023] In breast cancer, KAT6A is amplified and / or over-expressed in 10-15% of patients, and is known to directly regulate the transcription of ESRI, the gene encoding the estrogen receptor alpha (ERa).

[0024] The present disclosure addresses the need for more potent and selective KAT6 inhibitors.

[0025] In some embodiments, the present disclosure relates to a compound represented by structural formula (F) or a pharmaceutically acceptable salt thereof:Z H N W....POQ-00525- 9 -wherein:W is selected from the following moieties:X2^•xi R50, and 5-membered heteroaryl;A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further optionally substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;il is a single or double bond;each x1, x2, x3, and x4is independently selected from N and CH, wherein 1, 2, or 0 of x1, x2, x3, and x4is N;Z is selected from O and NR7;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and the following moiety:M is selected from a bond, C1-3 alkylene, and NRM,RMIS H, C1-6 alkyl, or C(=O)O(C1-6alkyl);each t, u, and v, is independently 1 or 2;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;POQ-00525- 10 -each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, C1-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-3 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14, R14*, R15, R15*, R16, R17, R16*, R17*, R18, R18a, R19, R20, R20a, R20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andPOQ-00525when one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C(=O)R28, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl optionally substituted with 1-3 C1-3 alkyl,wherein R28is C1-6 alkoxy or 4- to 12-membered heterocyclyl optionally substituted with C(=O)O(C1-6alkyl).

[0026] In some embodiments, the present disclosure relates to a compound represented by structural formula (I’) or a pharmaceutically acceptable salt thereof:wherein:W is selected from the following moieties:R5X2R2_^R5aR35bR4, and 5-membered heteroaryl;A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;: I is a single or double bond;each x1, x2, x3, and x4is independently selected from CH and N, wherein 0, 1, or 2 of x1, x2, x3, and x4is N;Z is selected from O and NR7;POQ-00525- 12 -R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, C1-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12- membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereinPOQ-00525- 73 -each R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21R22R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, eachis further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl optionally substituted with 1-3 C1-3 alkyl.

[0027] In some embodiments, the present disclosure relates to a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:wherein:W is selected from the following moieties:and 5-membered heteroaryl;A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;POQ-00525- 14 -:l is a single or double bond;each x1, x2, x3, and x4is independently selected from CH and N, wherein 0, 1, or 2 of x1, x2, x3, and x4is N;Z is selected from O and NR7;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, C1-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12- membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15,POQ-00525- 15 -NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21R22R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0028] It is to be understood that in some embodiments one or both atoms shared by A and B are nitrogen.

[0029] In some embodiments, Z is NR7. In some embodiments, R7is H. In some embodiments, R7is C1-6 alkyl, such as C1-3 alkyl, such as methyl.

[0030] In some embodiments, the compound is represented by structural formula (la) or a pharmaceutically acceptable salt thereof:

[0031] In some embodiments, the compound is represented by structural formula (lb) or a pharmaceutically acceptable salt thereof:POQ-00525- 16 -

[0032] In some embodiments, the compound is represented by structural formula (Ic) or a pharmaceutically acceptable salt thereof:wherein each U1and U2is independently C or N. In some embodiments, U1is C. In some embodiments, U1is N. In some embodiments, U2is C. In some embodiments, U2is N.

[0033] In some embodiments, the compound is represented by structural formula (Ic-1) or a pharmaceutically acceptable salt thereof:% N JRb AU(Ic-l).

[0034] In some embodiments, A is 6-membered heteroaryl.

[0035] In some embodiments, the compound is represented by structural formula (Id) or (le) or a pharmaceutically acceptable salt thereof:POQ-00525- 17 -wherein each U3and U4is independently C or N. In some embodiments, U3is C. In some embodiments, U3is N. In some embodiments, U4is C. In some embodiments, U4is N. In some embodiments, the compound is represented by structural formula (Id-1), (Id-2), (Ie-1), or (Ie-2) or a pharmaceutically acceptable salt thereof:

[0036] In some embodiments, B is 5- to 12-membered heteroaryl.

[0037] In some embodiments, B is 5- to 6-membered heteroaryl.

[0038] In some embodiments, B is 5-membered heteroaryl.

[0039] In some embodiments, B is 6-membered heteroaryl.POQ-00525- 18 -

[0040] In some embodiments, B is C6-12 aryl. In some embodiments, B is phenyl.

[0041] In some embodiments, B is 4- to 12-membered heterocyclyl.

[0042] In some embodiments, B is C4-12 cycloalkyl.

[0043] In some embodiments, B is C5-6 cycloalkyl.POQ-00525- 19 -XKiPOQ-00525- 20 -

[0045] In some embodiments, R2is 5- to 12-membered heteroaryl.

[0046] In some embodiments, R2is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0047] In some embodiments, R2is selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl. In someembodiments, R2is selected from^O, Cyand

[0048] In some embodiments, R2isPOQ-00525- 21 -

[0049] In some embodiments, R2is i-’N

[0050] In some embodiments,R2is

[0051] In some embodiments,R2is

[0052] In some embodiments,R2is

[0053] In some embodiments,R2is

[0054] In some embodiments, R2is halogen. In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R2is Br.

[0055] In some embodiments, R2is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0056] In some embodiments, R2is methyl.

[0057] In some embodiments, R2is selected from CH2F, CHF2, and CF3.

[0058] In some embodiments, R2is C3-12 cycloalkyl.

[0059] In some embodiments, R2is cyclopropyl.

[0060] In some embodiments, R2is 4- to 12-membered heterocyclyl.

[0061] In some embodiments, R2is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24,POQ-00525- 22 -C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0062] In some embodiments, R2is H.

[0063] In some embodiments, R3is C1-3 alkyl.

[0064] In some embodiments, R3is methyl.

[0065] In some embodiments, R3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form a C3-12 cycloalkyl.

[0066] In some embodiments, R50is H.

[0067] In some embodiments, the compound is represented by structural formula (Ib-2) or a pharmaceutically acceptable salt thereof:wherein each U5and U6is independently C or N. In some embodiments, U5is C. In some embodiments, U5is N. In some embodiments, U6is C. In some embodiments, U6is N.

[0068] In some embodiments, Qais C1-6 alkylene, such as C1-3 alkylene.

[0069] In some embodiments, Qais CH2.

[0070] In some embodiments, Qais O.

[0071] In some embodiments, Rais 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.POQ-00525- 23 -

[0072] In some embodiments, Rais selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl. In some embodiments, Rais selected from

[0073] In some embodiments, Rais

[0074] In some embodiments,Rais

[0075] In some embodiments,Rais

[0076] In some embodiments,Rais

[0077] In some embodiments,Rais

[0078] In some embodiments,RaisPOQ-00525- 24 -

[0079] In some embodiments, R2, R3, and R4are each H.

[0080] In some embodiments, the compound is represented by structural formula (If) or (Ig) or a pharmaceutically acceptable salt thereof:R2O o

[0081] In some embodiments, the compound is represented by structural formula (Ih) or a pharmaceutically acceptable salt thereof:R5X2In some embodiments, the compound is represented by structural formula (Ih-1) or a pharmaceutically acceptable salt thereof:In some embodiments, the compound is represented by structural formula (Ih-2) or a pharmaceutically acceptable salt thereof:POQ-00525- 25 -

[0082] In some embodiments, R5is C1-3 alkoxy, wherein the C1-3 alkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0083] In some embodiments, R5is methoxy.

[0084] In some embodiments, R5is selected from OCD3 and OCHF2.

[0085] In some embodiments, R5is C3-12 cycloalkoxy.

[0086] In some embodiments, R5is cyclopropoxy.

[0087] In some embodiments, R5is selected from halogen and C3-12 cycloalkyl.

[0088] In some embodiments, R5is C1-3 haloalkyl.

[0089] In some embodiments, R5is selected from CH2F, CHF2, and CF3.

[0090] In some embodiments, Q is C2-3 alkylene, wherein the C2-3 alkylene is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0091] In some embodiments, Q is a bond.

[0092] In some embodiments, R6is C1-3 alkoxy.

[0093] In some embodiments, R6is methoxy.

[0094] In some embodiments, R6is selected from OCD3 and OCHF2.

[0095] In some embodiments, R6is C3-12 cycloalkoxy.

[0096] In some embodiments, R6is cyclopropoxy.

[0097] In some embodiments, R6is C1-3 haloalkyl.

[0098] In some embodiments, R6is selected from CH2F, CHF2, and CF3.

[0099] In some embodiments, R6is 4- to 10-membered saturated heterocyclyl.

[0100] In some embodiments, R6is 5- to 6-membered saturated heterocyclyl, wherein the 5-to 6-membered saturated heterocyclyl is optionally substituted with 1 to 3 substituentsPOQ-00525- 26 -independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0101] In some embodiments, Q is C2-3 alkylene and R6is methoxy.

[0102] In some embodiments, the compound is represented by structural formula (Ii) or a pharmaceutically acceptable salt thereof:Rq2wherein Rqland Rq2is independently H or C1-3 alkyl.

[0103] In some embodiments, Rqland Rq2is each H

[0104] In some embodiments, Rqlis methyl.

[0105] In some embodiments, Rq2is methyl.

[0106] In some embodiments, the compound is represented by structural formula (Ij) or a pharmaceutically acceptable salt thereof:R5b(Ij),wherein R5bis 5- to 12-membered heteroaryl.

[0107] In some embodiments, R5is halogen. In some embodiments, R5is F. In some embodiments, R5is Cl.

[0108] In some embodiments, R5is C1-3 alkoxy, wherein the C1-3 alkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6POQ-00525- 27 -alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0109] In some embodiments, R5is methoxy.

[0110] In some embodiments, R5is selected from OCD3 and OCHF2.

[0111] In some embodiments, R5is C3-12 cycloalkyl.

[0112] In some embodiments, R5is cyclopropyl.

[0113] In some embodiments, R5is C1-3 haloalkyl.

[0114] In some embodiments, R5is selected from CH2F, CHF2, and CF3.

[0115] In some embodiments, R5is unsubstituted C1-3 alkyl.

[0116] In some embodiments, R5is methyl.

[0117] In some embodiments, R5ais H.

[0118] In some embodiments, R5bis 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0119] In some embodiments, R5bis selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0120] In some embodiments, x1is CH.POQ-00525- 28 -

[0121] In some embodiments, x1is N.

[0122] In some embodiments, W is 5-membered heteroaryl.

[0123] In some embodiments, W is selected from the following moieties:H / ,, and N-NH, ^gj-g^eac]1 oft elisted moieties is optionally substituted with 1 to 3, as valence permits, substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.S

[0124] In some embodiments,W is5.

[0125] In some embodiments, the compound is represented by structural formula (Ik) or a pharmaceutically acceptable salt thereof:R1\^°? srL*s(Ik),whereinL is selected from a bond, C1-3 alkylene, or NR30;R30is H or C1-6 alkyl;RLis C6-12 aryl or 5- to 12-membered heteroaryl; andRsis C1-6 alkyl.

[0126] In some embodiments, L is a bond.POQ-00525- 29 -

[0127] In some embodiments, RLis 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally independently substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0128] In some embodiments, R1is C6-12 aryl.

[0129] In some embodiments, R1is phenyl.

[0130] In some embodiments, R1is phenyl substituted with 2 substituents independently selected from C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein each C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl is optionally independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0131] In some embodiments, R1is selected from the following moieties:wherein each R31and R32is independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

[0132] In some embodiments, R31is methoxy.

[0133] In some embodiments, R1is selected from the following moieties:POQ-00525- 30 -independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

[0134] In some embodiments, R1is selected from the following moieties:JI J I JMeO / anj MeO ^^

[0135] In some embodiments, R1is 5- to 12-membered heteroaryl.

[0136] In some embodiments, R1is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OMe

[0137] In some embodiments, R1is ^eO

[0138] In some embodiments, R1is C3-12 cycloalkyl.

[0139] In some embodiments, R1is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6POQ-00525- 31 -alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0140] In some embodiments, R1is unsubstituted C5-6 cycloalkyl.

[0141] In some embodiments, R1is unsubstituted cyclohexyl.

[0142] In some embodiments, R1is 4- to 12-membered heterocyclyl.

[0143] In some embodiments, R1is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0144] In some embodiments, R1is unsubstituted 4- to 6-membered heterocyclyl.

[0145] In some embodiments, R1is saturated 4- to 6-membered heterocyclyl, wherein the saturated 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0146] In some embodiments, R1is unsubstituted saturated 4- to 6-membered heterocyclyl.

[0147] In some embodiments, R1is bicyclic fused or spirocyclic 7- to 12-membered heterocyclyl, wherein the bicyclic fused or spirocyclic 7- to 12-membered heterocyclyl is optionally independently substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0148] In some embodiments, R1is bicyclic fused 7- to 12-membered heterocyclyl.

[0149] In some embodiments, R1is saturated bicyclic fused 7- to 12-membered heterocyclyl.

[0150] In some embodiments, R1is bicyclic spirocyclic 7- to 12-membered heterocyclyl.

[0151] In some embodiments, the compound is selected from the compounds of Table A.POQ-00525- 32 - / A ^o

[0152] In some embodiments, R1is represented by the following moiety:M

[0153] In some embodiments, t is 1.

[0154] In some embodiments, u is 2, v is 2, and M is NH. In some embodiments, v is 1, and M is a bond.

[0155] In some embodiments, the compound is selected from the compounds of Table A or a pharmaceutically acceptable salt thereof.Table ACompound CompoundStructure Structure number numberci.... 1 AO c? I1 a, f ir 91 1 ‘-! AJ / A'A f'j- — 1 / \ NH?. r:::\N, S1 « °< J TZ \ 1 H O.. Z<A J '”o 2 2 i o9 A «A,. v. A r., o•’ s •• J i 0-1 * / / 'N n i i « A3 93 A I I J UA 'o O J 1 0 0Cl,. 11 In i i «4 94 i r>A.POQ-00525- 33 - y -x r \X '-■ Ai O O; J 10. A? S r i o oV V N A > A-Aos: A.s5 95 i Xz > *-'X z- -v x h l x- W _ V / o \ HN— X Xi ° a 1 s a o J > a A T A A rS 'wA Y A' -&r Y'N'X 6 < 3 j.!| H ° 96 VAJUH uA „ t vO y i o □ 7 97 A 1 O,k N JlH '•( / $'•. J N a XT?\ NN'", A.. A> C HiQ 1y'A'0i N-'\ n x r « ■*> 0:::S:::G8 98 / x<: V N* y-fK.Nr I,x% A A X 2 3 - "'> 9 3 ‘kA X 1 ) 99 f W Y^ AnO v A. Hj, NHs°QZV'i, X A vy 5 °' y < J" r- n wI X10 100A VTXXJ" If XXcrxx o 3. v A N 1' r J 11 A T>uVHv t. h LrX.-T 101 N A H i i“ XX. D X. 1 xX / 12 A'V rX° H I Q 102POQ-00525- 34 -NZ"3VS J''V,s-'"x 13 C. X UX r Uix103 _ <.. Ck XCAC J Aci r G JU "'O'b„, C\ XA o o || "1.. r... N14 O H •::: ) / j 104 [' r I H i) > x v N. O^x..c5Y-X' N^A o0.--^x X X, 0 o i "1 o o i h... Ns. AUY... N J V-xAxf 15 i I J » U 105XJU 'A -'SX ^x 'O-.2 °. 1 1... r c o' ° 9’ Cf’x'C. JI. N s A COa“ > - 1 a a f 'll 'J 16 106'"'X S Nxx AX( 1 X X y x o o & T O A^CCSA A X A17 0 107 -i rf aXUS' ^N \;;;; / x’>x 4-K'UAA ( A o' 0 Cl -. XX / sA-'1 rs - 'Q} A d' h X [I i 18 108 Y'N o,7 V -Vs, O- 7, NN ( vJ 'Se Ax N J f'- ' o 0 ■,u? ox19f109A JVU' N '" O'' oPOQ-00525- 35 - V hrN J A. „V. Avo20 JX vh. V OC 0 H A'J 110VA1 1 v i o o / " J X?6 "'o21 <u OC,3' YN111 1 u " " ■■(A '■-•' c I Y I'O'<1 0 X 1 J f G O N JI-N / 2 X rX ''' 2 V 1 11 X / 112p / '■'O'' COr / M Tnx / <p v?, J. °0z0- -Y / x / ’ 0A X. o O= X. 1 -1 23 X / > / •••• ° 113 AX<7"’. AA <3 j 'N'1, „, XJrb<x 'r J * y v HO'”' (> ) x 'V / ' -— / o, Uz...0§ o irANl>OV:::::::AN 0 N AY Y A -X24 Vi X / 1 V-Z JH114 M-A-x v / X )1 / u. 100, li 1] / A, O'. N, V. V V 25 '-J u « < 0AY'. A-. / 115; X J "boA, N JI-{. AX' x 26 A 6 116CO " ^O'~,i o oC'X "s'.11..u A 'h Hi' Y27 117 [( A X) V \xooPOQ-00525- 36 -11 X z¥ T■ 1 S-9.. A jj, N... XX £ iA N Y* ' V ' S, Ai xs-,.o i xO o H: A' N' O-X 28 d 118" A °H1. H 1 > L ANL \xX O X N '■x ".--1£t □ '■■ A SxA t x, Q!,* 'N Y' V o -\ 29 Y A N xO 119HklA / Q A Y '0 Q'xr'd 0 rj T i! [[ x:N x ) C\ xx A, S,S.'5'" V-NAsN “i; Y N W30 120 6AW \.. Y JN, y H<.0,. x ° V -x -^. n C- 0x_x' A U X.1 xJ AkH. N. A...-S31 / 'N-V'x0k:' ' 'A 121 ^,;. XxJ "b•0.,-x,x C 1 p 9; 0 0 I T -X M". AkrA X-X- Y AX A32 122 - Y ii h *> A ° " L, M " O"'if i) Q,W ° A H Y I A iiZ. N33 123 J 9, N.iMV / -f: WAYY T A F L xx J-' xr °0 / INp 34 Y % A 124 Y °v A, X5&,,-• yvAT ~nv\ O - X '-Q V-'- L XXA. -00POQ-00525- 37 -<oN-WO? j35 o v- H N A rv FG 125 s * 010)Y - 0 i j 6<3t-.-S / s. yOG IAA r / ' y3 V 'N H' y6 N k I / 1126 rx°: -. X. ■■- 'XY A T " 'u ''O''O"JN,^. N AyX% 1 1 / 37 127 '0 0 1 ii1 V., N. A' >k S‘ 1A I ~ -S' Y ’N'0X0’XC Ib"Np o.. j %•* 338 o H i::: Yd 128 < XI Jb'A1 | J 0 ‘Ysoz'o 9 X ]I "•£1.,s,ox,f< A,'s'' X X- ■■... / z "'3:39 o' $ | 129; Y r b,0.O O O'y'-'oT' YAAJ,..o U H | £ZN40 "d 130 IC1 -N P fO' '-‘ ]f ^^xAN^ <i o' A )y x0''Ax-.x( 0 o 6.,- S; A.li "] H n41 131 xx., f N. ■'"o Y A sK-,<< J A6' I!'0x;'zPOQ-00525- 38 - z; X.^2—.0, j 4z 1" / "'Q O o Fl \\ J " Yn 1 F F42 F F 132 Q<0.p., \ ^z / '. o o' T 1° / ^ K••••, JF \ / 5— KF X'o 0 d s, N \. \ x43 133 F FFC X tb0 A XX2 > ^0^ O 'O FQFv-s. A'v-No t! k I >44 F A- '^- F 134IT b 6 F-f%.'■■'■' / ) ■■'hLJ45 135ss Q, H £;£ j X kA'■AF-. k Y0"’■' A -Q- O--,vv% F FF'N • H n 0's. -A. / A AY 'V IXY Y 'SY A A-X 46 s / r i 136 F % F X 1 J 'O' '"- kF i_.o.•-> 0F' 016..,, A kF,.o F'N'ASXVN.47 "HFXF 137 CLIJ “bX-NSFPOQ-00525- 39 -fl A?, f fX48:° « U^N138 ii ' N Y 0N \ / ' S A JN[I A P 0 E* r\ ■>' 1 „N...-L r - o - 49 ■Cl--'" ’’’"'i,-'' "a n H r i 139 ^s' y N. 4.>r I X 8? A C Js5■■•• Y A r ( f 50 ' *<f hI J J 1 o140 '•J >--.vil- - 'k8 -N:':’,-■ 'V' i( J o <5° 1 N A - xf '■;-, >:4 HN 'y O i 0“S~O YJy A-A51 ^.yy 141 X XJOIf OiQ“6 t vO< / O 'N 52 < XIJrbA 142 u 1,A.:■> y: n" QO ' w1....... A.x 4 '- Jx. Os / y?y N. A I; rJ / N f- 'i; ': r.. K. °HL ” J53 14 o f s 3 iIf Ji0°O'POQ-00525- 40 -,.oxc C o A N^N 7 _;0HU JL P -bk 54 144 9. N," "k a;SY X XvXXxNP'P X X X Q ¥.¥I ^Y'NAT^VX0 HY.I IX55 145 Y X,AN VJ YArX u 1 oV'x X' VQ,"A.NL¥ [f i f P f Y Y YXA PA O H « YA56 "-PL' ' 146 4 A. IX, J '' YY ¥o a 2S ■'Y-O H [' J] 9 <v NY " Y AX'■ ^ 0 0 157 c 147 a, ■i. Y £ sX5C QY'P hit p p „-N Xs5 Y 4> N X. L? o «8 148 CM Y T1v° o AA A 0 Y, QcANYVsoFX>JA fl,., 59 A.. P 1 Xx? 149 - YQ jj O 0 ¥YJPOQ-00525- 41 - / N\ S N( X\6 ^x / I0? / 150 -j OS ^■ oZ'. - Vy J " ' " Q / / X2y Q- i? 'i. X / , L xA ^\ N ( o■ / xx / —ctX"bK7....61 151 f 1A 4- ■ ■- ■ 'X I< Ci4 ‘N o o y J62 0"' 152 N X JO r-N< i[ j o U...■, AXAL l.^k N. '? t- 63 “ y Oxyx153 o. n xM ryx ’ ~ 'A®,-o, Nvo64 154 x. y. J ri i A- -X0TT0'xr" / :::xNo., S"'o65 •J M jTO 155A / < ~. A V- - ■ v y1 44xAXQ{xA' °F66 > L MyC1^ 156 "'O oHr <>- I(y * « AA V^NoPOQ-00525- 42 - AF / U) ° — zX \ C, K X I J \ \ „ \ „ \ IZ IZ\P ■EZ67 A 157 j On j O on O A JO \' - 'M _ _ O \ / _ _ O \ / O \ / O \ / ''''UP <()O((l)A# / A o5 O O O-——- / Ad / / \dd / / G< <>,,s; X Z NTJ68 158[j J '6 6, N._o H r A ■>AAZ69 nX xx6® 159cXCl Vir it Ac A. N i V 5.hN_.y o70 's„ A i16 ZA / \\ o' '" 0 / AZ 1 I' CHO ° / \ _ d \ "0" \ / o.°^ O0C OCC, ^\ 'r \ c 'xZx ZIc i vO,,71 C1,, O 'K' ' 1610 1 3 H Qi t■'N'A"N:'S'X...,j;'72 162o £ I J 'F73 163 oHK NI AAMJ'L OT 'b fl jQJMVPOQ-00525- 43 -A. V F 74 G JU 'b F p164"? °o. N IQL rA \>ArA (fC^-NHZ^\\ 75 9 4- N J, L / 165r ‘ >xr Aru ’ / C J rnNO xj:• Q, HN H ) >) o H nd 76. A\, M 166 1 AN.'SI A •YrM ' |( )i 0 oA'lV-N77 -o o H nd 167A A-'dUn j"o''Cl78 j n. A AA 168A^ [. n EE v ~ ° 0 4 A A \cNA Y-S, N N79 > 9. s X O 169A A 'zo \ VX- -Q'\ °" A -a b o A{■::::< 0 '>.... X8 < / \ \ S 11-N•H \\7 / / 0; > H;: i i Ai %, 170 v tt / N-N N. ><x. X. / P -x.X'-xv — \ o %. A ' X 'A- j[a" / 9POQ-00525- 44 -V<< N\ / =\ N:'81 v q ^. O< A it x Jl J 171.,< ■,8' ° / IZ Y NL I J Y “° A ghs / ZX \\-4 YHN X. t ixi. H |sj, 0y;:., AU-NHsA82 '' Y, A'YX-- °Gis J 172i N) YaHRzO Y, CK^0 Y$.. XA83 o HN173 Y AY..o,.•■^ n,,084 Z O H.'YV 1 K,->% N'NY 174 / ^N / 0 ) A\>85 175 / °Y<jr ° °c / 'N-''*LfSx / ==\| Y y>— S-NH86 176 ML6MU\NH2 / d oNLJS• ■, N,p H87 Y -N.x- OU 177 tx / -, <4. a. no..• ••'’■ K..><; Y A v NX--' A o o '■x- oO--' YOPOQ-00525- 45 -" I 0 0W X* / -\88 z XU\ W:2178X, =. B Oi =<irO t " i '•^' 'O'zOs.xXA. XJL.. P ° N‘xK T r >89 179rrxv^VrWN<v J ' 1^X3ciX7>..ZOXi Y i S;. „A? „ Xo oO - • O H [(o 90 180 T ■ ••' ** x -A )J( y..J’j j N\ y 06° ~QI298 181 P. / x., 0 XXJ °HYOQ Ji C!9 182a 240aoO N / -'y 1 / •\O 9 A'X^'NH183a \ O=i=O 241aoPOQ-00525- 46 -184a 242a185a 243aITT o °_ N _ / d oFPJ<0 H7 \ I\ o= K ii i \ ( o — / _ „ —I) ° — / o(CPXC C C Czzzz / / * ) '< o o z—= M u MXJ >< o o z—=> O 1 115 ' 'xx° ° — — \ — \ Y^N'M X \ / 186a 244a d \d\7L^ / , J_H Q°\ \ / \ / I II i H _ _ o N? ° — / ° — \ o\ MJdd^o-"'1 £ ° ° or ° °HN^NM 187a 245a j ^dQq> N' / ==\1 1 ° °188a 246aO189a 247ad doM e,POQ-00525- 47 - 0Dz- w_ o ^ OZ> \'IZ\ / C)190a rr ° ° 248aVA0H, A K N jl Or ji ° °NvHN^NA 191a 249aYA60c^ °N\ ^192aN250aOc^ ° \ / =\G°^3AA ’ <" o O c,° \ O' ' / ZIA ’ )" oo=° / IZ193a 251a ZA )i ~ArO6 oo=AOps 0 o 0^^ t / / zYi- A[1 T ° °N °,« W / HN^, NA 194a 252aOIb°N\ ^195a 253aA IQ^PJIOOPOQ-00525\ - 48 - O / ° / ( / o \O=\ O — <UU I II / , <196a <( )) Z W-—N u / ' V II / - _ O° _ ° \ — / \uOu 254acYN197a 255a YO 1| I H0198a 256ad199a 257a9 2 7 °oZ Z- _ O \ / ' ° O' Ocr / ,Yo \ cr ' \ O' 'ZIZI)> « o— °^ O£0, / W o' ' \ZIZOA / IZ z doA0 / 0 J''ur 200a 258a d d 'oo201a 1 no 259aOOP1202a N UyOO 260a A^JpO oc^ ° O JubPOQ-00525- 49 - o203aNv no 261a / X V N' %00 ° || 1 H0204a 262a| A( YNo o205a 263aO / <.io \ ^ o o u Cz / z( z >< o o > o o- z z==206a 264a 55 \x( ° °)) — — —\ / — \ z — \O OAA\ / \ / I H I II ' _ _ O ° / — - \ O A \I2LIZoO, A tf'z- OU °207a 265a / =N A N O V Y VJA xv0H K jl v JUHn' — '" X208a 266aOl ° A? N O0'NHzvv \K ~V Ax / x( / POQ-00525- 50 -o oXoo209a K 267a) \° \ ° A ° j-jXs N O1 N w ^ oC / i X=I° / izox / °T^\o, -Q oO210a 268aXA ^Q- A'N''' A3’0 HI 'CV IX^'O / r211a ak ° 269a° H LC yl212a AT K\ )NI ° ° 270a« HXX "XT O O Cl 213a 271a X-XXN CN214a _x\ QN 272a >rX x X:>oN x^^wXNH T o O Cl A AA0 H1 11 J 215a 273asAPOQ-00525- 51 -W |T'0O- O Cl z216a 274aY• - YY AV / \O,OT OC / <. - S^N fc 'Y \Z_1>Z°f (V C \ '°zi\ / M k;- > o oo 0k / \ 217a 275ao o i??00 cicA * Q QoozHNV, ( Q Q Q Q218a 276ao V4, „ o N s ON=\C oz□ 9 " Y YY ZI \° b I QQx JO( ( Q QO jn <0 Y \\ \o / O o'ZIZ=_ O \YW “> o \ I.p Y\z'z\O o219a _ o O \ / '5 fz277a rV-P / A7 z Q\7? Q^°Qrf'" xPv220a 278ak0N'^3= / ZY-N-^VO o=i=o 221a 279a u OIA / H° A HN'PZY'YY N^\o=jroM\> P 222a 280aCOPOQ-00525- 52 -o o o o o oA A A p p p°°--- 223a ' o ° ° / — — / — / 281ao o ozlZIZI / 7 / Q Q / / / >. O O < K < / k / o \ / _<>M \ / \=224a 282ajf¥°° °A AAXA N N X JP0 HL 1L225a AY 283anr°o oAA^C-A PPG H1 1o 226a 284a227a 285aM ACC? i i A\ / O\JLX °22. A °8a 286a.x AFc N HAHL XV-AI 1 ° °F-^\ hr A A A229a °HL J 287aNGNPOQ-00525- 53 - Xji230a 288a>< % S' NUDU^Y XXl^'O'b''Y\ [fN V ° o\ °231a 289aXNF>^ KXB° V232a 290aM O M \'f if"IZO O ci233a 291a ^ "^04X V-NrO 'N234aXOHI^ Il J 292a^T XTX'-Ob'"Y235af / \ XX ° ° 293aFXX^''«XQOPOQ-00525- 54 -o236a 294a _ O \ / ' ^ 004i n n iO' GY*fc \ '’zi FL / \^7No (IP O— OCsQo237ao,, 295a N H | | X7, N X. N. zzej ’.<-oca - «238a 296aS \IZx OW_ O \ / 239a 297a

[0156] In some embodiments, the compound is selected from the compounds of Table B or a pharmaceutically acceptable salt thereof.Table BPOQ-00525POQ-00525- 56 - 306u u u u° p-- o ' o o, - / —307 / q / ~Z ~Z)) / / -- n n / / \\ / / \ \o \ / \ / ^ oc / kZIZI / / x O \° O / O / / x< o ox / x oW '\Q=x O / ' o o« WxxJK IZ / ° " a \ \O<<Q°)c / )o= / \ ^X°308z\ * / F^\z~y.o\ \z~. O oOC" / _ o O \ / -" ° / \ ^ oo - o n n309310311POQ-00525- 57 - 312? Dcr ^DoJJQ QOkJp( Q Q313JXA7 °nonj \ *y / \ °? " YzQo Y Y 'O\ \Zw H 'bo. o^ / \ c314315°0I IDI Y 7 H T- 316 °'x^\° °JQ / \ FDY DL > V il Y J1NH' b0^^<F317POQ-00525- 58 - 318 AA i ° °M A. A0 HA L iAL ^Q / 319rY o oA -A7.MN A0A^A^ 0HL AAI A'Q-^' 320f Y 0 0A 'A: _ NA o0 H^v^A"^L AIA-'v321 ANAA J ^ 1 SZ:0'.hr. A0 / NJJ A o0 HL! L322r AY '■" A JJ7° A °N NxOv-' \° H L AAI^\Q / 323r Y o oA •xA / / A N O0 HL A 1AL ^Q / 324S A:,,325A YPOQ-00525POQ-00525POQ-00525POQ-00525POQ-00525- 63 - 350351r v o o\ A o AAX^Q / 3523530 01 1o N1 J H03540 01 11 J H0355^V”yCOPOQ-00525- 64 - 3563570 01 1 o N JI 'b^i\r 1 |] H03580 01 1 A AMV^N / / N" A.1 J H0359M VyCO ^xS^O^360 / -X^XJNM VyOO361POQ-00525- 65 - 362° O°X1 I x 363364° °°X1 Jt / Al a V A365° Cxi A x '°iV « i / \ i ^0-'"''^''^366o N J0I0'S^ 1N^! LBrN xk.J! JH 0367 / °\ / \° ° 1 1•"" o X NiNH'A0 / \J J368x' XPOQ-00525POQ-00525POQ-00525POQ-00525POQ-00525POQ-00525- 71 -

[0157] In some embodiments, the compound is selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.Table 1Compound Compound Compound Compound Compound number number number number number9 43 80 118 151 10 44 81 119 152 11 45 82 121 153 12 46 83 122 154 13 47 84 123 155 14 48 85 124 156 15 49 86 125 157 16 50 87 126 158 17 53 88 127 159 18 54 89 129 160 19 55 90 130 161 20 56 91 131 162 21 58 92 132 163 22 59 93 133 164 26 60 94 134 165 27 62 95 135 166 28 63 97 136 167 29 64 104 138 168 30 65 105 139 169 32 66 106 140 170 33 67 107 141 171 34 68 108 142 172 35 69 109 143 173 36 70 110 144 174 37 72 111 145 175 38 75 112 146 176 39 76 113 147 17740 77 115 148 178POQ-00525- 72 -41 78 116 149 179 42 79 117 150 180181

[0158] In some embodiments, the compound is selected from the compounds of Table 2 or a pharmaceutically acceptable salt thereof.Table 2Compound Compound Compound Compound Compound number number number number number9 54 87 108 127 10 55 88 109 129 13 56 89 110 131 14 60 90 111 133 26 65 91 115 134 27 68 92 116 135 29 79 93 118 136 30 80 94 123 138 35 81 106 124 13939 86 107 126 140

[0159] A compound or a pharmaceutically acceptable salt thereof represented by structural formula (II):wherein:W* is selected from C6-12 aryl and 5- to 12-membered heteroaryl;Z* is O or NR7*;R1* is selected from C3-12 cycloalkyl and 4- to 12-membered heterocyclyl, whereinthe 4- to 12-membered heterocyclyl comprises at least one nitrogen atom and the nitrogen atom is attached to the sulfur atom in structural formula (II); andR7* is selected from H and C1-6 alkyl;wherein each C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 5 substituents independentlyPOQ-00525- 73 -selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;each R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, C6-12 aryl(Ci-3 alkyl)2, 4- to 12- membered heterocyclyl, 5- to 12-membered heteroaryl, and C1-6 haloalkyl, or one or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0160]

[0161] In some embodiments, the compound is represented by structural formula (II) or a pharmaceutically acceptable salt thereof:wherein:W* is selected from C6-12 aryl and 5- to 12-membered heteroaryl;Z* is O or NR7*;R1* is selected from C3-12 cycloalkyl and 4- to 12-membered heterocyclyl, whereinthe 4- to 12-membered heterocyclyl comprises at least one nitrogen atom and the nitrogen atom is attached to the sulfur atom in structural formula (II); andPOQ-00525- 74 -R7* is selected from H and C1-6 alkyl;wherein each C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;each R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20lR21R22R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, C6-12 aryl(C1-3 alkyl)2, 4- to 12- membered heterocyclyl, 5- to 12-membered heteroaryl, and C1-6 haloalkyl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, Ci- 6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0162] In some embodiments, Z* is NR7*. In some embodiments, R7* is H. In some embodiments, R7* is C1-6 alkyl, such as C1-3 alkyl, such as methyl.

[0163] In some embodiments, the compound is represented by structural formula (Ila) or a pharmaceutically acceptable salt thereof:

[0164] In some embodiments, W* is C6-12 aryl.POQ-00525- 75 -

[0165] In some embodiments, W* is phenyl, wherein the phenyl is substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22,OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0166] In some embodiments, the compound is represented by structural formula (lib) or a pharmaceutically acceptable salt thereof:R1-09A^' AR2‘R3(Hb),whereinR2* is C1-6 alkoxy, andR3* is C1-3 alkyl, wherein the C1-3 alkyl is substituted with 5- to 12-membered heteroaryl.

[0167] In some embodiments, the compound is represented by structural formula (IIb-1) or a pharmaceutically acceptable salt thereof:R1' 9 9s', A OMeA N ^A |<AA^ A / N(IIb l)

[0168] In some embodiments, W* is 5- to 12-membered heteroaryl.

[0169] In some embodiments, W* is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0170] In some embodiments, the compound is represented by structural formula (lie) or a pharmaceutically acceptable salt thereof:POQ-00525- 76 -whereinR2* is Ci-6 alkoxy, andR3* is Ci-3 alkyl, wherein the C1-3 alkyl is substituted with 5- to 12-membered heteroaryl.

[0171] In some embodiments, the compound is represented by structural formula (lie- 1 ) or a pharmaceutically acceptable salt thereof:OMe

[0172] In some embodiments, R1* is C3-12 cycloalkyl.

[0173] In some embodiments, R1* is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0174] In some embodiments, R1* is unsubstituted C5-6 cycloalkyl. In some embodiments, R1* is unsubstituted cyclohexyl.

[0175] In some embodiments, the compound is represented by structural formula (lid) or a pharmaceutically acceptable salt thereof:POQ-00525- 77 -

[0176] In some embodiments, R1* is 4- to 12-membered heterocyclyl.

[0177] In some embodiments, R1* is 4- to 7-membered heterocyclyl, wherein:the 4- to 7-membered heterocyclyl comprises at least one nitrogen atom;the nitrogen atom is attached to the sulfur atom in structural formula (II); and the 4- to 7- membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0178] In some embodiments, saturated 4- to 7-membered heterocyclyl.

[0179] In some embodiments, R1* is selected from the following moieties:wherein each Rband Rcis independently selected from C1-6 alkyl and C6-12 aryl, orRband Rctogether with the carbon atom to which they are attached form a C3-12 cycloalkyl.A

[0180] In some embodiments,R1* is

[0181] In some embodiments, R1* is bicyclic fused 7- to 12-membered heterocyclyl, wherein:the bicyclic fused 7- to 12-membered heterocyclyl comprises at least one nitrogen atom; the nitrogen atom is attached to the sulfur atom in structural formula (II); andthe bicyclic fused 7- to 12-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b,POQ-00525- 78 -C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0182] In some embodiments, R1* is unsubstituted bicyclic fused 7- to 12-membered heterocyclyl.

[0183] In some embodiments, R1* is saturated unsubstituted bicyclic fused 7- to 12-membered heterocyclyl.

[0184] In some embodiments, R1* is selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0185] In some embodiments,R1* is

[0186] In some embodiments,R1* is

[0187] In some embodiments, the compound is selected from the compounds of Table 3 or a pharmaceutically acceptable salt thereof.Table 3POQ-00525- 79 -Compound Compound Compoundnumber number number1 25 982 31 993 51 1004 52 1015 57 1026 61 1037 71 1148 73 12023 74 12824 96 137

[0188] In some embodiments, the compound is selected from the compounds of Table 4 or a pharmaceutically acceptable salt thereof.Table 4Compound Compound Compound Compound number number number number1 7 52 1002 8 57 1013 23 61 1024 25 71 1035 31 73 1286 51 98 137

[0189] In some embodiments, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof represented by structural formula (III):whereinB is 5- to 12-membered heteroaryl;each U5and U6is independently C or N, provided that if B is a 5-membered heteroaryl, then at least one of U5and U6is N;POQ-00525- 80 -each U7and U8is independently CH or N;i I is a single or double bond;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C6-12 aryl, phenyl, 4- to 12- membered heterocyclyl, 5-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orPOQ-00525- 81 -one or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0190]

[0191] In some embodiments, the compound is represented by structural formula (III) or a pharmaceutically acceptable salt thereof:O H NB%whereinB is 5- to 12-membered heteroaryl,each U5and U6is independently C or N, provided that if B is a 5-membered heteroaryl, then at least one of U5and U6is N;each U7and U8is independently CH or N;il is a single or double bond;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orPOQ-00525- 82 -R3and R4are atached to the same carbon atom, and R3and R4together with the carbon atom to which they are atached form C3-12 cycloalkyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C6-12 aryl, phenyl, 4- to 12- membered heterocyclyl, 5-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, eachis further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0192] In some embodiments, Qais C1-6 alkylene, such as C1-3 alkylene.POQ-00525- 83 -

[0193] In some embodiments, Qais CH2.

[0194] In some embodiments, Qais O.

[0195] In some embodiments, Rais 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.S O / _iL|

[0196] In some embodiments, Rais selected from the following moieties:, N hk bk JX. C>. N N 0 / Ca 0 vO vUoptionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0197] In some embodiments,Rais

[0198] In some embodiments,Rais

[0199] In some embodiments,Rais

[0200] In some embodiments, Rais selected from, and

[0201] In some embodiments, U5is N. In some embodiments, U5is C.POQ-00525- 84 -

[0202] In some embodiments, U6is N. In some embodiments, U6is C.

[0203] In some embodiments, U7is N. In some embodiments, U7is CH.

[0204] In some embodiments, U8is N. In some embodiments, U8is CH.

[0205] In some embodiments, B is 6-membered heteroaryl, wherein the 6-membered heteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0206] In some embodiments, R2, R3, and R4are each H.

[0207] In some embodiments, R1is phenyl substituted with 2 substituents independently selected from C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein each C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl is optionally independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl. In some embodiments,

[0208] In some embodiments, R1is selected from the following moieties:POQ-00525- 85 -wherein each R31and R32is independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

[0209] In some embodiments, R31is methoxy.

[0210] In some embodiments, R1is selected from the following moieties:independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

[0211] In some embodiments, R1is selected from the following moieties:J! J JI JMeO / anj MeO ^^

[0212] In some embodiments, R1is 5- to 12-membered heteroaryl.

[0213] In some embodiments, R1is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OMe

[0214] In some embodiments,R1isPOQ-00525- 86 -

[0215] In some embodiments, R1is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0216] In some embodiments, R1is 4- to 12-membered heterocyclyl.

[0217] In some embodiments, R1is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0218] In some embodiments, R1is saturated 4- to 6-membered heterocyclyl, wherein the saturated 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0219] In some embodiments, R1is bicyclic fused or spirocyclic 7- to 12-membered heterocyclyl, wherein the bicyclic fused or spirocyclic 7- to 12-membered heterocyclyl is optionally independently substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0220] In some embodiments, R1is bicyclic fused 7- to 12-membered heterocyclyl.

[0221] In some embodiments, R1is bicyclic spirocyclic 7- to 12-membered heterocyclyl.

[0222] In some embodiments, the compound is selected from the compounds of Table 5 or a pharmaceutically acceptable salt thereof.POQ-00525- 87 - 2:-^Table 5LL 40= Compound Compound i o rX4-1Structure Structure number numberCo4_ / O. _, NH JL N X / O \ " / S' " O T IiI X V, / > / >=< O N-7 182 o o ( hX 189, _ / O 'X _ / \ _ / \= / d183 190Il 1x> / O._NH > L, A X / ° 'SX n N X) 4=(0O N= / 184 191V_ / “ °\<dn-NH> ■ bbb / 0 NH JL A X / o -sc Y NX, \ / 0 II ' / )=< O N= / 185 192^-NH / O<. NH X Il A 1 ^1 ^=x7> 0 'S' >1 N Vi o=s=o \ / O II ' / nrsj o }=< O N=> 186 193&FaPOQ-00525- 88 -

[0223] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound represented by one of structural formulas (I) -(III) or a compound selected from the compounds of Tables A and 5) and a pharmaceutically acceptable excipient.

[0224] In some embodiments, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound represented by one of structural formulas (I)-(III) or a compound selected from the compounds of Tables A and 5) or a pharmaceutical composition disclosed herein, wherein the disease or disorder is selected from a cancer, a genetic disorder, an epigenetic disorder, a neurodegenerative disorder, a hematological disorder, and an inflammatory disorder.

[0225] In some embodiments, the disorder is cancer.

[0226] In some embodiments, the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, or drug resistant cancer.

[0227] In some embodiments, the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or a combination thereof.

[0228] In some embodiments, the cancer is selected from leukemia, lymphoma, prostate cancer, lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma, ovarian cancer, cervical cancer, medulloblastoma, and gastric cancer.

[0229] In some embodiments, the cancer is hematological cancer.

[0230] In some embodiments, the cancer is leukemia, and the leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or B-cell acute lymphoblastic leukemia.

[0231] In some embodiments, the cancer is lymphoma, and the lymphoma is MYC-induced lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, or lymphoma.POQ-00525- 89 -

[0232] In some embodiments, the cancer is breast cancer, and the breast cancer is estrogen receptor positive breast cancer.

[0233] In some embodiments, the cancer is lung cancer, and the lung cancer is non-small cell lung cancer.

[0234] In some embodiments, the cancer is a MYST overexpressing cancer.

[0235] In some embodiments, the cancer is a MYST copy number-amplified cancer.

[0236] In some embodiments, the method further comprises administering a second agent to the subject.

[0237] In some embodiments, the second agent is selected from a selective estrogen receptors modulator, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, an antiandrogen, a glucocorticoid, a thyroid hormone, a selective estrogen receptor degrader, a cyclin-dependent kinase 4 inhibitor, cyclin-dependent kinase 6 inhibitor, cyclin-dependent kinase 4 / 6 inhibitor, and ubiquitin specific protease 1 inhibitor, a HER2 inhibitor, or a combination thereof.

[0238] In some embodiments, the disorder is a genetic disorder.

[0239] In some embodiments, the genetic disorder is associated with dysregulation of histone acetylation.

[0240] In some embodiments, the genetic disorder is selected from genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome.

[0241] In some embodiments, the disorder is an epigenetic disorder.

[0242] In some embodiments, the epigenetic disorder is associated with dysregulation of histone acetylation.

[0243] In some embodiments, the disorder is a neurodegenerative disorder.

[0244] In some embodiments, the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Angelman syndrome, and Huntington’s disease.

[0245] In some embodiments, the disorder is a hematological disorder.

[0246] In some embodiments, the disorder is an inflammatory disorder.

[0247] DefinitionsPOQ-00525- 90 -

[0248] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0249] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268, E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972. The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0250] In a formula, — is absent or a single bond, and== or == is a single or double bond. An asterisk (*) next to an atom indicates that the atom is a stereocenter of unknown absolute configuration. For example, in a pair of enantiomers each can be depicted by a chemical structure with an asterisk (*) next to the stereocenter, which would indicate that the absolute configuration for the stereocenter of a given enantiomer is not defined.POQ-00525- 91 -

[0251] In a formula,indicates a point of attachment of the moiety to the remaining part of the molecule.

[0252] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each stereocenter. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0253] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0254] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, " C1-6 alkyl" is intended to encompass Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0255] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0256] The term "alkyl" refers to a radical of a straight- chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (" C1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms (" C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms (" Ci-s alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms (" C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms (" C1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms (" C1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms (" C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms (" C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms (" C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom (" Ci alkyl"). In somePOQ-00525- 92 -embodiments, an alkyl group has 2 to 6 carbon atoms (" C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).

[0257] The term "haloalkyl" refers to a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (" Ci-s haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (" C1-6 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (" C1-4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (" C1-3 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (" C1-2 haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0258] The term "deuteroalkyl" refers to an alkyl group, wherein one or more of the hydrogen atoms are independently replaced by deuterium. In some embodiments, the deuteroalkyl moiety has 1 to 8 carbon atoms (" Ci-s deuteroalkyl"). In some embodiments, the deuteroalkyl moiety has 1 to 6 carbon atoms (" C1-6 deuteroalkyl”). In some embodiments, the deuteroalkyl moiety has 1 to 4 carbon atoms (" C1-4 deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 3 carbon atoms (" C1-3 deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 2 carbon atoms (" C1-2 deuteroalkyl"). In some embodiments, the deuteroalkyl moiety is Ci, C2, C3, C4, C5, or Ce deuteroalkyl. A deuteroalkyl moiety having nPOQ-00525- 93 -carbon atoms can have from 1 to 2n+l deuterium atoms. Examples of deuteroalkyl groups include -CHD2, -CH2D, -CD3, -CH2CD3, -CD2CD3, -CD2CD2CD3, -CH(CD3)2, -CD(CD3)2, -C(CD3)3, and the like.

[0259] The term "hydroxyalkyl" is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms (" Ci-s hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms (" Ci-6 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms (" Ci-4 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms (" Ci-3hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms (" Ci-2hydroxyalkyl").

[0260] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms (" Ci-s alkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (" Ci-6 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (" Ci-4 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (" Ci-3alkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (" Ci-2alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0261] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms (" Ci-s haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (" Ci-6 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (" Ci-4 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (" Ci-3haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (" Ci-2haloalkoxy"). Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0262] The term "alkoxyalkyl" is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms (" Ci-s alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms (" Ci-6 alkoxyalkyl"). In somePOQ-00525- 94 -embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms (" Ci-4 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms (" C1-3 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (" C1-2 alkoxyalkyl").

[0263] The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-20 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-is alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-16 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-14 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-12 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in itsPOQ-00525- 95 -parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[0264] The term "alkenyl" refers to a radical of a straight- chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (" C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (" C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (" C2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (" C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (" C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (" C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (" C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms (" C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistryis not specified (e.g., -CH=CHCH3 or) may be an (E)- or (Z)-double bond.

[0265] The term "heteroalkenyl" refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur withinPOQ-00525- 96 -(i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkenyl").

[0266] In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-s alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

[0267] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (" C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (" C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (" C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (" C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (" C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (" C2-5 alkynyl"). In some embodiments,POQ-00525- 97 -an alkynyl group has 2 to 4 carbon atoms (" C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (" C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms (" C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkynyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0268] The term "heteroalkynyl" refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkynyl"). In somePOQ-00525- 98 -embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0269] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non- aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (" C3-14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (" C3-10 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (" C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (" C3-7 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (" C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (" C4-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (" C5-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (" C5-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl(C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H- indeny 1 (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. " Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or morePOQ-00525- 99 -aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0270] In some embodiments, "cycloalkyl" is a saturated monocyclic ("monocyclic cycloalkyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic cycloalkyl") or tricyclic system ("tricyclic cycloalkyl ")) carbocyclyl group having from 3 to 14 ring carbon atoms (" C3-14 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (" C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (" C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (" C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (" C4-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (" C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (" C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (Ce). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Exemplary polycyclic cycloalkyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[4.5]decanyl, cubanyl, and the like. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0271] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can eitherPOQ-00525- 100 -be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon or carbonheteroatom double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. " Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0272] In some embodiments, a heterocyclyl group is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0273] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclylPOQ-00525- 101 -groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5 -membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2- / ?]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1, 2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0274] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10aryl"; e.g.,POQ-00525- 102 -naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14aryl"; e.g., anthracyl). " Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0275] " Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0276] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1 -4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. " Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. " Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).POQ-00525- 103 -

[0277] In some embodiments, a heteroaryl group is a 5-12 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-12 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0278] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazo lyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3POQ-00525- 104 -or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0279] " Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0280] The term "unsaturated bond" refers to a double or triple bond.

[0281] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.

[0282] The term "saturated" refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0283] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0284] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. " Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted"POQ-00525- 105 -alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -0N(Rbb)2, -N(Rbb)2, -N(Rbb)3+X’, -N(0Rcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORcc)3, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=0)R33, -0S(=0)R33, -Si(Raa)3, -OSi(Raa)3, -C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -OP(=O)(Raa)2, -OP(=O)(ORcc)2, -P(=O)(N(Rbb)2)2,-OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X, -P(ORCC)3+X, -P(RCC)4, -P(ORCC)2, -OP(RCC)2, -OP(RCC)3+X, -OP(ORCC)2, -OP(ORCC)3+X, -OP(RCC)4, -OP(ORCC)4, -B(R33)2, -B(ORCC)2, -BRaa(ORcc), Ci-10 alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2- 10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10POQ-00525- 106 -carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbbor =NORCC; each instance of Raais, independently, selected from Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X-, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=0)N(Rff)2, -0C(=0)N(Rff)2, -NRffC(=0)Ree, -NRffCO2Ree, -NRffC(=0)N(Rff)2, -C(=NRff)0Ree, -0C(=NRff)Ree, -0C(=NRff)0Ree, -C(=NRff)N(Rff)2, -0C(=NRff)N(Rff)2, -POQ-00525- 107 -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6 alkyl, Ci-6perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-io carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-io carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-io carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(C1-6 alkyl)2, -N(C1-6alkyl)2, -N(C1-6 alkyl)3+X, -NH(C1-6 alkyl)2+X, -NH2(C1-6 alkyl)+X, -NH3+X, -N(OC1-6 alkyl)(C1-6alkyl), -N(0H)(C1-6 alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=0)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6 alkyl)C(=O)( C1-6alkyl), -NHCO2(C1-6 alkyl), -NHC(=O)N(C1-6 alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=0)NH2, -C(=NH)O(C1-6 alkyl), -OC(=NH)(C1-6 alkyl), -OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -0C(=NH)NH(C1-6 alkyl), -0C(=NH)NH2, -NHC(=NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2, -SO2(C1-6alkyl), -SO2O(C1-6alkyl), -OSO2(C1-6alkyl), -SO(C1-6alkyl), -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3, -C(=S)N(C1-6alkyl)2, -C(=S)NH(C1-6alkyl), -C(=S)NH2,POQ-00525- 108 --C(=O)S(C1-6 alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)(OC1-6alkyl)2, -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6 alkyl)2, -OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0285] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0286] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxyl," by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -0N(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -0C(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X, -OP(ORCC)2, -OP(ORCC)3+X, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb)2)2, whereinX-, Raa, Rbband Rccare as defined herein.

[0287] The term "amino" refers to the group -NH2. The term "substituted amino," by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a disubstituted amino group.

[0288] The term "monosubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa,-NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0289] The term "disubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, whereinPOQ-00525- 109 -Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0290] The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)2 and -N(Rbb)3 X, wherein Rbband X are as defined herein.

[0291] The term "sulfonyl" refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and-SO2ORaa, wherein Raaand Rbbare as defined herein.

[0292] The term "sulfinyl" refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0293] The term "acyl" refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)O(RX1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono-or di- heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring.

[0294] Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,POQ-00525- 110 -heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0295] The term "carbonyl" refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., -C(=O)Raa), carboxylic acids (e.g., -CO2H), aldehydes (-CHO), esters (e.g, -CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (e.g, -C(=O)N(Rbb)2,-C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (e.g., -C(=NRbb)Raa, -C(=NRbb)0Raa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0296] The term "oxo" refers to the group =0, and the term "thiooxo" refers to the group =S.

[0297] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=0)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, CI-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein.

[0298] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, CI-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,POQ-00525- Ill -heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein R^, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Greene ’s Protecting Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014.

[0299] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N1-dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy )propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide ando-(benzoyloxymethyl)benzamide.

[0300] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfa)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), 1, 1 -dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1 -(3, 5-di-t- butylphenyl)- 1 -methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, t- butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-POQ-00525- 112 -anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N, N-dimethylcarboxamido )benzyl carbamate, l,l-dimethyl-3-(N, N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo )benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3, 5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1 -phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0301] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), 2-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS ), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.POQ-00525- 113 -

[0302] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan- 2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3 -pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-picolylamino N'-oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N', N'-dimethylaminomethylene)amine, N, N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps ), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carboxybenzyl (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).POQ-00525- 114 -

[0303] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein X, R^, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Greene ’s Protecting Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014.

[0304] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1 -[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4, 4', 4"-tris(benzoyloxyphenyl)methy 1, 3 -(imidazol- 1 -yl)bis(4',4" -dimethoxyphenyl)methyl, 1, 1 -bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-POQ-00525- 115 -oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S- dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TEMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio )pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N', N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1 -ethoxy ethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP),POQ-00525- 116 -tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0305] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Greene ’s Protecting Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0306] A "counterion" as used herein can be an anionic counterion or a cationic counterion.

[0307] An “anionic counterion" is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary anionic counterions include halide ions (e.g., F, Cl", Br, I"), NO3", CIO4, OH, H2PO4, HCO3, HSO4, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2- sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1- sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4", PF4", PFe", AsF6", SbFe", B[3,5-(CF3)2C6H3]4- B(C6F5)4, BPh4, A1(OC(CF3)3)4, and carborane anions (e.g., CB11H12 or (HCBi iMesBre) ). Exemplary anionic counterions which may be multivalent include CO32, HPO42, PO43, B4O72, SO42, S2O32, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0308] A “cationic counterion" is a positively charged group associated with a negatively charged group in order to maintain electronic neutrality. A cationic counterion may bePOQ-00525- 117 -monovalent (i.e., including one formal positive charge). A cationic counterion may also be multivalent (i.e., including more than one formal positive charge), such as divalent or trivalent. Exemplary cationic counterions include, for example, cations of metals, such as alkali metals and alkaline earth metals, as well as NH4+, NH3(Ci-ealkyl)+, NH2(C1-6 alkyl)2+, NH (C1-6 alkyl)s+, and N+(CI 6 alkyl)4 cations, where the C1-6 alkyl can be optionally substituted as discussed above. Representative cations of alkali and alkaline earth metals include Li+, Na+, K+, Mg2+, and Ca2+, and the like.Formulation and Administration

[0309] Another embodiment of the invention is a composition comprising a compound of the disclosure (e.g, a compound represented by one of the structural formulas (I)-(Ip) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a composition of the disclosure is formulated for administration to a patient in need of the composition. In some embodiments, a composition of the disclosure is formulated for oral, intravenous, subcutaneous, intraperitoneal or dermatological administration to a patient in need thereof.

[0310] As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein, or a normal subject. The term “non-human animals” of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g, sheep, cow, pig, etc., and companion animals (dog, cat, horse, etc.). In a particular embodiment the subject is a human, for example, a adult male or female or a male or female child.

[0311] As used herein, an amount of a compound described herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), or (III) or a compound of Table A, Table B, or Table 5, or a pharmaceutically acceptable salt thereof) that is effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, relieving or improving one or more symptoms of a disorder.POQ-00525- 118 -

[0312] As used herein, an amount of a compound effective to prevent a disorder, or a “prophylactically effective amount” of the compound refers to an amount effective, upon single-or multiple-dose administration to the subject, in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of the disorder.

[0313] For administration to human subjects, the total daily dose of the compounds disclosed herein is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration. For example, oral administration can require a total daily dose of from about 1 mg to about 3000 mg, while an intravenous dose can only require a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in a single or divided doses (e.g., 2, 3, 4, 5 or 6 times per day at evenly spaced or randomly spaced intervals) or on an as needed basis. The typical daily dose can fall outside the ranges above based on the discretion of the physician or drug prescriber. Although these dosages are based on an average human subject having a mass of about 60 kg to 70 kg, the physician will be able to determine the appropriate dose for a subject (e.g., an infant) whose mass falls outside this weight range.

[0314] As used herein, the term “treat” or “treatment” is defined as the application or administration of a compound, alone or in combination with a second compound, to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, in order to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).

[0315] “Pharmaceutically or pharmacologically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards, as required by FDA Office of Biologies standards.

[0316] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and thePOQ-00525- 119 -like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds of this disclosure include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of patients.

[0317] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of a basic group, e.g., an amino group, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0318] In some embodiments, exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are morePOQ-00525- 120 -soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.

[0319] In some embodiments, acid addition salts of the compounds of the present disclosure (e.g., a compound represented by any one of structural formulas (I)-(Ip)) are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g., hydrochloric, sulfuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.

[0320] Other non-pharmaceutically acceptable salts, e.g., oxalates can be used, for example, in the isolation of compounds disclosed herein for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the disclosure are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the disclosure. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.

[0321] A “pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by any of the structural formulas (I)-(Ip), or any of its intermediates. Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0322] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alky 1)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0323] The phrase “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of thePOQ-00525- 121 -compound with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0324] Compositions of the present disclosure may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and / or intraperitoneally.

[0325] The term “parenteral,” as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously.

[0326] Pharmaceutically acceptable compositions of this disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.POQ-00525- 122 -

[0327] In some embodiments, an oral formulation is formulated for immediate release or sustained / delayed release.

[0328] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium salts, g) wetting agents, such as acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0329] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0330] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.

[0331] A compound of the disclosure can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound of the disclosure can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g.,POQ-00525- 123 -tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.

[0332] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.

[0333] In another embodiment, a compound of the disclosure can be provided in an extended (or “delayed” or “sustained”) release composition. This delayed-release composition comprises a compound of the disclosure in combination with a delayed-release component. Such a composition allows targeted release of a provided compound into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and / or the rectum. In certain embodiments, the delayed-release composition comprising a compound of the disclosure further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition provides controlled release to the small intestine and / or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pH dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and / or by acrylic acid linked to azoaromatic bonds coatings.

[0334] In certain embodiments, the delayed-release composition of the present disclosure comprises hypromellose, microcrystalline cellulose, and a lubricant. The mixture of a compound of the disclosure, hypromellose and microcrystalline cellulose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.

[0335] Alternatively, pharmaceutically acceptable compositions of this disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the compound of the disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.POQ-00525- 124 -

[0336] Pharmaceutically acceptable compositions of this disclosure can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0337] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically -transdermal patches can also be used.

[0338] For other topical applications, the pharmaceutically acceptable compositions of the disclosure can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, pharmaceutically acceptable compositions of the disclosure can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. In some embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. In other embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water and penetration enhancers.

[0339] For ophthalmic use, pharmaceutically acceptable compositions of the disclosure can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0340] Pharmaceutically acceptable compositions of this disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline,POQ-00525- 125 -employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0341] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

[0342] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for intravenous administration.

[0343] In some embodiments, pharmaceutically acceptable compositions of this disclosure are formulated for topical administration.

[0344] The amount of compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration and the activity of the compound employed. Preferably, compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving the composition.

[0345] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

[0346] Other pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as D-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,POQ-00525- 126 -polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- β-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein.

[0347] The pharmaceutical compositions of this disclosure are preferably administered by oral administration or by injection. The pharmaceutical compositions of this disclosure can contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

[0348] The pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0349] When the compositions of this disclosure comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between aboutPOQ-00525- 127 -1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agent(s) can be administered separately, as part of a multiple dose regimen, from the compounds of this disclosure. Alternatively, the additional agent(s) can be part of a single dosage form, mixed together with the compound of this disclosure in a single composition.

[0350] The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, intraocularly, intravitreally, subdermally, orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg of body weight or, alternatively, in a dosage ranging from about 1 mg to about 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of a compound of the disclosure, or a composition thereof, to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 6 times per day or, alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, a preparation can contain from about 20% to about 80% active compound.

[0351] Doses lower or higher than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0352] Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this disclosure can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have beenPOQ-00525- 128 -alleviated to the desired level. Patients may, however, require intermittent treatment on a longterm basis upon recurrence of disease symptoms.

[0353] Uses of Compounds and Pharmaceutically Acceptable Compositions

[0354] As used herein, “KAT6-mediated” disease, disorder or condition means any disease or other deleterious condition in which KAT6 plays a role. Accordingly, another embodiment of the present disclosure relates to treating, for example, lessening the severity of a KAT6-mediated disorder or condition. KAT6-mediated disorders include, for example, cancers, inflammatory disorders, autoimmune disorders, neurodegenerative disorders, and hematological disorders. Specific examples of KAT6-mediated disorders are set forth in detail below.

[0355] Compounds provided by this disclosure are also useful as tools, for example, to study KAT6 modulation in biological and pathological phenomena, to study cancer or for the identification and / or comparative evaluation of KAT6 modulators. Accordingly, in particular embodiments, the present disclosure provides a method for studying an effect of a compound described herein, or a salt or composition thereof, on a sample, the method comprising contacting a sample comprising cells in culture or KAT6 with the compound, or the salt or composition thereof; and measuring the effect of the compound, or salt or composition thereof, on the cells or KAT6. For example, the compounds described herein can be used as a standard or control substance in binding assays (e.g., competitive binding assays) to identify or evaluate potential KAT6 modulators or as a discovery tool to probe the role of KAT6 modulation in certain disorders or conditions, such as those described herein, including inflammatory disorders, autoimmune disorders, and other KAT6-mediated disorders or conditions.

[0356] In a certain embodiment, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a subject in need thereof a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein, wherein the disease or disorder is selected from cancers, inflammatory disorders, autoimmune disorders, neurodegenerative disorders, and hematological disorders.

[0357] Cancer

[0358] A pharmaceutical composition or compound described herein can be used to treat a neoplastic disorder. A “neoplastic disorder” is a disease or disorder characterized by cells thatPOQ-00525- 129 -have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders, e.g., tumors arising from prostate, brain, bone, colon, lung, breast, ovarian, and liver origin, hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors. Prevalent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.

[0359] The disclosed methods are useful in the prevention and treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof.

[0360] Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma / Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma / Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas / Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma / Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood;POQ-00525- 130 -Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary);Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer;Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary);Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult;Lymphoma, Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy;Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma / Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma,POQ-00525- 131 -Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer;Osteosarcoma / Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor;Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm / Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma;Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma) / Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant;Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood;Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor.

[0361] In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents aPOQ-00525- 132 -separate embodiment according to this disclosure. In some embodiments, the cancer is early cancer. In some embodiments, the cancer is advanced cancer. In some embodiments, the cancer is invasive cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is drug resistant cancer. In some embodiments, the cancer may be a MYST overexpressing cancer. In some embodiments, the cancer may over-express MYST protein relative to non-cancerous tissue. In some cases, the cancer overproduces MYST mRNA relative to non-cancerous tissue. In some embodiments, the overexpressed MYST protein or MYST mRNA may be any one KATs of the MYST family, i.e. any one of TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the cancer may overexpress more than one KATs of the MYST family, e.g. two or more selected from the group consisting of TIP60, KAT6B, KAT6A (MOZ), HB01, and MOF. In some embodiments, the cancer may be a cancer that evades immune recognition, e.g. via tumor-associated Treg cells.

[0362] In some embodiments, the cancer is selected from the group consisting of leukemia, lymphoma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma, and gastric cancer.

[0363] In some embodiments, the cancer is selected from the group consisting of adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, cancer of the female genital system, cancer of the male genital system, central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal tract cancer, hairy cell leukemia, head and neck cancer, hepatocellular cancer, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, stomach cancer,POQ-00525- 133 -testicular cancer, thyroid cancer, urinary system cancer, uterine sarcoma, vaginal cancer, vascular system, Waldenstrom's macroglobulinemia, and / or Wilms' tumor.

[0364] In some embodiments, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, and pituitary adenoma, or a combination of two or more of the foregoing cancers.

[0365] In some embodiments, the cancer is selected from the group consisting of bladder cancer (urothelial carcinoma), myelodysplasia, breast cancer, cervix cancer, endometrium cancer, esophagus cancer, head and neck cancer (squamous cell carcinoma), kidney cancer (e.g., renal cell carcinoma, clear cell renal cell carcinoma), liver cancer (hepatocellular carcinoma), lung cancer (e.g., metastatic, non-small cell, NSCLC, squamous cell carcinoma, small cell (SCLC)), metastatic cancer (e.g., to brain), nasopharynx cancer, solid tumor cancer, stomach cancer, adrenocortical carcinoma, Glioblastoma multiforme, acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma (e.g., Hodgkin's (classical), diffuse large B-cell, primary central nervous system), malignant melanoma, uveal melanoma, meningioma, multiple myeloma, breast cancer, metastatic breast cancer, anus cancer (e.g. squamous cell), biliary cancer, bladder cancer, muscle invasive urothelial carcinoma, colorectal cancer, metastatic colorectal cancer, fallopian tube cancer, gastroesophageal junction cancer (e.g., adenocarcinoma), larynx cancer (e.g., squamous cell), Merkel cell cancer, mouth cancer, ovary cancer (e.g., epithelial), pancreas cancer (e.g., adenocarcinoma, metastatic), penis cancer (e.g., squamous cell carcinoma), peritoneum cancer, prostate cancer (e.g., castration-resistant,POQ-00525- 134 -metastatic), rectum cancer, skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma), small intestine cancer (e.g., adenocarcinoma), testicular cancer, thymus cancer, anaplastic thyroid cancer, cholangiocarcinoma, chordoma, cutaneous T-cell lymphoma, digestive-gastrointestinal cancer, familial pheochromocytoma-paraganglioma, Glioma, HTLV-1 -associated adult T-cell leukemia- lymphoma, hematologic-blood cancer, hepatitis C (HCV), papillomaviral respiratory Infection, uterine leiomyosarcoma, acute lymphocytic leukemia, chronic myeloid leukemia, T-cell Lymphoma, follicular lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell testicular lymphoma, melanoma, malignant mesothelioma, pleural mesothelioma, mycosis fungoides, neuroendocrine cancer, oral epithelial dysplasia, Sarcoma, severe sepsis, Sezary syndrome, smoldering myeloma, soft tissue sarcoma, nasal natural killer (NK) cell T-cell lymphoma, and peripheral T-cell lymphoma.

[0366] In some embodiments, the cancer is selected from the group consisting of breast cancer, familial breast cancer, bladder cancer, cervical cancer, leukemia, chronic myelogenous leukemia, Fanconi leukemia colorectal cancer, endometrial cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, liver cancer, Lung cancer, Non-small cell lung cancer (NSCLC), melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, renal cell carcinoma, stomach cancer, squamous cell carcinoma, thyroid cancer, lymphoma, Familial cylindromatosis, Glioma, and urothelial cancer.

[0367] In some embodiments, the cancer is selected from ovarian cancer, breast cancer, renal cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, osteosarcoma, colorectal cancer, gastric cancer, multiple myeloma, B-Cell Acute Lymphoblastic Leukemia, and glioblastoma.

[0368] In some embodiments, the cancer is selected from breast cancer, ovarian carcinoma, renal cell carcinoma, hepatocellular carcinoma, multiple myeloma, B-cell acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large B-cell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroidPOQ-00525- 135 -cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer, and uterine cancer.

[0369] In some embodiments, the cancer may be selected from solid tumors and non-solid tumors.

[0370] In various embodiments, this disclosure is directed to a method for suppressing, reducing or inhibiting tumor growth in a subject, comprising administering a compound of this disclosure, to a subject under conditions effective to suppress, reduce or inhibit tumor growth in said subject.

[0371] In some embodiments, the tumor may be a solid tumor or a non-solid tumor.

[0372] In some embodiments, the solid tumor cancer is selected from breast cancer, ovarian carcinoma, renal cell carcinoma, hepatocellular carcinoma, prostate cancer, colon cancer, gastric cancer, multiple myeloma, B-cell acute lymphoblastic leukemia, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer, and uterine cancer.

[0373] In some embodiments, the solid tumor is a tumor of breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder.

[0374] In some embodiments, the solid tumor is a tumor of breast, lung, prostate, pancreatic, or ovarian. In some embodiments, the breast cancer is ER positive breast cancer. In some embodiments, the lung cancer is non-small cell lung cancer.

[0375] In some embodiments, the non-solid tumor cancer is selected from acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, glioblastoma, medulloblastoma, germinal center- derived lymphomas, myeloma, retinoblastoma, and Wilm’s tumor.

[0376] In some embodiments, this disclosure relates to methods of treating hematologic tumors in a patient. Some embodiments relate to the treatment of hematologic tumors in a patient comprising administering to the patient an amount of a compound described herein that is effective in treating the hematologic tumor. In some embodiments, the hematologic tumor isPOQ-00525- 136 -leukemia, lymphoma, or multiple myeloma. In some embodiments, the hematologic tumor is leukemia or lymphoma.

[0377] In some embodiments, the breast cancer is ER positive breast cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the cancer is hematologic. In some embodiments, the hematologic tumor is leukemia or lymphoma.

[0378] KAT6's importance in cancer treatment is particularly relevant in various cancer types, including but not limited to: leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, lymphoma, MYC-induced lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma, and gastric cancer.

[0379] In some embodiments, the hematologic tumor is leukemia, lymphoma or multiple myeloma. In some embodiments, the hematologic tumor is leukemia or lymphoma.

[0380] In various embodiments, this disclosure is directed to a method of treating leukemia comprising administering a compound of this disclosure to a subject suffering from leukemia under conditions effective to treat the leukemia. In some embodiments, the leukemia is early leukemia. In some embodiments, the leukemia is advanced leukemia. In some embodiments, the leukemia is invasive leukemia. In some embodiments, the leukemia is metastatic leukemia. In some embodiments, the leukemia is drug resistant leukemia. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure. In some embodiments, the leukemia is B-Cell Acute Lymphoblastic Leukemia (B-ALL), Acute Lymphocytic Leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML).

[0381] In various embodiments, this disclosure is directed to a method of treating Acute Lymphocytic Leukemia (ALL) comprising administering a compound of this disclosure to a subject suffering from acute lymphocytic leukemia (ALL) under conditions effective to treat the Acute Lymphocytic Leukemia (ALL). In some embodiments, the Acute Lymphocytic LeukemiaPOQ-00525- 137 -(ALL) is early Acute Lymphocytic Leukemia (ALL). In some embodiments, the Acute Lymphocytic Leukemia (ALL) is advanced Acute Lymphocytic Leukemia (ALL). In some embodiments, the Acute Lymphocytic Leukemia (ALL) is invasive Acute Lymphocytic Leukemia (ALL). In some embodiments, the Acute Lymphocytic Leukemia (ALL) is metastatic Acute Lymphocytic Leukemia (ALL). In some embodiments, the Acute Lymphocytic Leukemia (ALL) is drug resistant Acute Lymphocytic Leukemia (ALL). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0382] In various embodiments, this disclosure is directed to a method of treating Acute Myeloid Leukemia (AML) comprising administering a compound of this disclosure to a subject suffering from Acute Myeloid Leukemia (AML) under conditions effective to treat the Acute Myeloid Leukemia (AML). In some embodiments, the Acute Myeloid Leukemia (AML) is early Acute Myeloid Leukemia (AML). In some embodiments, the Acute Myeloid Leukemia (AML) is advanced Acute Myeloid Leukemia (AML). In some embodiments, the Acute Myeloid Leukemia (AML) is invasive Acute Myeloid Leukemia (AML). In some embodiments, the Acute Myeloid Leukemia (AML) is metastatic Acute Myeloid Leukemia (AML). In some embodiments, the Acute Myeloid Leukemia (AML) is drug resistant Acute Myeloid Leukemia (AML). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0383] In various embodiments, this disclosure is directed to a method of treating Chronic Lymphocytic Leukemia (CLL) comprising administering a compound of this disclosure to a subject suffering from Chronic Lymphocytic Leukemia (CLL) under conditions effective to treat the Chronic Lymphocytic Leukemia (CLL). In some embodiments, the Chronic Lymphocytic Leukemia (CLL) is early Chronic Lymphocytic Leukemia (CLL). In some embodiments, the Chronic Lymphocytic Leukemia (CLL) is advanced Chronic Lymphocytic Leukemia (CLL). InPOQ-00525- 138 -some embodiments, the Chronic Lymphocytic Leukemia (CLL) is invasive Chronic Lymphocytic Leukemia (CLL). In some embodiments, the Chronic Lymphocytic Leukemia (CLL) is metastatic Chronic Lymphocytic Leukemia (CLL). In some embodiments, the Chronic Lymphocytic Leukemia (CLL) is drug resistant Chronic Lymphocytic Leukemia (CLL). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TTP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0384] In various embodiments, this disclosure is directed to a method of treating Chronic Myeloid Leukemia (CML) comprising administering a compound of this disclosure to a subject suffering from Chronic Myeloid Leukemia (CML) under conditions effective to treat the Chronic Myeloid Leukemia (CML). In some embodiments, the Chronic Myeloid Leukemia (CML) is early Chronic Myeloid Leukemia (CML). In some embodiments, the Chronic Myeloid Leukemia (CML) is advanced Chronic Myeloid Leukemia (CML). In some embodiments, the Chronic Myeloid Leukemia (CML) is invasive Chronic Myeloid Leukemia (CML). In some embodiments, the Chronic Myeloid Leukemia (CML) is metastatic Chronic Myeloid Leukemia (CML). In some embodiments, the Chronic Myeloid Leukemia (CML) is drug resistant Chronic Myeloid Leukemia (CML). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0385] In various embodiments, this disclosure is directed to a method of treating B-Cell Acute Lymphoblastic Leukemia (B-ALL) comprising administering a compound of this disclosure to a subject suffering from B-Cell Acute Lymphoblastic Leukemia (B-ALL) under conditions effective to treat the B-Cell Acute Lymphoblastic Leukemia (B-ALL). In some embodiments, the B-Cell Acute Lymphoblastic Leukemia (B-ALL) is early B-Cell Acute Lymphoblastic Leukemia (B-ALL). In some embodiments, the B-Cell Acute Lymphoblastic Leukemia (B-ALL) is advanced B-Cell Acute Lymphoblastic Leukemia (B-ALL). In somePOQ-00525- 139 -embodiments, the B-Cell Acute Lymphoblastic Leukemia (B-ALL) is invasive B-Cell Acute Lymphoblastic Leukemia (B-ALL). In some embodiments, the B-Cell Acute Lymphoblastic Leukemia (B-ALL) is metastatic B-Cell Acute Lymphoblastic Leukemia (B-ALL). In some embodiments, the B-Cell Acute Lymphoblastic Leukemia (B-ALL) is drug resistant B-Cell Acute Lymphoblastic Leukemia (B-ALL). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0386] In various embodiments, this disclosure is directed to a method of treating lymphoma comprising administering a compound of this disclosure to a subject suffering from lymphoma under conditions effective to treat the lymphoma. In some embodiments, the lymphoma is early lymphoma. In some embodiments, the lymphoma is advanced lymphoma. In some embodiments, the lymphoma is invasive lymphoma. In some embodiments, the lymphoma is metastatic lymphoma. In some embodiments, the lymphoma is drug resistant lymphoma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure, in various embodiments, the lymphoma is a MYC-induced lymphoma, B-cell lymphoma, Non-Hodgkin's lymphoma, or Hodgkin's disease; each represents a separate embodiment according to this disclosure.

[0387] In various embodiments, this disclosure is directed to a method of treating B-cell lymphoma comprising administering a compound of this disclosure to a subject suffering from B-cell lymphoma under conditions effective to treat the B-cell lymphoma. In some embodiments, the B-cell lymphoma is early B-cell lymphoma. In some embodiments, the B-cell lymphoma is advanced B-cell lymphoma. In some embodiments, the B-cell lymphoma is invasive B-cell lymphoma. In some embodiments, the B-cell lymphoma is metastatic B-cell lymphoma. In some embodiments, the B-cell lymphoma is drug resistant B-cell lymphoma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60,POQ-00525- 140 -KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0388] In various embodiments, this disclosure is directed to a method of treating NonHodgkin's lymphoma comprising administering a compound of this disclosure to a subject suffering from Non-Hodgkin's lymphoma under conditions effective to treat the Non-Hodgkin's lymphoma. In some embodiments, the Non-Hodgkin's lymphoma is early Non-Hodgkin's lymphoma. In some embodiments, the Non-Hodgkin's lymphoma is advanced Non-Hodgkin's lymphoma. In some embodiments, the Non-Hodgkin's lymphoma is invasive Non-Hodgkin's lymphoma. In some embodiments, the Non-Hodgkin's lymphoma is metastatic Non-Hodgkin's lymphoma. In some embodiments, the Non-Hodgkin's lymphoma is drug resistant Non-Hodgkin's lymphoma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0389] In various embodiments, this disclosure is directed to a method of treating Hodgkin's disease comprising administering a compound of this disclosure to a subject suffering from Hodgkin's disease under conditions effective to treat the Hodgkin's disease. In some embodiments, the Hodgkin's disease is early Hodgkin's disease. In some embodiments, the Hodgkin's disease is advanced Hodgkin's disease. In some embodiments, the Hodgkin's disease is invasive Hodgkin's disease. In some embodiments, the Hodgkin's disease is metastatic Hodgkin's disease. In some embodiments, the Hodgkin's disease is drug resistant Hodgkin's disease. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.POQ-00525- 141 -

[0390] In various embodiments, this disclosure is directed to a method of treating breast cancer comprising administering a compound of this disclosure to a subject suffering from breast cancer under conditions effective to treat the breast cancer. In some embodiments, the breast cancer is early breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is drug resistant breast cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure. In some embodiments, the breast cancer is ER positive breast cancer.

[0391] Overexpression of KAT6 correlates with worse clinical outcome in ER+ / HER2-breast cancers.

[0392] In various embodiments, this disclosure is directed to a method of treating ovarian cancer comprising administering a compound of this disclosure to a subject suffering from ovarian cancer under conditions effective to treat the ovarian cancer. In some embodiments, the ovarian cancer is early ovarian cancer. In some embodiments, the ovarian cancer is advanced ovarian cancer. In some embodiments, the ovarian cancer is invasive ovarian cancer. In some embodiments, the ovarian cancer is metastatic ovarian cancer. In some embodiments, the ovarian cancer is drug resistant ovarian cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0393] In various embodiments, this disclosure is directed to a method of treating prostate cancer comprising administering a compound of this disclosure to a subject suffering from prostate cancer under conditions effective to treat the prostate cancer. In some embodiments, the prostate cancer is early prostate cancer. In some embodiments, the prostate cancer is advanced prostate cancer. In some embodiments, the prostate cancer is invasive prostate cancer. In somePOQ-00525- 142 -embodiments, the prostate cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is drug resistant prostate cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0394] In various embodiments, this disclosure is directed to a method of treating lung cancer comprising administering a compound of this disclosure to a subject suffering from lung cancer under conditions effective to treat the lung cancer. In some embodiments, the lung cancer is early lung cancer. In some embodiments, the lung cancer is advanced lung cancer. In some embodiments, the lung cancer is invasive lung cancer. In some embodiments, the lung cancer is metastatic lung cancer. In some embodiments, the lung cancer is drug resistant lung cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0395] In various embodiments, this disclosure is directed to a method of treating non-small cell lung cancer (NSCLC) comprising administering a compound of this disclosure to a subject suffering from non-small cell lung cancer (NSCLC) under conditions effective to treat the non-small cell lung cancer (NSCLC). In some embodiments, the non-small cell lung cancer (NSCLC) is early non-small cell lung cancer (NSCLC). In some embodiments, the non-small cell lung cancer (NSCLC) is advanced non-small cell lung cancer (NSCLC). In some embodiments, the non-small cell lung cancer (NSCLC) is invasive non-small cell lung cancer (NSCLC). In some embodiments, the non-small cell lung cancer (NSCLC) is metastatic non-small cell lung cancer (NSCLC). In some embodiments, the non-small cell lung cancer (NSCLC) is drug resistant non-small cell lung cancer (NSCLC). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In somePOQ-00525- 143 -embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0396] In various embodiments, this disclosure is directed to a method of treating melanoma comprising administering a compound of this disclosure to a subject suffering from melanoma under conditions effective to treat the melanoma. In some embodiments, the melanoma is early melanoma. In some embodiments, the melanoma is advanced melanoma. In some embodiments, the melanoma is invasive melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma is drug resistant melanoma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TTP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0397] In various embodiments, this disclosure is directed to a method of treating colorectal cancer comprising administering a compound of this disclosure to a subject suffering from colorectal cancer under conditions effective to treat the colorectal cancer. In some embodiments, the colorectal cancer is early colorectal cancer. In some embodiments, the colorectal cancer is advanced colorectal cancer. In some embodiments, the colorectal cancer is invasive colorectal cancer. In some embodiments, the colorectal cancer is metastatic colorectal cancer. In some embodiments, the colorectal cancer is drug resistant colorectal cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0398] In various embodiments, this disclosure is directed to a method of treating colon cancer comprising administering a compound of this disclosure to a subject suffering from colon cancer under conditions effective to treat the colon cancer. In some embodiments, the colon cancer is early colon cancer. In some embodiments, the colon cancer is advanced colon cancer. In some embodiments, the colon cancer is invasive colon cancer. In some embodiments, the colon cancer is metastatic colon cancer. In some embodiments, the colon cancer is drug resistantPOQ-00525- 144 -colon cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0399] In various embodiments, this disclosure is directed to a method of treating squamous cell carcinoma comprising administering a compound of this disclosure to a subject suffering from squamous cell carcinoma under conditions effective to treat the squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is early squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is advanced squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is invasive squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is metastatic squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is drug resistant squamous cell carcinoma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0400] In various embodiments, this disclosure is directed to a method of treating gastric cancer comprising administering a compound of this disclosure to a subject suffering from gastric cancer under conditions effective to treat the gastric cancer. In some embodiments, the gastric cancer is early gastric cancer. In some embodiments, the gastric cancer is advanced gastric cancer. In some embodiments, the gastric cancer is invasive gastric cancer. In some embodiments, the gastric cancer is metastatic gastric cancer. In some embodiments, the gastric cancer is drug resistant gastric cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.POQ-00525- 145 -

[0401] In various embodiments, this disclosure is directed to a method of treating osteosarcoma comprising administering a compound of this disclosure to a subject suffering from osteosarcoma under conditions effective to treat the osteosarcoma. In some embodiments, the osteosarcoma is early osteosarcoma. In some embodiments, the osteosarcoma is advanced osteosarcoma. In some embodiments, the osteosarcoma is invasive osteosarcoma. In some embodiments, the osteosarcoma is metastatic osteosarcoma. In some embodiments, the osteosarcoma is drug resistant osteosarcoma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0402] In various embodiments, this disclosure is directed to a method of treating multiple myeloma comprising administering a compound of this disclosure to a subject suffering from multiple myeloma under conditions effective to treat the multiple myeloma. In some embodiments, the multiple myeloma is early multiple myeloma. In some embodiments, the multiple myeloma is advanced multiple myeloma. In some embodiments, the multiple myeloma is invasive multiple myeloma. In some embodiments, the multiple myeloma is metastatic multiple myeloma. In some embodiments, the multiple myeloma is drug resistant multiple myeloma. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0403] In various embodiments, this disclosure is directed to a method of treating glioblastoma (GBM) comprising administering a compound of this disclosure to a subject suffering from glioblastoma (GBM) under conditions effective to treat the glioblastoma (GBM). In some embodiments, the glioblastoma (GBM) is early glioblastoma (GBM). In some embodiments, the glioblastoma (GBM) is advanced glioblastoma (GBM). In some embodiments, the glioblastoma (GBM) is invasive glioblastoma (GBM). In some embodiments, the glioblastoma (GBM) is metastatic glioblastoma (GBM). In some embodiments, the glioblastomaPOQ-00525- 146 -(GBM) is drug resistant glioblastoma (GBM). In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0404] In various embodiments, this disclosure is directed to a method of treating pancreatic cancer comprising administering a compound of this disclosure to a subject suffering from pancreatic cancer under conditions effective to treat the pancreatic cancer. In some embodiments, the pancreatic cancer is early pancreatic cancer. In some embodiments, the pancreatic cancer is advanced pancreatic cancer. In some embodiments, the pancreatic cancer is invasive pancreatic cancer. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is drug resistant pancreatic cancer. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the compound is any one of the compounds listed in Table A, B, or 5; each compound represents a separate embodiment according to this disclosure.

[0405] In various embodiments, this disclosure provides methods for increasing the survival of a subject suffering from metastatic cancer comprising the step of administering to said subject a compound of this disclosure. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the cancer is leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), -Cell Acute Lymphoblastic Leukemia (B-ALL), lymphoma, MYC-induced lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, nonsmall cell lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma or gastric cancer; each represents a separate embodiment according to this disclosure.POQ-00525- 147 -

[0406] In various embodiments, this disclosure provides methods for treating advanced cancer comprising the step of administering to said subject a compound of this disclosure. In some embodiments, the compound inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HB01 and MOF. In some embodiments, the compound is a Lysine AcetylTransferase 6 (KAT6) inhibitor. In some embodiments, the cancer is leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), -Cell Acute Lymphoblastic Leukemia (B-ALL), lymphoma, MYC-induced lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, non-small cell lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma or gastric cancer; each represents a separate embodiment according to this disclosure.

[0407] The compounds of the present disclosure provides methods for treating metastatic cancer, advanced cancer, or drug resistant cancer. In a preferred embodiment the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large B-cell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer; each represents a separate embodiment according to this disclosure. Preferred compounds of the present disclosure are selectively disruptive to cancer cells, causing ablation of cancer cells but preferably not normal cells. Significantly, harm to normal cells is minimized because the cancer cells are susceptible to disruption at much lower concentrations of the compounds of the present disclosure.

[0408] In various embodiments, other types of cancers that may be treatable with the Lysine AcetylTransferase 6 (KAT6) inhibitors according to this disclosure include: adrenocortical carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal, pineal tumors, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer,POQ-00525- 148 -esophageal cancer, extrahepatic bile duct cancer, Ewing’s family of tumors (Pnet), extracranial germ cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer, germ cell tumor, extragonadal, gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma, central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic squamous carcinoma, multiple myeloma, plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, exocrine, pancreatic cancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer, salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, small intestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant, thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancer of childhood, vaginal cancer, vulvar cancer, Wilms' tumor, hepatocellular cancer, and hematological cancer, or any combination thereof. In some embodiments the cancer is invasive. In some embodiments the cancer is metastatic cancer. In some embodiments the cancer is advanced cancer. In some embodiments the cancer is drug resistant cancer.

[0409] In various embodiments “metastatic cancer” refers to a cancer that spread (metastasized) from its original site to another area of the body. Virtually all cancers have the potential to spread. Whether metastases develop depends on the complex interaction of many tumor cell factors, including the type of cancer, the degree of maturity (differentiation) of the tumor cells, the location and how long the cancer has been present, as well as other incompletely understood factors. Metastases spread in three ways - by local extension from the tumor to the surrounding tissues, through the bloodstream to distant sites or through the lymphatic system to neighboring or distant lymph nodes. Each kind of cancer may have a typical route of spread. ThePOQ-00525- 149 -tumor is called by the primary site (ex. breast cancer that has spread to the brain is called metastatic breast cancer to the brain).

[0410] In various embodiments “drug-resistant cancer” refers to cancer cells that acquire resistance to chemotherapy. Cancer cells can acquire resistance to chemotherapy by a range of mechanisms, including the mutation or overexpression of the drug target, inactivation of the drug, or elimination of the drug from the cell. Tumors that recur after an initial response to chemotherapy may be resistant to multiple drugs (they are multidrug resistant). In the conventional view of drug resistance, one or several cells in the tumor population acquire genetic changes that confer drug resistance. Accordingly, the reasons for drug resistance, inter alia, are: a) some of the cells that are not killed by the chemotherapy mutate (change) and become resistant to the drug. Once they multiply, there may be more resistant cells than cells that are sensitive to the chemotherapy; b) Gene amplification. A cancer cell may produce hundreds of copies of a particular gene. This gene triggers an overproduction of protein that renders the anticancer drug ineffective; c) cancer cells may pump the drug out of the cell as fast as it is going in using a molecule called p-glycoprotein; d) cancer cells may stop taking in the drugs because the protein that transports the drug across the cell wall stops working; e) the cancer cells may learn how to repair the DNA breaks caused by some anti-cancer drugs; f) cancer cells may develop a mechanism that inactivates the drug. One major contributor to multi drug resistance is overexpression of P-glycoprotein (P-gp). This protein is a clinically important transporter protein belonging to the ATP-binding cassette family of cell membrane transporters. It can pump substrates including anticancer drugs out of tumor cells through an ATP-dependent mechanism; g) Cells and tumors with activating RAS mutations are relatively resistant to most anti-cancer agents. Thus, the resistance to anticancer agents used in chemotherapy is the main cause of treatment failure in malignant disorders, provoking tumors to become resistant. Drug resistance is the major cause of cancer chemotherapy failure.

[0411] In various embodiments “resistant cancer” refers to drug-resistant cancer as described herein above. In some embodiments “resistant cancer” refers to cancer cells that acquire resistance to any treatment such as chemotherapy, radiotherapy or biological therapy.POQ-00525- 150 -

[0412] In various embodiments, this disclosure is directed to treating cancer in a subject, wherein the subject has been previously treated with chemotherapy, radiotherapy or biological therapy.

[0413] In various embodiments “chemotherapy” refers to chemical treatment for cancer such as drugs that kill cancer cells directly. Such drugs are referred as "anti-cancer" drugs or "antineoplastics.". “Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.

[0414] Chemotherapy is used to control tumor growth when cure is not possible; to shrink tumors before surgery or radiation therapy; to relieve symptoms (such as pain); and to destroy microscopic cancer cells that may be present after the known tumor is removed by surgery (called adjuvant therapy). Adjuvant therapy is given to prevent a possible cancer reoccurrence.

[0415] In various embodiments, “radiotherapy” (also referred herein as “radiation therapy”) refers to high energy x-rays and similar rays (such as electrons) to treat disease.

[0416] In various embodiments “biological therapy” refers to substances that occur naturally in the body to destroy cancer cells. There are several types of treatment including monoclonal antibodies, cancer growth inhibitors, vaccines and gene therapy. Biological therapy includes immunotherapy.

[0417] When the compounds or pharmaceutical compositions of the present disclosure are administered to treat a cancerous condition, the pharmaceutical composition can also contain, or can be administered in conjunction with, other therapeutic agents or treatment regimen presently known or hereafter developed for the treatment of various types of cancer. Examples of other therapeutic agents or treatment regimen include, without limitation, radiation therapy, immunotherapy, chemotherapy, surgical intervention, and combinations thereof.

[0418] Inhibition of the KATs to reduce the extent of lysine acetylation of histones (and other nuclear proteins described herein) will likely sensitize tumor cells to chemo- and radiotherapy by attenuating the process of DNA damage repair, e.g. the repair of DNA double-POQ-00525- 151 -strand breaks (DSB), thus increasing the frequency of chemo- and radiotherapy induced cancer cell death. Therefore, it is likely that inhibition of the KAT proteins would synergize well with low dose chemo- or radiotherapy. Thus, in some cases, a MYST protein antagonist disclosed herein may be administered in conjunction with a radiotherapeutic or chemotherapeutic regime. It may be administered simultaneously or sequentially with radio and / or chemotherapy. Suitable chemotherapeutic agents and radiotherapy protocols will be readily appreciable to the skilled person. In particular, the compound described herein may be combined with low dose chemo or radio therapy. Appropriate dosages for "low dose" chemo or radio therapy will be readily appreciable to the skilled practitioner.

[0419] Inflammatory Disorders

[0420] In some embodiments, compounds and compositions described herein are useful for treating inflammatory disorders in a subject in need thereof. Thus, in certain embodiments, the present disclosure provides a method for treating an inflammatory disorder, comprising the step of administering to a subject in need thereof a compound of the present disclosure (e.g., a compound represented by any one of structural formulas (I)-(Ip) or a pharmaceutically acceptable salt thereof) or a composition thereof.

[0421] In certain aspects, the inflammatory disease can include, but is not limited to uveitis, interleukin- 1 converting enzyme fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, inflammatory bowel disease (IBD), ischemia reperfusion injury in a solid organ transplant, sepsis, liver disease, allergic disease, and graft versus host disease.

[0422] Alternatively, the inflammatory disease can include but is not limited to rheumatoid arthritis, inflammatory arthritis, peritonitis, ischemia reperfusion injury in kidney transplant, nonalcohol steatohepatitis, alcohol steatohepatitis, insulin-resistant type 2 diabetes, allergic rhinitis, asthma, atopic dermatitis, Sjogren’s syndrome, ankylosing spondylitis, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, thrombosis, a-synucleinopathy, Parkinson’s disease, dementia with Lewy body, multiple system atrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, and chronic obstructive pulmonary disease.

[0423] In certain embodiments, the disclosure relates to a method of treating a subject suffering from an inflammatory disorder as described herein comprising administering to thePOQ-00525- 152 -subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and an anti-inflammatory agent and / or an anti-TNF agent.

[0424] Inflammatory disorders treatable by the pharmaceutical compositions or compounds of this invention include, but are not limited to, multiple sclerosis, rheumatoid arthritis, degenerative joint disease, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium and large vessel), atherosclerosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, sepsis, psoriasis and other dermatological inflammatory disorders (such as eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, and dermatosis with acute inflammatory components, pemphigus, pemphigoid, allergic dermatitis), and urticarial syndromes.

[0425] Neurodegenerative Disorders

[0426] In some embodiments, the disease or disorder is a neurodegenerative disorder. For example, the neurological disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig’s Disease), Parkinson’s disease, Angelman syndrome, Huntington’s disease, multiple sclerosis, diabetic neurophathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke’s disease, Wilson’s disease, cerebral ischemia, a prion disorder, dementia, corticobasal degeneration, progressive supranuclear palsy, spinocerebellar atrophies, brain injury and spinal cord injury.

[0427] Autoimmune disorders

[0428] Autoimmune diseases and disorders are a group of conditions characterized by an abnormal immune response against the body's own tissues and organs. These conditions can affect virtually any part of the body and result in a wide range of symptoms, making them a significant global health concern. Examples of autoimmune diseases and disorders include but not limited to: Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Inflammatory Bowel Disease (IBD), and Psoriasis.

[0429] Combination Therapies

[0430] In various embodiments, the compounds of this disclosure (e.g., a compound represented by any one of structural formulas (I)-(Ip) or a pharmaceutically acceptable salt thereof) can be used alone or in combination with other therapeutic agents. CombinationPOQ-00525- 153 -therapies according to the present disclosure comprise the administration of at least one compound of the disclosure, and the use of at least one other therapeutically active agent. For example, combination therapies according to the present disclosure comprise the administration of at least one compound of the disclosure and at least one other therapeutically active agent to a subject in need of treatment for a given disease or disorder, for example, the cancers, inflammatory diseases, hematological, and neurodegenerative diseases described herein.

[0431] The compounds of the disclosure (e.g., a compound represented by any one of structural formulas (I)-(Ip) or a pharmaceutically acceptable salt thereof) and the other therapeutically active agent can be administered together in a single pharmaceutical composition or separately and, when administered separately this can occur simultaneously or sequentially in any order. The amounts of the compounds of the disclosure and other therapeutically active agents and the relative timings of administration can be selected in order to achieve the desired combined therapeutic effect. Thus in a further aspect, there is provided a combination comprising a compound of the disclosure together with one or more other therapeutically active agents.

[0432] Cancer

[0433] In various embodiments, the composition for cancer treatment of the present disclosure can be used together with existing chemotherapy drugs or be made as a mixture with them. Such a chemotherapy drug includes, for example, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, alkaloids derived from plant, topoisomerase inhibitors, hormone therapy medicines, hormone antagonists, aromatase inhibitors, P-gly coprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer agents. Further, they can be used together with hypoleukocytosis (neutrophil) medicines that are cancer treatment adjuvant, thrombopenia medicines, antiemetic drugs, and cancer pain medicines for patient's QOL recovery or be made as a mixture with them. In some embodiments, the compound of this disclosure is administered in combination with an agent including but not limited to: tamoxifen, selective estrogen receptor degrader (SERF), e.g., Fulvestrant), CDK4 / 6 inhibitor, and / or CDK4 inhibitor.

[0434] In certain embodiments, the disclosure relates to a method of treating a subject with cancer comprising administering to the subject an effective amount of a compound disclosedPOQ-00525- 154 -herein or a pharmaceutically acceptable salt thereof and a second agent, such as a anti-cancer agent. An "anti-cancer agent" is a compound, which when administered in an effective amount to a subject with cancer, can achieve, partially or substantially, one or more of the following: arresting the growth, reducing the extent of a cancer (e.g., reducing size of a tumor), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components) or increasing longevity of the subject.

[0435] The anti-cancer agents suitable for use in the methods described herein include any anti-cancer agents that have been approved for the treatment of cancer. In some embodiments, the anti-cancer agent includes, but is not limited to, a targeted antibody, an angiogenesis inhibitor, an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a podophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplastic agent and other antineoplastic agents.

[0436] In some embodiments, the anti-cancer agents that can be used in methods described herein are antibody-drug-conjugates (ADCs). Examples of HER2-targeting ADCs include Kadcyla® (trastuzumab emtansine), ENHERTU® (trastuzumab deruxtecan), RC48 (disitamab vedotin), ZRC-3256, and ARX788. Examples of TROP-2-targeting ADCs include sacituzumab govitecan and atopotamab deruxtecan.

[0437] In some embodiments, the anti-cancer agents that can be used in methods described herein include, but are not limited to, paclitaxel, docetaxel, 5-fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin and adriamycin and a combination thereof.

[0438] In some embodiments, the anti-cancer agent and the compound disclosed herein are administered contemporaneously. When administered contemporaneously, the anti-cancer agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-cancer agent can be administered separately at different times.POQ-00525- 155 -

[0439] In some embodiments, the compound according to this disclosure, is administered in combination with an anticancer agent. In some embodiments, the compound according to this disclosure, is administered in combination with hormonal therapy, including but not limited to: Selective Estrogen Receptors Modulators (SERMs) (e.g., tamoxifen, raloxifene), complete estrogen receptor antagonists (CERANs) (e.g., palazestrant), Selective Estrogen Receptors Degraders (SERDs) (e.g., Fulvestrant (Faslodex®, Palazestrant), Aromatase Inhibitors (AIs)(e.g., Anastrozole, Letrozole, Exemestane), Gonadotropin-Releasing Hormone (GnRH) Agonists (e.g., Leuprolide, Goserelin), Antiandrogens (e.g. Bicalutamide), Glucocorticoids (e.g., Prednisone, Dexamethasone) and / or Thyroid Hormones (e.g., Levothyroxine); each represents a separate embodiment according to this disclosure. In some embodiments, the compound is administered in combination with a complete estrogen receptor antagonist (CERAN), including but not limited to palazestrant. In some embodiments, the compound is administered in combination with a selective estrogen receptor degrader (SERD), including but not limited to Fulvestrant (Faslodex®) or palazestrant. In some embodiments, the compound is administered in combination with a Cyclin-dependent kinase 4 (CDK4) inhibitor (e.g., PF-07220060, Palbociclib (Ibrance), Abemaciclib (Verzenio), Ribociclib (Kisqali), Lerociclib (G1T38), Trilaciclib, P276-00, LY2835219, SHR6390, GDC-0980, and / or GDC-0994; each represents a separate embodiment according to this disclosure). In some embodiments, the compound is administered in combination with a Cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor (e.g., Palbociclib (Ibrance), Abemaciclib (Verzenio), Ribociclib (Kisqali), Pictilisib (GDC-0941), Trilaciclib (Cosela); each represents a separate embodiment according to this disclosure). In some embodiments, the compound is administered in combination with a Cyclin-dependent kinase 6 (CDK6) inhibitor (e.g., Palbociclib (trade name: Ibrance), Ribociclib (trade name: Kisqali), Abemaciclib (trade name: Verzenio), LY2835219 (Abemaciclib analog), SHR6390, G1T38, G1T48, G1T58, G1T107, G1T48, P276-00 and / or LSI 04; each represents a separate embodiment according to this disclosure).

[0440] In some embodiments, one or more other therapeutic agents can be an immune checkpoint inhibitor. In some embodiments, the checkpoint inhibitors include but are not limited to anti programed cell death receptor-I (aPD-I) monoclonal antibodies such as pembrolizumab, nivolumab, cemiplimab, or anti programed cell death receptor-I ligand (aPD-LI) monoclonalPOQ-00525- 156 -antibodies such as atezolizumab, dostarlimab, durvalumab and avelumab, or anti cytotoxic T lymphocyte-associated antigen (anti-CTLA4) monoclonal antibodies such as ipilimumab and tremelimumab, or anti lymphocyte activated gene-3 (LAG-3) monoclonal antibodies such as relatlimab.

[0441] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL).

[0442] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between p53 and MDM2. Said MDM2 inhibitors include but are not limited to navtemadlin (AMG-232, KRG 232, Amgen), idasanutlin (RG7388, Hoffman-La Roche), milademetan (RAIN-32), MK-8242 (Merck), SAR405838, NVP-CGM097, RG7112, andDS-3032b.

[0443] In some embodiments, one or more other therapeutic agent is an MDM2 targeted protein degrader such as MD-224.

[0444] In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[0445] In some embodiments, one or more other therapeutic agent is a CDK inhibitor such as a CDK4 / CDK6 inhibitor. In some embodiments, a CDK 4 / 6 inhibitor is selected from Palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (GIT28, G1 Therapeutics).

[0446] In some embodiments, a CDK inhibitor is a CDK9 selective inhibitor selected from dinaciclib, AT-7519, P276-00, AZD-4573, alvocidib / flavopiridol, CYC065, atuveciclib, BAY-1251152, voruciclib or GFH009.POQ-00525- 157 -

[0447] In some embodiments, one or more other therapeutic agent is an inhibitor of antiapoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie / Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott). Other therapeutic agents targeting BCL family proteins via E3 ligase-mediated target protein degradation may be used in the present invention.

[0448] In some embodiments, one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.

[0449] In some embodiments, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0450] In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis / Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.).

[0451] In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[0452] In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacytidinePOQ-00525- 158 -(pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate. (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi- Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidinebased nucleoside analog and thymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology).

[0453] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PBK inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202(formerly RP5230, TG Therapeutics).

[0454] In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech / Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech / Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis / Genentech / Roche); trametinib (MEKINIST®, Novartis); Bcr-AblPOQ-00525- 159 -

[0455] tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech / Roche / Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (IMBRUVICA®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (RYDAPT®, Novartis).

[0456] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP- 547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib ( Amgen / Takeda).

[0457] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).

[0458] In some embodiments, one or more other therapeutic agent is an AKT inhibitor. In some embodiments, the AKT inhibitor is capivasertib (AstraZeneca).

[0459] In some embodiments, one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).POQ-00525- 160 -

[0460] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and Osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).

[0461] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).

[0462] In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).

[0463] In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).

[0464] In some embodiments, a pharmaceutical composition described herein is coadministered with a chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. “Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.

[0465] Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others). Exemplary agentsPOQ-00525- 161 -include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carfilzomib, Carmofur, Carmustine, Celecoxib, Cetuximab, Chlorambucil, Chlormethine, CHOEP-21, CHOP, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine or ara-C, Dacarbazine, Dactinomycin, DA EPOCH, Daratumumab, Daunorubicin, Decitabine, Demecolcine, Dexamethasone, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Eribulin, Estramustine, Etoglucid, Etoposide, FLAG (Flu + Cyt), Floxuridine, Fludarabine, Fluorouracil (5FU), FOLFOX, Fotemustine, Gemcitabine, gemcitabine-oxaliplatin (GemOx), Gliadel implants, Hydroxycarbamide, Hydroxyurea, Ibrutinib, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Ixazomib, Larotaxel, Lenalidomide, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nab-paclitaxel, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, PLD (pegylated liposomal doxorubicin), Plicamycin, Pomalidomide, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, R-CHOP, r-dhaox, r-dhap, Rituximab, Romidepsin Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Sorafonib, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.

[0466] Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, the chemotherapy agents (including combination chemotherapy) can be used in combination with a pharmaceutical composition described herein.Targeted therapyPOQ-00525- 162 -

[0467] Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2 / neu antibody trastuzumab (Herceptin®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, ENHERTU® (trastuzumab deruxtecan), Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include Aflibercept and Denileukin diftitox. In some embodiments, the targeted therapy can be used in combination with a pharmaceutical composition described herein, e.g., Gleevec (Vignari and Wang 2001).

[0468] Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.Angiogenesis

[0469] Pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with angiogenesis. Diseases associated with angiogenesis include cancer, cardiovascular disease and macular degeneration.

[0470] Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one.Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature.POQ-00525- 163 -

[0471] Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair. Other diseases, such as age-related macular degeneration, may be created by a local expansion of blood vessels, interfering with normal physiological processes.

[0472] Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network.Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries.

[0473] Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g., VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion.

[0474] Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.

[0475] Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision.

[0476] Anti-angiogenic therapy can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sunitinib, sorafenib, or monoclonal antibodies or receptorPOQ-00525- 164 -“decoys” to VEGF or VEGF receptor including bevacizumab or VEGF-Trap, or thalidomide or its analogs (lenalidomide, pomalidomide), or agents targeting non- VEGF angiogenic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin or endostatin.Epigenetics

[0477] Pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with epigenetics. Epigenetics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, stem cells become the various cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.

[0478] Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

[0479] Exemplary diseases associated with epigenetics include ATR-syndrome, fragile X-syndrome, ICF syndrome, Angelman’s syndrome, Prader-Wills syndrome, BWS, Rett syndrome, oc-thalassaemia, cancer, leukemia, Rubinstein-Taybi syndrome and Coffin-Lowry syndrome.

[0480] The first human disease to be linked to epigenetics was cancer. Researchers found that diseased tissue from patients with colorectal cancer had less DNA methylation than normal tissue from the same patients. Because methylated genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chromatin. On the other hand, too much methylation can undo the work of protective tumor suppressor genes.POQ-00525- 165 -

[0481] DNA methylation occurs at CpG sites, and a majority of CpG cytosines are methylated in mammals. However, there are stretches of DNA near promoter regions that have higher concentrations of CpG sites (known as CpG islands) that are free of methylation in normal cells. These CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off. This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer. Hypermethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes. In fact, these types of changes may be more common in human cancer than DNA sequence mutations.

[0482] Furthermore, although epigenetic changes do not alter the sequence of DNA, they can cause mutations. About half of the genes that cause familial or inherited forms of cancer are turned off by methylation. Most of these genes normally suppress tumor formation and help repair DNA, including 06-methylguanine-DNA methyltransferase (MGMT), MLH1 cyclin-dependent kinase inhibitor 2B (CDKN2B), and RASSF1A. For example, hypermethylation of the promoter of MGMT causes the number of G-to-A mutations to increase.

[0483] Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA. Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH1 can make a microsatellite unstable and lengthen or shorten it. Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers.

[0484] Fragile X syndrome is the most frequently inherited mental disability, particularly in males. Both sexes can be affected by this condition, but because males only have one X chromosome, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and “autistic-like” behavior.

[0485] Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a microscope; it usually appears as if it is hanging by a thread and easily breakable. The syndrome is caused by an abnormality in the FMRI (fragile X mental retardation 1) gene. People who do not have fragile X syndrome have 6 to 50 repeats of the trinucleotide CGG in their FMRI gene. However, individuals with over 200 repeats have aPOQ-00525- 166 -full mutation, and they usually show symptoms of the syndrome. Too many CGGs cause the CpG islands at the promoter region of the FMRI gene to become methylated; normally, they are not. This methylation turns the gene off, stopping the FMRI gene from producing an important protein called fragile X mental retardation protein. Loss of this specific protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMRI methylation is the real syndrome culprit.

[0486] Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein-Taybi, Coffin-Lowry, Prader-Willi, Angelman, Beckwith- Wiedemann, ATR-X, and Rett syndromes.

[0487] Epigenetic therapies include inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, which have shown promising anti-tumorigenic effects for some malignancies, as well as antisense oligonucleotides and siRNA.Immunotherapy

[0488] In some embodiments, a pharmaceutical composition described herein is administered with an immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, prostate cancer vaccine Provenge, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients.

[0489] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor’s immune cells will often attack the tumor in a graft- versus-tumor effect. In some embodiments, the immunotherapy agent(s) can be used in combination with a pharmaceutical composition described herein.Hormonal therapy

[0490] In some embodiments, a pharmaceutical composition described herein is administered with a hormonal therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers, as well as certain types of leukemia which respond to certainPOQ-00525- 167 -retinoids / retinoic acids. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a pharmaceutical composition described herein.

[0491] Hormonal therapy agents include the administration of hormone agonists or hormone antagonists and include retinoids / retinoic acid, compounds that inhibit estrogen or testosterone, as well as administration of progestogens.

[0492] Inflammatory Disorders

[0493] In certain embodiments, a compound described herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), or (III) or a compound of Table A, Table B, or Table 5, or a pharmaceutically acceptable salt thereof) may be administered alone or in combination with other compounds useful for treating or preventing inflammation. Exemplary antiinflammatory agents include, for example, steroids (e.g., cortisol, cortisone, fludrocortisone, prednisone, 6[alpha]-methylprednisone, triamcinolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NS AIDS (e.g., aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide). In another embodiment, the other therapeutic agent is an antibiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampinmetronidazole, doxycycline or streptomycin). In another embodiment, the other therapeutic agent is a PDE4 inhibitor (e.g., roflumilast or rolipram). In another embodiment, the other therapeutic agent is an antihistamine (e.g., cyclizine, hydroxyzine, promethazine or diphenhydramine). In another embodiment, the other therapeutic agent is an anti-malarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine). In one embodiment, the other compound is drotrecogin alfa. In a specific embodiment, the compound of Structural Formula I or (single) crystalline form thereof (e.g., in a pharmaceutical composition described herein) is administered in combination with dexamethasone.

[0494] Further examples of anti-inflammatory agents include, for example, aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S -adenosylmethionine, alclofenac, alclometasone, alfentanil, algestone, allylprodine,POQ-00525- 168 -alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4- hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antrafenine, apazone, beclomethasone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, betamethasone, betamethasone-17-valerate, bezitramide, [alpha] -bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, budesonide, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butorphanol, carbamazepine, carbiphene, caiprofen, carsalam, chlorobutanol, chloroprednisone, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clobetasol, clocortolone, clometacin, clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cortisone, cortivazol, cropropamide, crotethamide, cyclazocine, deflazacort, dehydrotestosterone, desomorphine, desonide, desoximetasone, dexamethasone, dexamethasone-21- isonicotinate, dexoxadrol, dextromoramide, dextropropoxyphene, deoxycorticosterone, dezocine, diampromide, diamorphone, diclofenac, difenamizole, difenpiramide, diflorasone, diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, enoxolone, epirizole, eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine, fluazacort, flucloronide, flufenamic acid, flumethasone, flunisolide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocoitolone, fluoresone, fluorometholone, fluperolone, flupirtine, fluprednidene, fluprednisolone, fluproquazone, flurandrenolide, flurbiprofen, fluticasone, formocortal, fosfosal, gentisic acid, glafenine, glucametacin, glycol salicylate, guaiazulene, halcinonide, halobetasol, halometasone, haloprednone, heroin, hydrocodone, hydro cortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone cypionate, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac,POQ-00525- 169 -isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p- lactophenetide, lefetamine, levallorphan, levorphanol, levophenacyl-morphan, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, medrysone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mesalamine, metazocine, methadone, methotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptnate, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, mometasone, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, nalorphine, 1 -naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paramethasone, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, pirazolac, piritramide, piroxicam, pirprofen, pranoprofen, prednicarbate, prednisolone, prednisone, prednival, prednylidene, proglumetacin, proheptazine, promedol, propacetamol, properidine, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverine, simetride, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen and zomepirac.

[0495] In some embodiments, the compound described herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), or (III) or a compound of Table A, Table B, or Table 5, or a pharmaceutically acceptable salt thereof) may be administered with a selective COX-2 inhibitor for treating or preventing inflammation. Exemplary selective COX-2 inhibitors include,POQ-00525- 170 -for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, and lumiracoxib.

[0496] In some embodiments, the compound described herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), or (III) or a compound of Table A, Table B, or Table 5, or a pharmaceutically acceptable salt thereof) is administered in combination with an anthracy cline or a Topo II inhibitor. In certain embodiments, the compound is administered in combination with Doxorubicin (Dox). In certain embodiments, the compound is administered in combination with bortezomib (and more broadly including carfilzomib).

[0497] Neurodegenerative Disorders

[0498] In a particular embodiment, the disclosure relates to a method of treating a subject suffering from a neurodegenerative disease as described herein such as Parkinson’s disease, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents typically used in the treatment of Parkinson’ s disease. Such additional therapeutic agents include, but are not limited to levodopa, carbodopa or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl, or amantadine, or a pharmaceutically acceptable salt thereof.

[0499] In a particular embodiment, the disclosure relates to a method of treating a subject suffering from a neurodegenerative disease as described herein such as Alzheimer’s disease comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic agents typically used in the treatment of Alzheimer’s disease. Such additional therapeutic agents include, but are not limited to donepezil, galantamine, memantine, rivastigmine, anti-Abeta (amyloid beta) therapies including aducanumab, crenezumab, solanezumab, and gantenerumab, small molecule inhibitors ofBACEl including verubecestat, AZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or anti-tau therapies such as LMTM (leuco-methylthioninium-bis(hydromethanesulfonate)), or a pharmaceutically acceptable salt thereof.

[0500] In some embodiments, the compound described herein (e.g., a compound represented by one of structural formulas (I’), (I), (II), or (III) or a compound of Table A, Table B, or TablePOQ-00525- 171 -5, or a pharmaceutically acceptable salt thereof) is administered in combination with a ubiquitin specific protease 1 (USP1) inhibitor. Examples of USP1 inhibitors include KSQ-4279 (KSQ Therapeutics, Inc)., XL309 / ISM3091 (InSilico Medicine / Exelixis, Inc.), Debio 0432 (Debiopharm), VRTX531A (VRise Therapeutics, Inc.), SIM-05001 (Simcere Innovation, Inc.), LAE 120 (Laekna Inc.), HSK39755 (Haisco Pharmaceutical Group Co., Ltd.), and AIG-Onco3 (Aigen Sciences, Inc.).ExemplificationExample 1 — Synthesis of N-((2,6-dimethoxyphenyl)sulfonyl)-l-methyl-lH-indole-6-carboxamide (compound 17)EDCI, DMAPDCM, rt, 1 hTo a solution of 1 -methyl- lH-indole-6-carboxylic acid (30.0 mg, 171.3 pmol, 1 eq) and 2,6-dimethoxybenzenesulfonamide (44.6 mg, 205 pmol, 1.2 eq) in DCM (4 mL) was added DMAP (62.8 mg, 513 pmol, 3 eq) and EDCI (65.7 mg, 342 pmol, 2 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 um; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 22%-52% B over 15.0 min) and lyophilized to give compound 17 (21.6 mg, 33.7% yield) as a white solid.MS (ESI+) obsd. [(M+H)+]: 374.9'H NMR (400 MHz, METHANOL-d4) 8: 8.04 (s, 1H), 7.64 - 7.54 (m, 2H), 7.50 (t, J= 8.4 Hz, 1H), 7.40 (d, J= 3.2 Hz, 1H), 6.78 (d, J= 8.8 Hz, 2H), 6.52 (d, J= 3.2 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 6H).Example 2 — Synthesis of additional sulfonyl carboxamide compoundsPOQ-00525- 172 -The following compounds were prepared from the appropriate reagents according to the method described in Example 1.Compound # Structure Analytical dataMS (ESI+) obsd. [(M+H)+]: 373.0'H NMR (400 MHz, MeOD-4) d: = ^O O O 8.50 (d, J= 8.4 Hz, 1H), 8.28 (d, J= 8.4 Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 8.04 15(d, J= 8.4 Hz, 1H), 7.90 (t, J= 7.6 Hz, o zi1H), 7.80 - 7.70 (m, 1H), 7.52 (t, J= 8.4 ow=zHz, 1H), 6.78 (d, J= 8.4 Hz, 2H), 3.86 O—(s, 6H)MS (ESI+) obsd. [(M+H)+]: 399.01H NMR (400 MHz, MeOD-4) d: 8.48 (d, J= 8.8 Hz, 1H), 8.28 (d, J= 8.8 Hz, 16 1H), 8.08-8.06 (m, 2H), 8.02 (d, J=7.6 Hz, 1H), 7.92-7.88 (m, 1H), 7.78 - 7.66 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 1.38 (s, 9H)POQ-00525- 173 -MS (ESI+) obsd. [(M+H) +]: 418.1 'H NMR (400 MHz, CDCl3) 8: 9.16 - 9.10 (m, 1H), 7.51 (s, 1H), 7.49 - 7.47 39(m, 1H), 7.44 (d, J= 4.4 Hz, 4H), 7.41 - 7.37 (m, 1H), 6.67 (d, J= 8.8 Hz, 2H), 3.97 (s, 6H), 2.28 (s, 3H).MS (ESI+) obsd. [(M+H)+]: 400.11H NMR (400 MHz, DMSO-6) d: 12.14 - 11.96 (m, 1H), 9.18 - 9.12 (m, 1H), 8.70 - 8.60 (m, 2H), 8.22 (d, J= 428.8 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.90 (d, J= 2.4 Hz, 1H), 7.76 - 7.68 (m, 1H), 7.16 (d, J= 8.8 Hz, 1H), 3.82 (s, 3H), 1.30 (s, 9H).POQ-00525- 174 -MS (ESI+) obsd. [(M+H)+]: 479.1 'H NMR (400 MHz, MeOD-4) d: 8.58 l 0 O (d, J= 8.4 Hz, 1H), 8.27 (dd, J= 1.2,7.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 498.09 - 8.03 (m, 2H), 7.71 (dd, J= 2.4, 8.8 Hz, 1H), 7.65 (t, J= 8.0 Hz, 1H), 7.10 (d, J= 8.8 Hz, 1H), 3.90 (s, 3H), 2.04 (s, 1H), 1.37 (s, 9H)MS (ESI+) obsd. [(M+H)+]: 417.0 'H NMR (400 MHz, DMSO-6) d: 11.85 (s, 1H), 8.69 (d, J= 8.4 Hz, 1H), 50 8.08 (d, J= 8.8 Hz, 1H), 7.99 - 7.94 (m,1H), 7.90 (d, J= 2.4 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.75-7.72 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 1.31 (s, 9H).POQ-00525- 175 - MS (ESI+) obsd. [(M+H)+]: 413.1 'H NMR (400 MHz, DMSO-d6) δ: i C) O 11.76 (s, 1H), 8.56 (d, J= 8.4 Hz, 1H),8.01 (d, J= 8.4 Hz, 1H), 7.96 - 7.88 (m, 532H), 7.78 (d, J= 7.2 Hz, 1H), 7.74-7.71 (m, 1H), 7.70 - 7.64 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 2.90 (s, 3H), 1.31 (s, 9H).MS (ESI+) obsd. [(M+H) +]: 422.0 'H NMR (400 MHz, CDCl3) d: 9.07 (s, f ]0 01H), 7.48 - 7.42 (m, 2H), 6.66 (d, J = 56 Uso_ZJ ' A5---U 8.4 Hz, 2H), 6.47 (d, J = 3.2 Hz, 1H),6.11 (d, J= 2.4 Hz, 1H), 3.95 (s, 6H), 2.36 (s, 3H), 2.31 (s, 3H)POQ-00525- 176 -MS (ESI+) obsd. [(M+H)+]: 399.0 'H NMR (400 MHz, MeOD-4) d: 9.36 (s, 1H), 8.54 (s, 1H), 8.30 - 8.17 (m, 621H), 8.09 (s, 2H), 7.96 - 7.79 (m, 2H), 7.70 (d, J= 6.8 Hz, 1H), 7.09 (d, J= 8.0 Hz, 1H), 3.86 (s, 3H), 1.37 (s, 9H)MS (ESI+) obsd. [(M+H)+]: 399.1 'H NMR (400 MHz, DMSO-6) d: 12.87 (s, 1H), 9.21 (d, J= 2.0 Hz, 1H), 63 8.97 (s, 1H), 8.16 - 8.04 (m, 2H), 7.96 - 7.88 (m, 2H), 7.77 - 7.65 (m, 2H), 7.17 (d, J= 8.8 Hz, 1H), 3.84 (s, 3H), 1.32 (s, 9H)POQ-00525- 177 -MS (ESI+) obsd. [(M+H)+]: 417.1 'H NMR (400 MHz, DMSO-d6) δ: l o ^ o 12.06 (d, J = 2.4 Hz, 1H), 8.70 (d, J =8.8 Hz, 1H), 8.15 (d, J= 8.8 Hz, 1H), 678.08 (d, J= 8.8 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.91 (d,.7= 2,4 Hz, 1H), 7.74-7.71 (m, 1H), 7.67-7.62 (m, 1H), 7.17 (d, J= 8.8 Hz, 1H), 3.82 (s, 3H), 1.31 (s, 9H).MS (ESI+) obsd. [(M+H)+]: 433.1 'H NMR (400 MHz, DMSO-d6) δ: 12.10 (s, 1H), 8.76 (d, J= 8.8 Hz, 1H), 68 8.28 (d, <7= 8.4 Hz, 1H), 8.14 (d, J= 8.8Hz, 1H), 8.00 - 7.96 (m, 1H), 7.95 - 7.89 (m, 2H), 7.73-7.71 (m, 1H), 7.16 (d, J= 8.8 Hz, 1H), 3.81 (s, 3H), 1.31 (s, 9H).POQ-00525- 178 -MS (ESI+) obsd. [(M+H)+]: 433.0 'H NMR (400 MHz, MeOD-4) d: 8.38 n ° °- 8.33 (m, 2H), 8.18 (s, 1H), 8.08 (d, J= 70 2.4 Hz, 1H), 7.99 (dt, J = 1.2, 7.6 Hz,1H), 7.93 - 7.85 (m, 1H), 7.71 (dd, J = 2.4, 8.8 Hz, 1H), 7.11 (d, J= 8.8 Hz, 1H), 3.87 (s, 3H), 1.38 (s, 9H)MS (ESI+) obsd. [(M+H)+]: 413.21H NMR (400 MHz, CDCl3) d: 11.11 - 10.81 (m, 1H), 8.22 - 8.14 (m, 2H), 8.10 72 - 7.99 (m, 2H), 7.83 (t, J= 7.6 Hz, 1H),7.76 - 7.68 (m, 1H), 7.59 (d, J= 8.0 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 3.87 (s, 3H), 2.76 (s, 3H), 1.37 (s, 9H)18 —o °x_ / ° o MS (ESI+) obsd. [(M+H)+]: 401.2 'H NMR (400 MHz, DMSO-d6) 8: 12.20 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), - 5 7.66 (d, J= 8.0 Hz, 1H), 7.60 - 7.48 (m,3H), 7.12 (d, J = 9.2 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 1.30 (s, 9H).POQ-00525- 179 -11 MS (ESI+) obsd. [(M+H)+]: 376.0'H NMR (400 MHz, DMSO-d6) δ: 11.42 (s, 1H), 8.14 (d, J= 8.0 Hz, 1H), 7.84 (d, J= 3.6 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.52 (t, J= 8.4 Hz, 1H), 6.78 (d, J= 8.4 Hz, 2H), 6.62 (d, J= 3.4 Hz, 1H), 4.00 (s, 3H), 3.76 (s, 6H).12 MS (ESI+) obsd. [(M+H)+]: 402.1'H NMR (400 MHz, DMSO-d6) δ: 11.75 (s, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.88 (d, J= 2.4 Hz, 1H), 7.82 (d, J= 2.8 ^ °= ~~ Hz, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.14XO ZT C ZI> / ) \) z \ / \'O OW= (d, J= 8.8 Hz, 1H), 6.60 (d, J= 3.6 Hz, o 1H), 4.00 (s, 3H), 3.80 (s, 3H), 1.30 (s, / 9H).Additionally, the following compounds were prepared from the appropriate reagents according to the method described in Example 1: 37, 45, 46, 66, 69, 82, 104, and 105. The following compounds can be prepared from the appropriate reagents according to the method described in Example 1: 156-164.Example 3 — Synthesis of 4-((lH-pyrazol-l-yl)methyl)-3-methoxy-N-((2-propylpiperidin-l-yl)sulfonyl)benzamide (compound 128)Compound 2418 can been synthesized according to the following synthetic scheme.° NH2ci o 'bPOQ-00525- 180 -Example 4 — Synthesis of additional sulfonyl carboxamide compoundsThe following compounds were prepared from the appropriate reagents according to the synthetic route shown in Example 3.Compound # Structure Analytical dataMS (ESI+) obsd. [(M+H)+]: 383.01H NMR (400 MHz, CDCl3) 8: 8.36 (s, 1H), 7.86 (d, J= 1.6 Hz, 1H), 7.62 (d, J= 1.6 Hz, 1H), 7.58X-ZO H 1 T1 (dd, J= 1.6, 8.0 Hz, 1H), 7.52N (d, J= 2.4 Hz, 1H), 6.94 (d, J= 8.0 17 Hz, 1H), 6.36 (t, J= 2.4 Hz, 1H),5.50 (s, 2H), 3.44 (t, J= 1.2 Hz, 4H), 1.71 - 1.65 (m, 6H).MS (ESI+) obsd. [(M+H)+]: 379.01H NMR (400 MHz, CDCl3) d: 8.41 (s, 1H), 7.57 (d, J= 1.6 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.40 (s, 2x— °H1 1 1H), 7.21 (dd, J= 1.6, 7.6 Hz, 1H),N 6.95 (d, J= 8.0 Hz, 1H), 6.31 (t, J= 17 2.0 Hz, 1H), 5.38 (s, 2H), 3.93 (s,3H), 3.45 (t, J= 1.6 Hz, 4H), 1.71 - 1.66 (m, 6H).MS (ESI+) obsd. [(M+H)+]: 378.0 o o1H NMR (400 MHz, CDCl3) 8: 8.39 < o (s, 1H), 7.57 (d, J= 2.0 Hz, 1H), ' —...

Claims

POQ-00525- 382 -CLAIMSWhat is claimed is:

1. A compound or a pharmaceutically acceptable salt thereof represented by structural formula (I’):wherein:W is selected from the following moieties:, and 5-membered heteroaryl;A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further optionally substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;i I is a single or double bond;each x1, x2, x3, and x4is independently selected from N and CH, wherein 1, 2, or 0 of x1, x2, x3, and x4is N;Z is selected from O and NR7;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and the following moiety:M is selected from a bond, C1-3 alkylene, and NRM,POQ-00525- 383 -RMis H, C1-6alkyl, or C(=O)O(C1-6alkyl);each t, u, and v, is independently 1 or 2;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, Ci-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, C1-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-3 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereinPOQ-00525- 384 -each R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21R22R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C(=O)R28, C1-6 alkyl, Ci-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl optionally substituted with 1-3 C1-3 alkyl,wherein R28is Ci-6 alkoxy or 4- to 12-membered heterocyclyl optionally substituted with C(=O)O(C1-6alkyl).

2. The compound of claim 1, wherein the compound is represented by structural formula (I’) or a pharmaceutically acceptable salt thereof:wherein:W is selected from the following moieties:R5X2X3\', and 5-membered heteroaryl;POQ-00525- 385 -A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;:l is a single or double bond;each x1, x2, x3, and x4is independently selected from CH and N, wherein 0, 1, or 2 of x1, x2, x3, and x4is N;Z is selected from O and NR7;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, C1-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,POQ-00525- 386 -wherein each C1-6 alkyl, C1-6 alkylene, Ci-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12- membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl optionally substituted with 1-3 C1-3 alkyl,3. The compound of claim 2, wherein the compound is represented by structural formula (I) or a pharmaceutically acceptable salt thereof:wherein:POQ-00525- 387 -W is selected from the following moieties:and 5-membered heteroaryl;A is selected from phenyl and 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is not further substituted;B is selected from 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, C6-12 aryl, and C4-12 cycloalkyl, with an understanding that the atoms shared by A and B are included in the definitions of each of A and B;: I is a single or double bond;each x1, x2, x3, and x4is independently selected from CH and N, wherein 0, 1, or 2 of x1, x2, x3, and x4is N;Z is selected from O and NR7;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R5and R5ais selected from H, halogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C3-12 cycloalkoxy, and C3-12 cycloalkyl;R5bis selected from 5- to 12-membered heteroaryl and QR6;Q is selected from a bond and C1-6 alkylene;R6is selected from OH, C1-6 alkoxy, C3-12 cycloalkyl, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), NR8R9, and 4- to 10-membered saturated heterocyclyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;POQ-00525- 388 -R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;R50is selected from H, halogen, unsubstituted C1-3 alkyl, and QaRa, provided that if R50is QaRathen B is not 5- to 12-membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C4-12 cycloalkyl, C3-12 cycloalkoxy, C6-12 aryl, phenyl, 4- to 12-membered heterocyclyl, 4- to 10-membered saturated heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and 5- to 12- membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22 R2!*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.POQ-00525- 389 -4. The compound of any one of claims1-3, wherein Z is NR7.

5. The compound of claim 4, wherein R7is H.

6. The compound of claim 4, wherein R7is C1-6 alkyl.

7. The compound of any one of claims 1-3, wherein the compound is represented by structural formula (la) or a pharmaceutically acceptable salt thereof:

8. The compound of claim 7, wherein the compound is represented by structural formula (lb) or a pharmaceutically acceptable salt thereof:

9. The compound of claim 8, wherein the compound is represented by structural formula (Ic) or a pharmaceutically acceptable salt thereof:wherein each U1and U2is independently C or N.

10. The compound of claim 9, wherein the compound is represented by structural formula (Ic-1) or a pharmaceutically acceptable salt thereof:POQ-00525- 390 -11. The compound of claim 9, wherein A is 6-membered heteroaryl.

12. The compound of claim 11, wherein the compound is represented by structural formula (Id) or (le) or a pharmaceutically acceptable salt thereof:wherein each U3and U4is independently C or N.

13. The compound of claim 12, wherein the compound is represented by structural formula (Id-1), (Id-2), (Ie-1), or (Ie-2) or a pharmaceutically acceptable salt thereof:RR1 00R2R3D4(Id-2);POQ-00525- 391 -14. The compound of any one of claims 8-13, wherein B is 5- to 12-membered heteroaryl.

15. The compound of claim 14, wherein B is 5- to 6-membered heteroaryl.

16. The compound of claim 15, wherein B is 5-membered heteroaryl.

17. The compound of claim 7, wherein B is C6-12 aryl.

18. The compound of any one of claims 8-13, wherein B is phenyl.

19. The compound of any one of claims 8-13, wherein B is 4- to 12-membered heterocyclyl.

20. The compound of claim 19, wherein B is 5- to 6-membered heterocyclyl.

21. The compound of any one of claims 8-13, wherein B is C4-12 cycloalkyl.

22. The compound of claim 21, wherein B is C5-6 cycloalkyl.POQ-00525POQ-00525- 393 - R2R2R2j< Kl R2R3R2R2R2R2 R2POQ-00525- 394 -24. The compound of any one of claims 8-23, wherein R2is 5- to 12-membered heteroaryl.

25. The compound of claim 24, wherein R2is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.S26. The compound of claim 24, wherein R2is selected from the following moieties:5,wherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.S28. The compound of claim 27, wherein R2isPOQ-00525- 395 -29. The compound of claim 27, wherein R2is30. The compound of claim 27, wherein R2is31. The compound of claim 27, wherein R2isThe compound of claim 27, wherein R2is33. The compound of claim 27, wherein R2is34. The compound of any one of claims 8-23, wherein R2is halogen.

35. The compound of any one of claims 8-23, wherein R2is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12- membered heterocyclyl, and 5- to 12-membered heteroaryl.

36. The compound of claim 35, wherein R2is methyl.

37. The compound of claim 35, wherein R2is selected from CH2F, CHF2, and CF3.POQ-00525- 396 -38. The compound of any one of claims 8-23, wherein R2is C3-12 cycloalkyl.

39. The compound of claim 38, wherein R2is cyclopropyl.

40. The compound of any one of claims 8-23, wherein R2is 4- to 12-membered heterocyclyl.

41. The compound of claim 40, wherein R2is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

42. The compound of any one of claims 8-23, wherein R2is H.

43. The compound of any one of claims 8-42, wherein R3is C1-3 alkyl.

44. The compound of claim 43, wherein R3is methyl.

45. The compound of any one of claims 8-42, wherein R3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form a C3-12 cycloalkyl.

46. The compound of claim 8, wherein R50is H.

47. The compound of claim 8, wherein the compound is represented by structural formula (Ib-2) or a pharmaceutically acceptable salt thereof:POQ-00525- 397 -wherein each U5and U6is independently C or N.

48. The compound of claim 47, wherein Qais C1-6 alkylene.

49. The compound of claim 48, wherein Qais CH2.

50. The compound of claim 47, wherein Qais O.

51. The compound of any one of claims claim 46-49, wherein Rais 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

52. The compound of any one of claims claim 47-50, wherein Rais selected from thewherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13),POQ-00525- 398 -NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

53. The compound of claim 52, wherein Rais selected from54. The compound of claim 53, wherein Rais55. The compound of claim 53, wherein Rais56. The compound of claim 53, wherein Rais57. The compound of claim 53, wherein Rais58. The compound of claim 53, wherein Rais59. The compound of claim 53, wherein Rais60. The compound of any one of claims 8-23 and 46-59, wherein R2, R3, and R4are each H.POQ-00525- 399 -61. The compound of any one of claims 24-46, wherein the compound is represented by structural formula (If) or (Ig) or a pharmaceutically acceptable salt thereof:R2O O62. The compound of claim 7, wherein the compound is represented by structural formula (Ih) or a pharmaceutically acceptable salt thereof:R5X263. The compound of claim 62, wherein the compound is represented by structural formula (Ih-1) or a pharmaceutically acceptable salt thereof:

64. The compound of claim 63, wherein the compound is represented by structural formula (Ih-2) or a pharmaceutically acceptable salt thereof:POQ-00525- 400 -65. The compound of any one of claims 62-64, wherein R5is C1-3 alkoxy, wherein the C1-3 alkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

66. The compound of claim 65, wherein R5is methoxy.

67. The compound of claim 65, wherein R5is selected from OCD3 and OCHF2.

68. The compound of any one of claims 62-64, wherein R5is C3-12 cycloalkoxy.

69. The compound of claim 68, wherein R5is cyclopropoxy.

70. The compound of any one of claims 62-64, wherein R5is selected from halogen and C3-12 cycloalkyl.

71. The compound of any one of claims 62-64, wherein R5is C1-3 haloalkyl.

72. The compound of claim 71, wherein R5is selected from CH2F, CHF2, and CF3.

73. The compound of any one of claims 63-72, wherein Q is C2-3 alkylene, wherein the C2-3 alkylene is optionally substituted with 1 to 3 substituents independently selected fromPOQ-00525- 401 -deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

74. The compound of any one of claims 63-72, wherein Q is a bond.

75. The compound of any one of claims 63-74, wherein R6is C1-3 alkoxy.

76. The compound of claim 75, wherein R6is methoxy.

77. The compound of claim 75, wherein R6is selected from OCD3 and OCHF2.

78. The compound of any one of claims 63-74, wherein R6is C3-12 cycloalkoxy.

79. The compound of claim 78, wherein R6is cyclopropoxy.

80. The compound of any one of claims 63-74, wherein R6is C1-3 haloalkyl.

81. The compound claim 80, wherein R6is selected from CH2F, CHF2, and CF3.

82. The compound of any one of claims 63-74, wherein R6is 4- to 10-membered saturated heterocyclyl.

83. The compound of claim 82, wherein R6is 5- to 6-membered saturated heterocyclyl, wherein the 5- to 6-membered saturated heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6POQ-00525- 402 -alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

84. The compound of any one of claims 63-72, wherein Q is C2-3 alkylene and R6is methoxy.

85. The compound of claim 64, wherein the compound is represented by structural formula (Ii) or a pharmaceutically acceptable salt thereof:wherein each Rqland Rq2is independently H or C1-3 alkyl.

86. The compound of claim 85, wherein Rqland Rq2is each H.

87. The compound of claim 85, wherein Rqlis methyl.

88. The compound of claim 85 or 87, wherein Rq2is methyl.

89. The compound of claim 62, wherein the compound is represented by structural formula (Ij) or a pharmaceutically acceptable salt thereof:Rwherein R5bis 5- to 12-membered heteroaryl.POQ-00525- 403 -90. The compound of claim 89, wherein R5is halogen.

91. The compound of claim 90, wherein R5is F.

92. The compound of claim 89, wherein R5is C1-3 alkoxy, wherein the C1-3 alkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12- membered heterocyclyl, and 5- to 12-membered heteroaryl.

93. The compound of claim 92, wherein R5is methoxy.

94. The compound of claim 92, wherein R5is selected from OCD3 and OCHF2.

95. The compound of claim 89, wherein R5is C3-12 cycloalkyl.

96. The compound of claim 95, wherein R5is cyclopropyl.

97. The compound of claim 89, wherein R5is C1-3 haloalkyl.

98. The compound of claim 97, wherein R5is selected from CH2F, CHF2, and CF3.

99. The compound of claim 89, wherein R5is unsubstituted C1-3 alkyl.

100. The compound of claim 99, wherein R5is methyl.

101. The compound of any one of claims 89-100, wherein R5ais H.POQ-00525- 404 -102. The compound of any one of claims 89-101, wherein R5bis 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

103. The compound of any one of claims 89-101, wherein R5bis selected from the followingwherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

104. The compound of any one of claims 64-103, wherein x1is CH.

105. The compound of any one of claims 64-103, wherein x1is N.

106. The compound of claim 7, wherein W is 5-membered heteroaryl.POQ-00525- 405 -107. The compound of claim 106, wherein W is selected from the following moieties:wherein each of the listed moieties is optionally substituted with 1 to 3, as valence permits, substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.S108. The compound of claim 107, wherein W is109. The compound of claim 107, wherein the compound is represented by structural formula (Ik) or a pharmaceutically acceptable salt thereof:R1\^°? srL*s(Ik),whereinL is selected from a bond, C1-3 alkylene, or NR30;R30is H or C1-6 alkyl;RLis C6-12 aryl or 5- to 12-membered heteroaryl; andRsis C1-6 alkyl.

110. The compound of claim 109, wherein L is a bond.POQ-00525- 406 -111. The compound of claim 109 or 110, wherein RLis 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally independently substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

112. The compound of any one of claims 1-111, wherein R1is C6-12 aryl.

113. The compound of claim 112, wherein R1is phenyl.

114. The compound of claim 113, wherein R1is phenyl substituted with 2 substituents independently selected from C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein each C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl is optionally independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

115. The compound of claim 114, wherein R1is selected from the following moieties:POQ-00525- 407 -wherein each R31and R32is independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

116. The compound of claim 115, wherein R1is selected from the following moieties:wherein each R31and R32is independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

117. The compound of claim 115 or 116, wherein R31is methoxy.

118. The compound of claim 115, wherein R1is selected from the following moieties:POQ-00525- 408 -119. The compound of any one of claims 1-111, wherein R1is 5- to 12-membered heteroaryl.

120. The compound of claim 119, wherein R1is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OMe121. The compound of claim 120, wherein R1is MeO122. The compound of any one of claims 1-111, wherein R1is C3-12 cycloalkyl.

123. The compound of claim 122, wherein R1is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12- membered heterocyclyl, and 5- to 12-membered heteroaryl.

124. The compound of claim 123, wherein R1is unsubstituted C5-6 cycloalkyl.

125. The compound of claim 123, wherein R1is unsubstituted cyclohexyl.POQ-00525- 409 -126. The compound of any one of claims 1-111, wherein R1is 4- to 12-membered heterocyclyl.

127. The compound of claim 126, wherein R1is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

128. The compound of claim 127, wherein R1is unsubstituted 4- to 6-membered heterocyclyl.

129. The compound of claim 126, wherein R1is saturated 4- to 6-membered heterocyclyl, wherein the saturated 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

130. The compound of claim 129, wherein R1is unsubstituted saturated 4- to 6-membered heterocyclyl.

131. The compound of any one of claims 1-111, wherein R1is bicyclic fused or spirocyclic 7 - to 12-membered heterocyclyl, wherein the bicyclic fused or spirocyclic 7- to 12- membered heterocyclyl is optionally independently substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6POQ-00525- 410 -alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

132. The compound of claim 131, wherein R1is bicyclic fused 7- to 12-membered heterocyclyl.

133. The compound of claim 131, wherein R1is saturated bicyclic fused 7- to 12-membered heterocyclyl.

134. The compound of claim 131, wherein R1is bicyclic spirocyclic 7- to 12-membered heterocyclyl.

135. The compound of any one of claims 1-111, wherein R1is represented by the followingmoiety:

136. The compound of claim 135, wherein t is 1.

137. The compound of claims 135 or 136, wherein u is 2, v is 2, and M is NH.

138. The compound of claims 135 or 136, wherein u is 1, v is 1, and M is a bond.

139. The compound of any one of claims 1-3, wherein the compound is selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

140. The compound of any one of claims 1-3, wherein the compound is selected from the compounds of Table 2 or a pharmaceutically acceptable salt thereof.POQ-00525- 411 -141. A compound or a pharmaceutically acceptable salt thereof represented by structural formula (II):wherein:W* is selected from C6-12 aryl and 5- to 12-membered heteroaryl;Z* is O or NR7*;R1* is selected from C3-12 cycloalkyl and 4- to 12-membered heterocyclyl, whereinthe 4- to 12-membered heterocyclyl comprises at least one nitrogen atom and the nitrogen atom is attached to the sulfur atom in structural formula (II); andR7* is selected from H and C1-6 alkyl;wherein each C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;each R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, C6-12 aryl(C1-3 alkyl)2, 4- to 12- membered heterocyclyl, 5- to 12-membered heteroaryl, and C1-6 haloalkyl, or one or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6POQ-00525- 412 -alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

142. The compound of claim 141, wherein the compound is represented by structural formula (II) or a pharmaceutically acceptable salt thereof:wherein:W* is selected from C6-12 aryl and 5- to 12-membered heteroaryl;Z* is O or NR7*;R1* is selected from C3-12 cycloalkyl and 4- to 12-membered heterocyclyl, whereinthe 4- to 12-membered heterocyclyl comprises at least one nitrogen atom and the nitrogen atom is attached to the sulfur atom in structural formula (II); andR7* is selected from H and C1-6 alkyl;wherein each C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;each R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20a, R20b, R21, R22R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, C6-12 aryl(C1-3 alkyl)2, 4- to 12- membered heterocyclyl, 5- to 12-membered heteroaryl, and C1-6 haloalkyl, or one or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andPOQ-00525- 413 -when each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, Ci- 6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

143. The compound of claim 141 or 142, wherein Z* is NR7*.

144. The compound of claim 143, wherein R7* is H.

145. The compound of claim 143, wherein R7* is C1-6 alkyl.

146. The compound of claim 141 or 142, wherein the compound is represented by structural formula (Ila) or a pharmaceutically acceptable salt thereof:

147. The compound of any one of claims 141-146, wherein W* is C6-12 aryl.

148. The compound of claim 147, wherein W* is phenyl, wherein the phenyl is substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

149. The compound of claim 148, wherein the compound is represented by structural formula (lib) or a pharmaceutically acceptable salt thereof:POQ-00525- 414 -0 0whereinR2* is Ci-6 alkoxy, andR3* is Ci-3 alkyl, wherein the C1-3 alkyl is substituted with 5- to 12-membered heteroaryl.

150. The compound of claim 149, wherein the compound is represented by structural formula (IIb-1) or a pharmaceutically acceptable salt thereof:

151. The compound of any one of claims 141-146, wherein W* is 5- to 12-membered heteroaryl.

152. The compound of claim 151, wherein W* is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

153. The compound of claim 152, wherein the compound is represented by structural formula (lie) or a pharmaceutically acceptable salt thereof:POQ-00525- 415 -pl- O oRX A N R2‘K(lie),whereinR2* is C1-6 alkoxy, andR3* is C1-3 alkyl, wherein the C1-3 alkyl is substituted with 5- to 12-membered heteroaryl.

154. The compound of claim 153, wherein the compound is represented by structural formula (IIc-1) or a pharmaceutically acceptable salt thereof:

155. The compound of any one of claims 141-154, wherein R1* is C3-12 cycloalkyl.

156. The compound of claim 155, wherein R1* is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

157. The compound of claim 156, wherein R1* is unsubstituted C5-6 cycloalkyl.

158. The compound of claim 157, wherein the compound is represented by structural formula (lid) or a pharmaceutically acceptable salt thereof:POQ-00525159. The compound of any one of claims 141-154, wherein R1* is 4- to 12-membered heterocyclyl.

160. The compound of claim 159, wherein R1* is 4- to 7-membered heterocyclyl, wherein: the 4- to 7-membered heterocyclyl comprises at least one nitrogen atom;the nitrogen atom is attached to the sulfur atom in structural formula (II); andthe 4- to 7-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

161. The compound of claim 160, wherein R1* is saturated 4- to 7-membered heterocyclyl.

162. The compound of claim 155, wherein R1* is selected from the following moieties:wherein each Rband Rcis independently selected from C1-6 alkyl and C6-12 aryl, orRband Rctogether with the carbon atom to which they are attached form a C3-12 cycloalkyl.POQ-00525- 417 -163. The compound of claim 162, wherein R1* is164. The compound of any one of claims 141-154, wherein R1* is bicyclic fused 7- to 12-membered heterocyclyl, wherein:the bicyclic fused 7- to 12-membered heterocyclyl comprises at least one nitrogen atom; the nitrogen atom is attached to the sulfur atom in structural formula (II); andthe bicyclic fused 7- to 12-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b,C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

165. The compound of claim 164, wherein R1* is unsubstituted bicyclic fused 7- to 12-membered heterocyclyl.

166. The compound of claim 164, wherein R1* is saturated bicyclic fused 7- to 12-membered heterocyclyl.

167. The compound of claim 164, wherein R1* is saturated unsubstituted bicyclic fused 7- to 12-membered heterocyclyl.

168. The compound of any one of claims 141-154, wherein R1* is selected from the following moieties:POQ-00525- 418 -wherein each of the listed moieties is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

169. The compound of claim 168, wherein R1* is170. The compound of claim 168, wherein R1* is171. The compound of claim 141, wherein the compound is selected from the compounds of Table 3 or a pharmaceutically acceptable salt thereof.

172. The compound of claim 141, wherein the compound is selected from the compounds of Table 4 or a pharmaceutically acceptable salt thereof.

173. A compound or a pharmaceutically acceptable salt thereof represented by structural formula (III):POQ-00525- 419 -(III),whereinB is 5- to 12-membered heteroaryl;each U5and U6is independently C or N, provided that if B is a 5-membered heteroaryl, then at least one of U5and U6is N;each U7and U8is independently CH or N;il is a single or double bond;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C6-12 aryl, phenyl, 4- to 12- membered heterocyclyl, 5-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27,POQ-00525- 420 -C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14* R15R15*, R16, R17, R16*, R17*, R18R18a, R19, R20, R20a, R20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andwhen one or more of the 1 to 5 substituents comprises C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of the one or more substituents is further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

174. The compound of claim 173, wherein the compound is represented by structural formula (Ill) or a pharmaceutically acceptable salt thereof:(III),whereinB is 5- to 12-membered heteroaryl;each U5and U6is independently C or N, provided that if B is a 5-membered heteroaryl, then at least one of U5and U6is N;each U7and U8is independently CH or N;POQ-00525- 421 -:l is a single or double bond;R1is selected from C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;each R2, R3, and R4is independently selected from H, halogen, OH, CN, NR10R10a, C1-6 alkyl, C1-6 alkoxy, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, orR3and R4are attached to the same carbon atom, and R3and R4together with the carbon atom to which they are attached form C3-12 cycloalkyl;each R7, R8, R10, and R10ais independently selected from H and C1-6 alkyl;R9is selected from C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12- membered heteroaryl;Qais selected from C1-6 alkylene and O; andRais 5- to 12-membered heteroaryl,wherein each C1-6 alkyl, C1-6 alkylene, C1-6 alkoxy, C3-12 cycloalkyl, C6-12 aryl, phenyl, 4- to 12- membered heterocyclyl, 5-membered heteroaryl, and 5- to 12-membered heteroaryl, unless specified otherwise, is optionally substituted with 1 to 5 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, OC(=O)OR20b, C(=O)NR21R22, OC(=O)NR21*R22*, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;whereineach R11, R12, R13, R14R14*, R15, R15*, R16, R17, R16*, R17*, R18R18a, R19, R20R20aR20b, R21, R22, R21*, R22*, R23, R24, R25, R26, and R27is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, orone or more of the pairs of variables selected from R12and R13, R16and R17, R16* and R17*, R21and R22, R21* and R22*, and R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring, andPOQ-00525- 422 -when each of the 1 to 5 substituents is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, eachis further optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14*, SR15*, NR16*R17*, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

175. The compound of claim 173 or 174, wherein Qais C1-6 alkylene.

176. The compound of claim 175, wherein Qais CH2.

177. The compound of claim 173 or 174, wherein Qais O.

178. The compound of any one of claims claim 173-177, wherein Rais 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

179. The compound of any one of claims claim 173-177, wherein Rais selected from thewherein each of the listed moieties is optionally substituted with 1 to 3 substituents, as valence permits, independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17,POQ-00525- 423 -S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

180. The compound of claim 179, wherein Rais selected from181. The compound of claim 180, wherein Rais182. The compound of claim 180, wherein Rais183. The compound of claim 180, wherein Rais184.

185. The compound of any one of claims 173-184, wherein U5is N.

186. The compound of any one of claims 173-184, wherein U6is N.

187. The compound of any one of claims 173-186, wherein B is 6-membered heteroaryl, wherein the 6-membered heteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15,POQ-00525- 424 -NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

188. The compound of any one of claims 173-187, wherein R2, R3, and R4are each H.

189. The compound of any one of claims 173-188, wherein R1is phenyl substituted with 2 substituents independently selected from C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein each C1-3 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocyclyl is optionally independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

190. The compound of claim 189, wherein R1is selected from the following moieties:wherein each R31and R32is independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.POQ-00525- 425 -191. The compound of claim 190, wherein R1is selected from the following moieties:wherein each R31and R32is independently selected from C1-3 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl, and C3-6 cycloalkyl.

192. The compound of claim 190 or 191, wherein R31is methoxy.

193. The compound of claim 190, wherein R1is selected from the following moieties:

194. The compound of any one of claims 173-188, wherein R1is 5- to 12-membered heteroaryl.

195. The compound of claim 194, wherein R1is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12POQ-00525- 426 -cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.OMe196. The compound of claim 195, wherein R1is Me VO i197. The compound of any one of claims 173-188, wherein R1is C3-12 cycloalkyl.

198. The compound of claim 197, wherein R1is C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12- membered heterocyclyl, and 5- to 12-membered heteroaryl.

199. The compound of any one of claims 173-188, wherein R1is 4- to 12-membered heterocyclyl.

200. The compound of claim 199, wherein R1is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

201. The compound of claim 200, wherein R1is saturated 4- to 6-membered heterocyclyl, wherein the saturated 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22,POQ-00525- 427 -NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

202. The compound of any one of claims 173-188, wherein R1is bicyclic fused or spirocyclic 7- to 12-membered heterocyclyl, wherein the bicyclic fused or spirocyclic 7- to 12- membered heterocyclyl is optionally independently substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, NO2, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR11C(=O)N(R12)(R13), NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl.

203. The compound of claim 202, wherein R1is bicyclic fused 7- to 12-membered heterocyclyl.

204. The compound of claim 202, wherein R1is bicyclic spirocyclic 7- to 12-membered heterocyclyl.

205. The compound of claim 173, wherein the compound is selected from the compounds of Table 5 or a pharmaceutically acceptable salt thereof.

206. A compound selected from the compounds of Table A or a pharmaceutically acceptable salt thereof.

207. A compound selected from the compounds of Table B or a pharmaceutically acceptable salt thereof.

208. A pharmaceutical composition comprising a compound of any one of claims 1-207 and a pharmaceutically acceptable excipient.POQ-00525- 428 -209. A method of treating a disease or disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-207 or a pharmaceutical composition of claim 208, wherein the disease or disorder is selected from a cancer, a genetic disorder, an epigenetic disorder, a neurodegenerative disorder, a hematological disorder, and an inflammatory disorder.

210. The method of claim 209, wherein the disorder is cancer.

211. The method of claim 210, wherein the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, or drug resistant cancer.

212. The method of claim 209 or 210, wherein the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or a combination thereof.

213. The method of any one of claims 210-212, wherein the cancer is selected from leukemia, lymphoma, prostate cancer, lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma, ovarian cancer, cervical cancer, medulloblastoma, and gastric cancer.

214. The method of any one of claims 210-212, wherein the cancer is hematological cancer.

215. The method of claim 213, wherein the leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or B-cell acute lymphoblastic leukemia.

216. The method of claim 213, wherein the lymphoma is MYC-induced lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, or lymphoma.POQ-00525- 429 -217. The method of claim 213, wherein the breast cancer is estrogen receptor positive breast cancer.

218. The method of claim 213, wherein the lung cancer is non-small cell lung cancer.

219. The method of any one of claims 210-212, wherein the cancer is a MYST overexpressing cancer.

220. The method of any one of claims 210-212, wherein the cancer is a MYST copy number-amplified cancer.

221. The method of any one of claims 210-212, wherein the method further comprises administering a second agent to the subject.

222. The method of claim 221, wherein the second agent is selected from a selective estrogen receptors modulator, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, an antiandrogen, a glucocorticoid, a thyroid hormone, a selective estrogen receptor degrader, a cyclin-dependent kinase 4 inhibitor, cyclin-dependent kinase 6 inhibitor, cyclin-dependent kinase 4 / 6 inhibitor, and ubiquitin specific protease 1 inhibitor, HER2 inhibitor, or a combination thereof.

223. The method of claim 209, wherein the disorder is a genetic disorder.

224. The method of claim 223, wherein the genetic disorder is associated with dysregulation of histone acetylation.

225. The method of claim 223, wherein the genetic disorder is selected from genitopatellar syndrome and Say-Barber-Biesecker- Young-Simpson syndrome.

226. The method of claim 209, wherein the disorder is an epigenetic disorder.POQ-00525- 430 -227. The method of claim 226, wherein the epigenetic disorder is associated with dysregulation of histone acetylation.

228. The method of claim 209, wherein the disorder is a neurodegenerative disorder.

229. The method of claim 228, wherein the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Angelman syndrome, and Huntington’s disease.

230. The method of claim 209, wherein the disorder is a hematological disorder.

231. The method of claim 209, wherein the disorder is an inflammatory disorder.

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