PYRIDIN-2-ONE COMPOUNDS USEFUL AS SMARCA2 ANTAGONISTS

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

This application incorporates by reference a Computer Readable Form (CRF) of a Sequence Listing in ASCII text format submitted with this application, entitled “13015-025-228_ST25.txt”, was created on Jul. 22, 2019, and is 14 kilobytes in size.

FIELD OF DISCLOSURE

This disclosure generally relates to pyridine-2-one compounds and methods of using them in the treatment of a disorder, such as cancer or a SMARCA2-associated disorder, including as antagonists (e.g., inhibitors) of SMARCA2.

SUMMARY

In some aspects, the present disclosure features a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

X₁and X₂are each independently selected from —CH and N;

Y is selected from the group consisting of a bond, —NH, —C(O), C₁-C₆alkyl, —C(CH₃)₂—O—, and —CH₂—NH—CH₂—;

R₁is selected from the group consisting of H, halo, COOH, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, heterocycloalkyl, heteroaryl, and —(CH₂)_mR₄;

R₂is selected from the group consisting of H, halo, COOH, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, heterocycloalkyl, heteroaryl, —(CH₂)_mR₄, —NR₅R_5′, —S(O)_0-2R₅, —OR₅, —C(O)NH₂, —NO₂;

R₄and R_4′ are each independently selected from the group consisting of halo, hydroxyl, COOH, cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —NR₅R_5′;

each R₅is independently selected from the group consisting of H, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₁-C₆alkylcarbonyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —(CH₂)_mR_4′;

each R_5′ is independently selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkylcarbonyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, heterocycloalkyl, heteroaryl, and —(CH₂)_mR_4′;

each R₃is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, aminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅,

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

each R₆is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —NR₅R_5′;

R₇is selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₁-C₆alkylcarbonyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —(CH₂)_mR_4′;

R₈and R_9′ are each independently selected from the group consisting of H, halo, and C₁-C₃alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (IA):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

each R₅is independently selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₁-C₆alkylcarbonyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —(CH₂)_mR_4′;

each R₃is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, aminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅,

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some embodiments, for a compound Formula (IA) or a pharmaceutically acceptable salt thereof,

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (IB):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

R₇is selected from the group consisting of H and C₁-C₆alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted

In some embodiments, for a compound Formula (IB) or a pharmaceutically acceptable salt thereof,

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

R₇is selected from the group consisting of H and C₁-C₆alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted

In some aspects, the present disclosure features a compound of Formula (IC):

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or a pharmaceutically acceptable salt thereof, wherein

A is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some embodiments, for a compound Formula (IC) or a pharmaceutically acceptable salt thereof,

A is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (ID):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

each Q is independently selected from the group consisting of C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, and C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted;

provided that at least one R₃is QR₆, wherein Q is C₂-C₆alkynyl.

In some aspects, the present disclosure features a compound of Formula (IE)

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or a pharmaceutically acceptable salt thereof, wherein

A is a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some embodiments, one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof may be used in the treatment of a disorder, such as cancer or a SMARCA2-associated disorder.

In some embodiments, one or more of the compounds disclosed herein are antagonists (e.g., inhibitors) of SMARCA2. In some embodiments, one or more of the compounds disclosed herein inhibit SMARCA2 with an enzyme inhibition IC₅₀value of about 50 μM or less, 1 μM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, about 50 nM or less, or about 10 nM or less.

Also provided herein are pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and one or more compounds of Formula (I), (IA), (IB), (IC), (ID), or (E) or a pharmaceutically acceptable salt thereof, described herein.

Some aspects of this disclosure provide methods of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (E) or a pharmaceutically acceptable salt thereof) to the subject or a cell of the subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of the disclosure relate to a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (E) or a pharmaceutically acceptable salt thereof) for use in the treatment of cancer in a cell or subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of the disclosure relate to a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) for use as a medicament for the treatment of cancer in a cell or subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of the disclosure relate to the use of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of cancer in a cell or subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide methods of modulating (e.g., inhibiting) an activity of SMARCA2, comprising contacting SMARCA2 enzyme with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof). In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, and the method comprises contacting the cell with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, wherein the cell comprises a biomarker of sensitivity to the SMARCA2 antagonist (e.g. a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) for use in inhibiting an activity of SMARCA2, wherein the SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) is contacted with a SMARCA2 enzyme. In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, wherein the cell comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) for use as a medicament for inhibiting an activity of SMARCA2, wherein the medicament is contacted with a SMARCA2 enzyme. In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, wherein the cell comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide the use of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting an activity of SMARCA2, wherein the medicament is to be contacted with a SMARCA2 enzyme. In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, wherein the cell comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof), wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) for use in treating cancer in a subject in need thereof, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) for use as a medicament for treating cancer in a subject in need thereof, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

Some aspects of this disclosure provide the use of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

In some embodiments, the biomarker is a decreased activity or function of SMARCA4. In certain embodiments, the biomarker is loss of function of SMARCA4.

Some aspects of this disclosure provide methods of identifying a subject sensitive to treatment with a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof), comprising detecting a decreased activity or function of SMARCA4 compared to a control level of the activity or the function of SMARCA4 in the subject and administering a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) to the subject, wherein the subject has a cancer and wherein an improvement in a sign or symptom of the cancer indicates a sensitivity of the subject or of a cancer cell of the subject for SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

In some embodiments, the control level is the level of activity of SMARCA4 in a subject that does not have cancer.

In some embodiments, the subject is a participant in a clinical trial. In some embodiments, a criterion for participation of a subject in the clinical trial is a decreased activity or function of SMARCA4, or loss of function of SMARCA4, in said subject or a cell of said subject.

In some embodiments, the present disclosure features a method comprising inhibiting a SMARCA2 activity in a cell exhibiting loss of function of SMARCA4, comprising contacting the cell with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof).

In certain embodiments of the methods disclosed herein, the cell is in a subject, and the method comprises administering a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) to the subject.

In some aspects, this present disclosure features methods of treating cancer, comprising inhibiting a SMARCA2 activity in a subject in need thereof, wherein the subject has a cancer characterized by loss of function of SMARCA4.

In some aspects, this present disclosure features methods of treating cancer, comprising inhibiting a SMARCA2 activity, e.g., a SMARCA2 helicase activity or a SMARCA2 ATPase activity, in a subject in need thereof, wherein the subject has a cancer characterized by loss of function of SMARCA4.

Some aspects of this disclosure provide methods comprising modulating (e.g., inhibiting) a SMARCA2 activity in a cell or subject. In some embodiments this disclosure provides methods comprising modulating (e.g., inhibiting) a SMARCA2 activity in a cell or subject Some aspects of this disclosure provide methods comprising modulating a SMARCA2 activity in a cell exhibiting a decreased activity or function of SMARCA4. In some embodiments, the cell is in vivo, ex vivo, in vitro, or in situ. In some embodiments, the cell is in a subject, and the method comprises administering a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) to the subject. In some embodiments, the cell is ex vivo or in vitro, and wherein the cell is isolated or derived from a subject that has a tumor. In some embodiments, the tumor is malignant. In some embodiments, the tumor is metastatic.

Some aspects of this disclosure provide methods of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) to the subject or a cell of the subject, wherein said subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.

Some aspects of this disclosure provide a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) for use in treating cancer in a subject in need thereof, wherein said subject or a cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof as a medicament for treating cancer in a subject in need thereof.

Some aspects of this disclosure provide a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) as a medicament for treating cancer in a subject in need thereof, wherein said subject or a cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide the use of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

Some aspects of this disclosure provide the use of a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein said subject or a cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

In some embodiments, the control level is the level of activity or function of SMARCA4 in a subject that does not have cancer. In some embodiments, the method comprises administering the SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) to the cell or the subject based on the decreased activity or function of SMARCA4 in the cell or the subject.

Some aspects of this disclosure provide methods of identifying a subject having a cancer as a candidate for treatment with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof), comprising detecting a level of activity or function of SMARCA4 in a cancer cell in the subject, comparing the level of activity or function of SMARCA4 detected in the cancer cell to a control or reference level, wherein the subject is identified as a candidate for treatment with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof), if the level of activity or function of SMARCA4 in the cancer cell is decreased as compared to the control or reference level. In some embodiments, the method comprises obtaining a sample comprising a cancer cell from the subject.

Some aspects of this disclosure provide methods of identifying a cancer cell as sensitive to treatment with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof), comprising detecting a level of activity or function of SMARCA4 in the cancer cell, comparing the level of activity or function of SMARCA4 detected in the cancer to a control or reference level, wherein the cell is identified as sensitive to treatment with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof), if the level of activity or function of SMARCA4 is decreased as compared to the control or reference level. In some embodiments, the control or reference level of SMARCA4 activity or function is a level of SMARCA4 observed or expected in a healthy cell of the same origin as the cancer cell.

Some aspects of this disclosure provide methods of treating cancer, comprising inhibiting a SMARCA2 activity in a subject in need thereof, wherein the subject has a cancer characterized by decreased activity of SMARCA4. Some aspects of this disclosure provide methods of treating cancer, comprising inhibiting a SMARCA2 activity in a subject in need thereof, wherein the subject has a cancer characterized by loss of function of SMARCA4.

In some embodiments, the methods of the disclosure comprise contacting a cell with a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof). In certain embodiments, the cell is in vivo, ex vivo, in vitro, or in situ. In certain embodiments of the methods disclosed herein, the cell is in a subject. In some embodiments, the methods of the disclosure comprise administering a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) to the subject.

In some embodiments, the SMARCA2 antagonist is a SMARCA2 inhibitor. In some embodiments, the SMARCA2 antagonist is a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof. In some embodiments, the SMARCA2 antagonist is a compound of Table 2, 2a, 2b, 2c, or 2d. In some embodiments, the SMARCA2 inhibitor is a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof. In some embodiments, the SMARCA2 inhibitor is a compound of Table 2, 2a, 2b, 2c, or 2d.

In some embodiments, the SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) inhibits SMARCA2 helicase activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, or abolishes SMARCA2 activity. In some embodiments, the SMARCA2 antagonist (e.g., a SMARCA2 inhibitor, e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof) inhibits SMARCA2 ATPase activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, or abolishes SMARCA2 activity.

BRIEF DESCRIPTION OF THE DRAWINGS

The skilled artisan will understand that the drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g., functionally similar and/or structurally similar elements).

FIG. 1 illustrates the inhibition of SMARCA2 (IC₅₀) by Compound 139 in the lung cancer cell lines of Table 5. The figure shows that cell lines comprising a loss or absence of SMARCA4 were more sensitive to inhibition of SMARCA2 by Compound 139 than cell lines in which the SMARCA4 protein was present.

FIG. 2 illustrates the results of body weight change of mice (RCBW %) in a Compound 82c efficacy study in a A549 subQ model.

FIG. 3 illustrates mice tumor volume change (%) in a Compound 82c efficacy study in a A549 subQ model.

FIG. 4 illustrates tumor weights (g) in a Compound 82c efficacy study in a A549 subQ model.

FIG. 5 illustrates Day 21 plasma PK (ng/mL) in a Compound 82c efficacy study in a A549 subQ model. The (x) axis represents the vehicle po BIDx21; each set of 4 bars for each time period (pre or post dose), from left to right, represent: (1) Compound 82c 5 mg/kg, po, BIDx21; (2) Compound 82c 12.5 mg/kg, po, BIDx10, QDx11; (3) Compounds 82c 25 mg/kg, po, BIDx7, QDx14; (4) Compound 82c 50 mg/kg, po, QDx10, 3 day soff, 30 mg/kg, po, QDx8.

DETAILED DESCRIPTION

The present disclosure provides compounds, methods, strategies, compositions, combinations, and dosage forms for the treatment of cell proliferative disorders, e.g., cancers, associated with decreased activity or function of SMARCA4 (e.g., loss of function of SMARCA4).

Some aspects of this disclosure provide methods of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof to the subject or a cell of the subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

While many of the embodiments herein describe compounds of Formula (I), (IA), (IB), (IC), (ID), or (IE), it should be understood that such reference also include any pharmaceutically acceptable salts of Formula (I), (IA), (IB), (IC), (ID), or (IE), however, such language has not been included for conciseness.

Some aspects of the disclosure relate to a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use in the treatment of cancer in a cell or subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of the disclosure relate to a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use as a medicament for the treatment of cancer in a cell or subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of the disclosure relate to the use of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) in the manufacture of a medicament for the treatment of cancer in a cell or subject. In some embodiments, the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide methods of modulating (e.g., inhibiting) an activity of SMARCA2, comprising contacting SMARCA2 enzyme with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d). In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, and the method comprises contacting the cell with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), wherein the cell comprises a biomarker of sensitivity to the SMARCA2 antagonist (e.g. a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use in inhibiting an activity of SMARCA2, wherein the compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) is contacted with a SMARCA2 enzyme. In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, wherein the cell comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use as a medicament for inhibiting an activity of SMARCA2, wherein the medicament is contacted with a SMARCA2 enzyme. In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, wherein the cell comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide the use of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) in the manufacture of a medicament for inhibiting an activity of SMARCA2, wherein the medicament is to be contacted with a SMARCA2 enzyme. In some embodiments, the SMARCA2 enzyme is within a cell, e.g., a cancer cell, wherein the cell comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use in treating cancer in a subject in need thereof, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use as a medicament for treating cancer in a subject in need thereof, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

Some aspects of this disclosure provide the use of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

In some embodiments, the biomarker is a decreased activity or function of SMARCA4. In certain embodiments, the biomarker is loss of function of SMARCA4.

Some aspects of this disclosure provide methods of identifying a subject sensitive to treatment with a SMARCA2 antagonist (e.g., a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), comprising detecting a decreased activity or function of SMARCA4 compared to a control level of the activity or the function of SMARCA4 in the subject and administering a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) to the subject, wherein the subject has a cancer and wherein an improvement in a sign or symptom of the cancer indicates a sensitivity of the subject or of a cancer cell of the subject for the compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

In some embodiments, the control level is the level of activity of SMARCA4 in a subject that does not have cancer.

In some embodiments, the present disclosure features a method comprising inhibiting a SMARCA2 activity in a cell exhibiting loss of function of SMARCA4, comprising contacting the cell with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d).

In certain embodiments of the methods disclosed herein, the cell is in a subject, and the method comprises administering a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) to the subject.

In some embodiments, a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof is a SMARCA2 inhibitor.

Some aspects of this disclosure provide methods comprising modulating (e.g., inhibiting) a SMARCA2 activity in a cell or subject. In some embodiments, this disclosure provides methods comprising modulating a SMARCA2 activity in a cell exhibiting a decreased activity or function of SMARCA4. In some embodiments, the cell is in vivo, ex vivo, in vitro, or in situ. In some embodiments, the cell is in a subject, and the method comprises administering a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) to the subject. In some embodiments, the cell is ex vivo or in vitro, and wherein the cell is isolated or derived from a subject that has a tumor. In some embodiments, the tumor is malignant. In some embodiments, the tumor is metastatic.

Some aspects of this disclosure provide methods of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) to the subject or a cell of the subject, wherein said subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) for use in treating cancer in a subject in need thereof, wherein said subject or a cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) as a medicament for treating cancer in a subject in need thereof, wherein said subject or a cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide the use of a SMARCA2 antagonist in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein said subject or a cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

In some embodiments, the control level is the level of activity or function of SMARCA4 in a subject that does not have cancer. In some embodiments, the method comprises administering the SMARCA2 antagonist to the cell or the subject based on the decreased activity or function of SMARCA4 in the cell or the subject. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Some aspects of this disclosure provide methods of identifying a subject having a cancer as a candidate for treatment with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), comprising detecting a level of activity or function of SMARCA4 in a cancer cell in the subject, comparing the level of activity or function of SMARCA4 detected in the cancer cell to a control or reference level, wherein the subject is identified as a candidate for treatment with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), if the level of activity or function of SMARCA4 in the cancer cell is decreased as compared to the control or reference level. In some embodiments, the method comprises obtaining a sample comprising a cancer cell from the subject.

Some aspects of this disclosure provide methods of identifying a cancer cell as sensitive to treatment with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), comprising detecting a level of activity or function of SMARCA4 in the cancer cell, comparing the level of activity or function of SMARCA4 detected in the cancer to a control or reference level, wherein the cell is identified as sensitive to treatment with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d), if the level of activity or function of SMARCA4 is decreased as compared to the control or reference level. In some embodiments, the control or reference level of SMARCA4 activity or function is a level of SMARCA4 observed or expected in a healthy cell of the same origin as the cancer cell.

In some embodiments, the methods of the disclosure comprise contacting a cell with a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d). In certain embodiments, the cell is in vivo, ex vivo, in vitro, or in situ. In certain embodiments of the methods disclosed herein, the cell is in a subject. In some embodiments, the methods of the disclosure comprise administering a SMARCA2 antagonist to the subject.

In some embodiments, the cell is ex vivo or in vitro. In further embodiments, the cell is isolated or derived from a subject that has a tumor.

In some embodiments, the tumor is malignant. In some embodiments, the tumor is metastatic.

In some embodiments of the disclosure, a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) targets an ATPase domain of SMARCA2. In certain embodiments of the methods disclosed herein, the SMARCA2 inhibitor inhibits an ATPase activity of SMARCA2.

In some embodiments, the SMARCA2 antagonist (e.g. a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) is a SMARCA2 inhibitor.

In certain embodiments of the methods disclosed herein, the SMARCA2 activity is an ATPase activity.

In certain embodiments of the methods, uses, or medicaments disclosed herein, the SMARCA2 activity is not a bromodomain activity.

In certain embodiments of the disclosure, the SMARCA2 inhibitor inhibits an ATPase activity of SMARCA2.

In some embodiments of the disclosure, the decreased activity of SMARCA4 is caused by a genetic mutation.

In some embodiments of the disclosure, the decreased activity of SMARCA4 is caused by an epigenetic alteration.

In some embodiments of the disclosure, the decreased activity of SMARCA4 is caused by a decrease in SMARCA4 gene transcription, SMARCA4 gene transcript translation, or a combination thereof.

In some embodiments of the disclosure, the decreased activity of SMARCA4 is caused by an epigenetic process, e.g., silencing of a SMARCA4 gene, post-transcriptional or post-translational modulation of the half-life of a SMARCA4 gene product, e.g., inhibition of translation of a SMARCA4 transcript into SMARCA4 protein, or increased turnover of a SMARCA4 protein.

In some embodiments of the disclosure, the decreased activity of SMARCA4 is caused by a decrease in SMARCA4 gene transcription, SMARCA4 gene transcript translation, or a combination thereof.

In some embodiments, the compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) inhibits SMARCA2 helicase activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, or abolishes SMARCA2 activity. In some embodiments, the compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d) inhibits SMARCA2 ATPase activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, or abolishes SMARCA2 activity.

SMARCA2/SMARCA4

Some aspects of this disclosure are based on the recognition that SMARCA2 is a synthetic lethal target in SMARCA4-mutated cancers or cancers associated with decrease or loss of activity or a function of SMARCA4. Some aspects of this disclosure thus provide methods or medicaments for decreasing or abolishing survival and/or proliferation of cancer cells that exhibit a loss of SMARCA4 function by inhibiting SMARCA2 in such cells.

SMARCA2 and SMARCA4 are SWI/SNF related, matrix associated, actin dependent regulators of chromatin and mutually exclusive paralogs in the SWF/SNF complex. SWF/SNF complexes regulate many cell processes by direct modulation of nucleosomal structure. The catalytic subunits SMARCA2 and SMARCA4 have ATP-dependent helicase activity that repositions nucleosomes.

SWI/SNF complex members are mutated in about 20% of human cancers (Kardoch et al. Nat. Genet., 2013, 45(6), 592-601, incorporated herein by reference in its entirety). For example SMARCA4 mutations occur across a diverse range of cancer types with varying population size and clinical need.

Table 1 below provides a summary of the frequency of SMARCA4 mutations in certain cancer types.

TABLE 1

SMARCA4 mutations in certain cancers

Estimated

SMARCA4
US
5 Year
SMARCA4-Mutant

Cancer Type
Mutations (%)
Cases/Year
Survival (%)
Patients/Year

Ovary - SCCOHT
>95%
<300
33%
<300

Bladder
8%
75,000
77%
6000

Stomach
6%
22,000
28%
1320

Lung
4-5% (NSCLC)
220,000
17%
~10,000

Glioma/GBM
2-5%
20,000
Variable
~360

Head and Neck
4%
36,000
56%
1440

Kidney
3-4% (Clear cell,
64,000
72%
~2000

Papillary)

Uterine/Cervical
3-4%
12,000
68%
~400

Pancreas
3%
46,000
7%
1380

However, SMARCA4 expression can also be regulated by post-transcriptional and post-translational mechanisms. As such, an analysis of mutation frequencies only is likely to underestimate protein loss, and observing only mutations of SMARCA4 may underestimate decrease or loss of activity or a function of SMARCA4 in a patient. Decrease or loss of activity or a function of SMARCA4 can appear in patients who have no mutation of SMARCA4. These patients can by identified by methods such as mRNA or protein assays. In some embodiments of the present disclosure, methods comprising detecting a loss of activity or function of SMARCA4 in a cell or tissue comprise assaying SMARCA4 protein expression levels by a suitable method, such as, e.g., antibody-based assays allowing for quantification of expressed protein in the cell or tissue (e.g., western blot, immunohistochemistry, ELISA, etc.).

Exemplary sequences for SMARCA2 and SMARCA4 are provided herein.

Exemplary sequences for SMARCA2:

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2), transcript variant 3 (GenBank Accession No. NM_001289396.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2), transcript variant 2 (GenBank Accession No. NM_139045.3)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2), transcript variant 4 (GenBank Accession No. NM_001289397.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2), transcript variant 5 (GenBank Accession No. NM_001289398.1)

Protein sequence of human probable global transcription activator SNF2L2 isoform a (GenBank Accession No. NP_001276325.1)

Protein sequence of human probable global transcription activator SNF2L2 isoform b (GenBank Accession No. NP_620614.2)

Protein sequence of human probable global transcription activator SNF2L2 isoform c (GenBank Accession No. NP_001276326.1)

Protein sequence of human probable global transcription activator SNF2L2 isoform d (GenBank Accession No. NP_001276327.1)

Exemplary Sequences for SMARCA4:

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), transcript variant 1 (GenBank Accession No. NM_001128849.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), transcript variant 2 (GenBank Accession No. NM_001128844.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), transcript variant 4 (GenBank Accession No. NM_001128845.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), transcript variant 5 (GenBank Accession No. NM_001128846.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), transcript variant 6 (GenBank Accession No. NM_001128847.1)

mRNA sequence of human SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), transcript variant 7 (GenBank Accession No. NM_001128848.1)

Protein sequence of human transcription activator BRG1 isoform A (GenBank Accession No. NP_001122321.1)

Protein sequence of human transcription activator BRG1 isoform B (GenBank Accession No. NP_001122316.1)

Protein sequence of human transcription activator BRG1 isoform C (GenBank Accession No. NP_001122317.1)

Protein sequence of human transcription activator BRG1 isoform D (GenBank Accession No. NP_001122318.1)

Protein sequence of human transcription activator BRG1 isoform E (GenBank Accession No. NP_001122319.1)

Protein sequence of human transcription activator BRG1 isoform F (GenBank Accession No. NP_001122320.1

SMARCA2 Antagonists

In some embodiments, reduced expression or function, or loss of function, of SMARCA4 confers sensitivity of said cell to inhibition of SMARCA2.

In certain aspects of the disclosure, the inhibitor or antagonist targets the helicase domain of SMARCA2. In some embodiments, the inhibitor or antagonist targets the ATP domain of SMARCA2. In some embodiments, the inhibitor or antagonist does not target the bromodomain of SMARCA2. In some embodiments, the inhibitor or antagonist targets the bromodomain of SMARCA2.

In some aspects, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 10%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 20%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 30%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 40%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 50%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 60%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 70%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 80%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 90%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 95%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by at least 98%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity by or at least 99%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 helicase activity and abolishes SMARCA2 activity.

In some aspects, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 10%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 20%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 30%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 40%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 50%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 60%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 70%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 80%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 90%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 95%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by at least 98%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity by or at least 99%. In some embodiments, a SMARCA2 antagonist (e.g., a SMARCA2 inhibitor) inhibits SMARCA2 ATPase activity and abolishes SMARCA2 activity

In certain aspects of the disclosure, the SMARCA2 antagonist or inhibitor inhibits SMARCA2 activity. Inhibition of SMARCA2 activity can be detected using any suitable method. The inhibition can be measured, for example, either in terms of rate of SMARCA2 activity or as product of SMARCA2 activity.

The inhibition is a measurable inhibition compared to a suitable control. In some embodiments, inhibition is at least 10 percent inhibition compared to a suitable control. That is, the rate of enzymatic activity or the amount of product with the inhibitor is less than or equal to 90 percent of the corresponding rate or amount made without the inhibitor. In some embodiments, inhibition is at least 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, or 95 percent inhibition compared to a suitable control. In some embodiments, inhibition is at least 99 percent inhibition compared to a suitable control. That is, the rate of enzymatic activity or the amount of product with the inhibitor is less than or equal to 1 percent of the corresponding rate or amount made without the inhibitor.

In some embodiments, the SMARCA2 antagonist is a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

X₁and X₂are each independently selected from —CH and N;

Y is selected from the group consisting of a bond, —NH, —C(O), C₁-C₆alkyl, —C(CH₃)₂—O—, and —CH₂—NH—CH₂—;

R₈and R_9′ are each independently selected from the group consisting of H, halo, and C₁-C₃alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (IA) (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

each R₃is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆—C₁₀aryloxyl, heterocycloalkyl, heteroaryl, aminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅,

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some embodiments, for a compound Formula (IA) or a pharmaceutically acceptable salt thereof,

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (IB):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

R₇is selected from the group consisting of H and C₁-C₆alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted

In some embodiments, for a compound Formula (IB) or a pharmaceutically acceptable salt thereof,

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

R₇is selected from the group consisting of H and C₁-C₆alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (IC):

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or a pharmaceutically acceptable salt thereof, wherein

A is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

each R₃is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆—C₁₀aryloxyl, heterocycloalkyl, heteroaryl, aminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅,

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some embodiments, for a compound Formula (IC) or a pharmaceutically acceptable salt thereof,

A is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some aspects, the present disclosure features a compound of Formula (ID) (e.g., a compound of Table 2, 2a, 2b, 2c, or 2d):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

each Q is independently selected from the group consisting of C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, and C₂-C₆alkynyl; each R₆is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —NR₅R_5′;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

provided that at least one R₃is QR₆, wherein Q is C₂-C₆alkynyl.

In some embodiments, the SMARCA2 antagonist is a compound of Formula (IE):

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or a pharmaceutically acceptable salt thereof, wherein

A is a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

each R₃is independently selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆—C₁₀aryloxyl, heterocycloalkyl, heteroaryl, aminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅,

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

In some embodiments, each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of an alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, aminosulfonyl, alkylsulfonyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, cycloalkyl, heterocyclyl, alkylaryl, aromatic and heteroaromatic substituent.

In some embodiments, each alkyl, alkoxyl, alkenyl, alkynyl, alkylcarbonyl, or alkylsulfonyl is unsubstituted or substituted with one or more substituents from the group consisting of halo, amino, alkoxyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.

In some embodiments, each cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted with one or more substituents from the group consisting of halo, alkyl, haloalkyl, alkoxyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl. In some embodiments, each cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted with one or more substituents from the group consisting of halo, alkyl, haloalkyl, and alkoxyl.

In some embodiments, each aminocarbonyl, or aminosulfonyl is unsubstituted or substituted with one or more substituents from the group consisting of halo, alkyl, alkoxyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.

In some embodiments, each cycloalkyl is independently a C₃-C₁₄cycloalkyl. In some embodiments, each cycloalkyl is independently a C₃-C₈cycloalkyl.

In some embodiments, each aryl is independently a C₆-C₁₀aryl.

In some embodiments, each heteroaryl is independently a 5 to 6 membered heteroaryl.

In some embodiments, each heterocycloalkyl is independently a 3 to 8-membered heterocycloalkyl or a 7 to 12-membered heterocycloalkyl.

In some embodiments, A is a 6 membered heteroaryl. In some embodiments, A is a 7-12 membered heteroaryl.

In some embodiments, A is a 3 to 8-membered heterocycloalkyl having 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is a 7 to 12-membered heterocycloalkyl having 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is a 10-membered heterocycloalkyl having 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is a monocyclic heterocycloalkyl. In some embodiments, A is a bicyclic heterocycloalkyl.

In some embodiments, A is C₃-C₁₄cycloalkyl. In some embodiments, A is C₃-C₈cycloalkyl. For example, in some embodiments, A is a C₃cycloalkyl. For example, in some embodiments, A is a C₄cycloalkyl. For example, in some embodiments, A is a C₅cycloalkyl. For example, in some embodiments, A is a C₆cycloalkyl. In some embodiments, A is cyclopropyl.

In some embodiments, A is selected from thiazolyl, isothiazolyl, thiazol-2-onyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,4-triazolyl, and 1,2,3-triazolyl.

In some embodiments, A is selected from the group consisting of thiazolyl, thiophenyl, pyrrolyl, and pyrazolyl. In some embodiments, A is selected from thiazolyl and thiophenyl.

In some embodiments, A is thiazolyl.

In some embodiments, A is isothiazolyl.

In some embodiments, A is thiazol-2-onyl.

In some embodiments, A is thiophenyl.

In some embodiments, A is pyrrolyl.

In some embodiments, A is pyrazolyl.

In some embodiments, A is pyridinyl.

In some embodiments, A is pyrrolidinyl.

In some embodiments, A is imidazolyl.

In some embodiments, A is 1,2,3-thiadiazolyl.

In some embodiments, A is 1,2,4-thiadiazolyl.

In some embodiments, A is benzothiophenyl.

In some embodiments, A is furanyl.

In some embodiments, A is tetrahydrofuranyl.

In some embodiments, A is oxazolyl.

In some embodiments, A is isoxazolyl.

In some embodiments, A is 1,2,4-triazolyl.

In some embodiments, A is 1,2,3-triazolyl.

In some embodiments, A is N-substituted pyrrolyl.

In some embodiments, A is

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In some embodiments, A is

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In some embodiments, Y is a bond.

In some embodiments, Y is —NH.

In some embodiments, Y is —C(O).

In some embodiments, Y is C₁-C₆alkyl.

In some embodiments, Y is —CH₃.

In some embodiments, Y is CH₂CH₃.

In some embodiments, Y is —C(CH₃)₂—O—.

In some embodiments, Y is —CH₂—NH—CH₂.

In some embodiments, X₁is —CH.

In some embodiments, X₁is N.

In some embodiments, X₂is —CH.

In some embodiments, X₂is —N.

In some embodiments, R₁is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, C₃-C₈cycloalkyl, and —(CH₂)_mR₄.

In some embodiments, R₁is selected from the group consisting of H, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments, R₁is H.

In some embodiments, R₁is C₁-C₆alkyl. For example, in some embodiments, R₁is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl.

In some embodiments, R₁is C₁-C₆haloalkyl. For example, in some embodiments, R₁is fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, chloromethyl, chloroethyl, chloropropyl, dichloromethyl, dichloroethyl, dichloropropyl, trichloromethyl, trichloroethyl, trichloropropyl, bromomethyl, bromoethyl, bromopropyl, dibromomethyl, dibromoethyl, dibromopropyl, tribromomethyl, tribromoethyl, tribromopropyl, iodomethyl, iodoethyl, iodopropyl, diiodomethyl, diiodoethyl, diiodopropyl, triiodomethyl, triiodoethyl, or triiodopropyl.

In some embodiments, R₁is methyl, ethyl, halomethyl or haloethyl.

In some embodiments, R₁is C₁-C₆fluoroalkyl. In some embodiments, R₁is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

In some embodiments, R₁is 1,1-difluoroethyl, 1,2-difluoroethyl, 2,1-difluoroethyl, 2,2-difluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, 2,2,1-trifluoroethyl, or 2,2,2-trifluoroethyl.

In some embodiments, R₁is difluoromethyl.

In some embodiments, R₁is difluoroethyl.

In some embodiments, R₁is 2,2-difluoroethyl

In some embodiments, R₁is C₃-C₈cycloalkyl. For example, in some embodiments, R₁is a C₃cycloalkyl. For example, in some embodiments, R₁is a C₅cycloalkyl. For example, in some embodiments, R₁is a C₆cycloalkyl. In some embodiments, R₁is cyclopropyl.

In some embodiments, R₁is C₆-C₁₀aryl. For example, in some embodiments, R₁is phenyl.

In some embodiments, R₁is —(CH₂)_mR₄. In some embodiments where R₁is —(CH₂)_mR₄, R₄is selected from the group consisting of C₁-C₆alkoxyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is hydroxyl.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is C₁-C₆alkoxyl. For example, in some embodiments, R₄is methoxyl, ethoxyl, or propyloxyl. In some embodiments, R₄is methoxyl.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is mono-C₁-C₆alkylamino. For example, in some embodiments R₄is methylamino, ethylamino, or propylamino. In some embodiments, R₄is methylamino.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is di-C₁-C₆alkylamino. For example, in some embodiments R₄is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments R₄is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments, R₄is dimethylamino.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is C₆-C₁₀aryl. For example, in some embodiments, R₄is phenyl.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is C₃-C₈cycloalkyl. For example, in some embodiments, R₄is a C₃cycloalkyl. For example, in some embodiments, R₄is a C₅cycloalkyl. For example, in some embodiments, R₄is a C₆cycloalkyl. For example, in some embodiments, R₄is cyclopropyl.

In some embodiments where R₁is —(CH₂)_mR₄, R₄is a 5-membered heteroaryl. For example, in some embodiments, R₄is pyrazolyl. For example, in some embodiments, R₄is imidazolyl.

In some embodiments, R₄is 5-membered a heterocycloalkyl. For example, in some embodiments, R₄is pyrrolidinyl.

In some embodiments where R₁is —(CH₂)_mR₄, m is 1. In some embodiments where R₁is —(CH₂)_mR₄, m is 2. In some embodiments where R₁is —(CH₂)_mR₄, m is 3, 4, 5, or 6.

In some embodiments, R₂is selected from the group consisting of H, halo, cyano, C₁-C₆alkyl, —(CH₂)_mR_4′, —NR₅R_5′, and —OR₅.

In some embodiments, R₂is H.

In some embodiments, R₂is cyano.

In some embodiments, R₂is halo. For example, in some embodiments, R₂is fluoro, chloro, or bromo. In some embodiments, R₂is fluoro.

In some embodiments, R₂is C₁-C₆alkyl. For example, in some embodiments, R₂is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, R₂is methyl, ethyl, or propyl (e.g., n-propyl, or i-propyl).

In some embodiments, R₂is —(CH₂)_mR₄.

In some embodiments wherein R₂is —(CH₂)_mR₄, m is 1 or 2. In some embodiments wherein R₂is —(CH₂)_mR₄, R₄is C₁-C₆aryl. For example, in some embodiments, R₄is phenyl. In some embodiments wherein R₂is —(CH₂)_mR₄, R₄is a 5-membered heteroaryl. For example, in some embodiments, R₄is 1-methyl-pyrazolyl.

In some embodiments, R₂is —NR₅R_5′.

In some embodiments where R₂is —NR₅R_5′, R₅is H and R_5′ is C₁-C₆alkyl. For example, in some embodiments, R_5′ is methyl. For example, in some embodiments, R₂is methylamino.

In some embodiments where R₂is —NR₅R_5′, R₅and R_5′ are both C₁-C₆alkyl. For example, in some embodiments, R₅is methyl and R_5′ is methyl. For example, in some embodiments, R₂is dimethylamino.

In some embodiments where R₂is —NR₅R_5′, R₅is H and R_5′—(CH₂)_mR_4′. In some embodiments, R_4′ is C₁-C₆alkoxyl. For example, in some embodiments, R_4′ is methoxyl. In some embodiments, R_4′ is di-C₁-C₆alkylamino. For example, in some embodiments, R_4′ is dimethylamino. In some embodiments, R_4′ is a 6-membered heteroaryl. For example, in some embodiments, R_4′ is pyridinyl. In some embodiments, R_4′ is a 6-membered heterocycloalkyl. For example, in some embodiments, R_4′ is morpholinyl. In some embodiments, R_4′ is a 5-membered heteroaryl. For example, in some embodiments, R_4′ is 1-methylpyrazolyl. For example, in some embodiments, R_4′ is imidazolyl. In some embodiments, R_4′ is a 5-membered heterocyclyl. For example, in some embodiments, R_4′ is pyrrolidinyl.

In some embodiments, R₂is —OR₅. In some embodiments, R₂is —OR₅and R₅is —(CH₂)_mR_4′.

In some embodiments where R₂is —OR₅and R₅is —(CH₂)_mR_4′, R_4′ is selected from the group consisting of C₁-C₆alkoxyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

In some embodiments where R₂is —OR₅and R₅is —(CH₂)_mR_4′, R_4′ is C₁-C₆alkoxyl. For example, in some embodiments, R_4′ is methoxyl, ethoxyl, or propyloxyl. In some embodiments, R_4′ is methoxyl.

In some embodiments where R₂is —OR₅and R₅is —(CH₂)_mR_4′, R_4′ is mono-C₁-C₆alkylamino. For example, in some embodiments R_4′ is methylamino, ethylamino, or propylamino. In some embodiments, R_4′ is methylamino.

In some embodiments R₂is —C(O)NH₂.

In some embodiments R₂is —NO₂.

In some embodiments where R₂is —OR₅and R₅is —(CH₂)_mR_4′, R_4′ is di-C₁-C₆alkylamino. For example, in some embodiments R_4′ is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments R_4′ is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments R_4′ is dimethylamino.

In some embodiments where R₂is —OR₅and R₅is —(CH₂)_mR_4′, R_4′ is a 6-membered heterocycloalkyl. For example, in some embodiments, R_4′ is 1-methylpiperazine or morpholinyl.

In some embodiments wherein R₂is —OR_5′ or —NR₅R_5′ and R₅is —(CH₂)_mR₄, m is 1. In some embodiments wherein R₂is —OR_5′ or —NR₅R_5′ and R₅is —(CH₂)_mR₄, m is 2.

In some embodiments, m is 1 or 2. In some embodiments, m is 2, 3, 4, 5, or 6.

In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

In some embodiments, R₄is halo, COOH, or cyano.

In some embodiments, R₄is C₂-C₆alkenyl, or C₂-C₆alkynyl.

In some embodiments, R₄is hydroxyl.

In some embodiments, R₄is C₁-C₆alkoxyl. For example, in some embodiments, R₄is methoxyl, ethoxyl, or propyloxyl. In some embodiments, R₄is methoxyl. In some embodiments, R₄is ethoxyl.

In some embodiments, R₄is C₃-C₈cycloalkyl. For example, in some embodiments, R₄is a C₃cycloalkyl. For example, in some embodiments, R₄is a C₅cycloalkyl. For example, in some embodiments, R₄is a C₆cycloalkyl. For example, R₄is cyclopropyl.

In some embodiments, R₄is C₆-C₁₀aryl, or C₆-C₁₀aryloxyl. In some embodiments, R₄is C₆-C₁₀aryl. For example, in some embodiments R₄is phenyl.

In some embodiments, R₄is 3 to 8-membered heterocycloalkyl or a 7 to 12-membered heterocycloalkyl. In some embodiments, R₄is a 5-membered heterocycloalkyl. For example, in some embodiments, R₄is pyrrolidinyl. In some embodiments, R₄is a 6-membered heterocycloalkyl. For example, in some embodiments, R₄is morpholinyl. For example, in some embodiments, R₄is methylpiperazinyl. For example, in some embodiments, R₄is pyrrolidinyl.

In some embodiments, R₄is 5 to 6-membered heteroaryl. In some embodiments, R₄is a 5-membered heteroaryl. For example, in some embodiments, R₄is 1-methylpyrazolyl. In some embodiments, R₄is a 6-membered heteroaryl. For example, in some embodiments, R₄is pyridinyl. For example, in some embodiments, R₄is pyrazolyl. For example, in some embodiments, R₄is imidazolyl.

In some embodiments, R₄is mono-C₁-C₆alkylamino. For example, in some embodiments, R₄is methylamino, ethylamino, or propylamino. In some embodiments, R₄is methylamino.

In some embodiments, R₄is di-C₁-C₆alkylamino. In some embodiments, R₄is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments, R₄is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments, R₄is dimethylamino.

In some embodiments, R_4′ is halo, COOH, or cyano.

In some embodiments, R_4′ is C₂-C₆alkenyl, or C₂-C₆alkynyl.

In some embodiments, R_4′ is hydroxyl.

In some embodiments, R_4′ is C₁-C₆alkoxyl. For example, in some embodiments, R_4′ is methoxyl. For example, in some embodiments, R_4′ is ethoxyl. For example, in some embodiments, R_4′ is methoxyl, ethoxyl, or propyloxyl. In some embodiments, R_4′ is methoxyl.

In some embodiments, R_4′ is C₃-C₈cycloalkyl. For example, in some embodiments, R_4′ is a C₃cycloalkyl. For example, in some embodiments, R_4′ is a C₅cycloalkyl. For example, in some embodiments, R_4′ is a C₆cycloalkyl.

In some embodiments, R_4′ is C₆-C₁₀aryl, or C₆-C₁₀aryloxyl. In some embodiments, R_4′ is C₆-C₁₀aryl.

In some embodiments, R_4′ is mono-C₁-C₆alkylamino. For example, in some embodiments, R_4′ is methylamino, ethylamino, or propylamino. In some embodiments, R_4′ is methylamino

In some embodiments, R_4′ is di-C₁-C₆alkylamino. For example, in some embodiments R_4′ is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments, R_4′ is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments, R_4′ is dimethylamino.

In some embodiments, R_4′ is a 3 to 8-membered heterocycloalkyl or a 7 to 12-membered heterocycloalkyl. In some embodiments, R_4′ is a 5-membered heterocycloalkyl. For example, in some embodiments, R_4′ is pyrrolidinyl. In some embodiments, R_4′ is a 6-membered heterocycloalkyl. For example, in some embodiments, R_4′ is morpholinyl. For example, in some embodiments, R_4′ is methylpiperazinyl.

In some embodiments, R_4′ is a 5 to 6-membered heteroaryl. In some embodiments, R_4′ is a 5-membered heteroaryl. For example, in some embodiments, R_4′ is 1-methylpyrazolyl. For example, in some embodiments, R_4′ is imidazolyl. In some embodiments, R_4′ is a 6-membered heteroaryl. For example, in some embodiments, R_4′ is pyridinyl.

In some embodiments, R₄and R_4′ are each independently selected from the group consisting of hydroxyl, C₁-C₆alkoxyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, 3 to 8-membered heterocycloalkyl, a 7 to 12-membered heterocycloalkyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino. For example, in some embodiments, R₄and R_4′ are each independently selected from the group consisting of methoxyl, cyclopropyl, phenyl, morpholino, methylpiperazinyl, methylamino, and di-methylamino.

In some embodiments, R₅is H.

In some embodiments, R₅is cyano.

In some embodiments, R₅is C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl. For example, in some embodiments, R₅is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, R₅is methyl. In some embodiments, R₅is i-propyl.

In some embodiments, R₅is C₁-C₆alkoxyl. For example, in some embodiments, R₅is methoxyl, ethoxyl, or propyloxyl.

In some embodiments, R₅is C₁-C₆alkylcarbonyl. For example, in some embodiments, R₅is methanoyl, ethanonyl, or propanoyl. In some embodiments, R₅is ethanonyl.

In some embodiments, R₅is C₃-C₈cycloalkyl. For example, R₅is a C₃cycloalkyl. For example, R₅is a C₅cycloalkyl. For example, R₅is a C₆cycloalkyl. For example, R_5′ is cyclopentyl.

In some embodiments, R₅is C₆-C₁₀aryl, or C₆-C₁₀aryloxyl. For example, R₅is phenyl. For example, in some embodiments, R₅is phenyloxy.

In some embodiments, R₅is a 3 to 8-membered heterocycloalkyl or a 7 to 12-membered heterocycloalkyl.

In some embodiments, R₅is 5 to 6-membered heteroaryl.

In some embodiments, R₅is —(CH₂)_mR₄.

In some embodiments, R_5′ is H.

In some embodiments, R_5′ is C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl. For example, in some embodiments, R_5′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, R_5′ is methyl.

In some embodiments, R_5′ is C₃-C₈cycloalkyl. For example, in some embodiments, R_5′ is a C₃cycloalkyl. For example, in some embodiments, R_5′ is a C₅cycloalkyl. For example, in some embodiments, R_5′ is a C₆cycloalkyl. For example, R_5′ is cyclopentyl. In some embodiments, R₅is i-propyl.

In some embodiments, R_5′ is C₆-C₁₀aryl.

In some embodiments, R_5′ is C₁-C₆alkylcarbonyl. For example, in some embodiments, R_5′ is methanoyl, ethanonyl, or propanoyl. In some embodiments, R_5′ is ethanonyl.

In some embodiments, R_5′ is a 3 to 8-membered heterocycloalkyl or a 7 to 12-membered heterocycloalkyl.

In some embodiments, R_5′ is 5 to 6-membered heteroaryl.

In some embodiments, R_5′ is —(CH₂)_mR₄.

In some embodiments, R₅is H and R_5′ is C₁-C₆alkyl. For example, R_5′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl.

In some embodiments, R₅is H and R_5′ is —(CH₂)_mR₄.

In some embodiments, R_5′ is H and R₅is —(CH₂)_mR₄.

In some embodiments, where R₅is —(CH₂)_mR_4′, R_4′ is selected from hydroxyl, C₁-C₆alkoxyl, 3 to 8-membered heterocycloalkyl, 7 to 12-membered heterocycloalkyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

In some embodiments, R_4′ is C₁-C₆alkoxyl. For example, in some embodiments, —(CH₂)_mR_4′ is methoxyl, ethoxyl, or propyloxyl. In some embodiments, R_4′ is methoxyl. For example, in some embodiments, R_4′ is methylamino, ethylamino, or propylamino. For example, in some embodiments R_4′ is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments R_4′ is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments, R_4′ is dimethylamino. In some embodiments, m is 1 or 2.

In some embodiments, where R_5′ is —(CH₂)_mR_4′, R_4′ is selected from hydroxyl, C₁-C₆alkoxyl, 3 to 8-membered heterocycloalkyl or 7 to 12-membered heterocycloalkyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino. In some embodiments, R_4′ is C₁-C₆alkoxyl. For example, in some embodiments, R_4′ is methoxyl, ethoxyl, or propyloxyl. In some embodiments, R_4′ is methoxyl. For example, in some embodiments R_4′ is methylamino, ethylamino, or propylamino. For example, in some embodiments R_4′ is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments R_4′ is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments, R_4′ is dimethylamino. In some embodiments, m is 1 or 2.

In some embodiments, where R_5′ is —(CH₂)_mR₄, R₄is C₁-C₆aryl. For example, in some embodiments R₄is phenyl.

In some embodiments, where R₅is —(CH₂)_mR₄, R₄is C₁-C₆aryl. For example, in some embodiments R₄is phenyl.

In some embodiments, each R₃is selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, 3 to 8-membered heterocycloalkyl, 7 to 12-membered heterocycloalkyl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

In some embodiments, each R₃is selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

In some embodiments, each R₃is selected from the group consisting of halo, cyano, nitro, oxo, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, heteroaryl, heterocycloalkyl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, -QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

In some embodiments, each R₃is selected from the group consisting of halo, cyano, nitro, oxo, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, heterocycloalkyl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, -QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

In some embodiments, R₃is halo. For example, in some embodiments R₃is chloro, fluoro, or bromo. In some embodiments R₃is chloro or fluoro.

In some embodiments, R₃is hydroxyl or COOH.

In some embodiments, R₃is cyano.

In some embodiments, R₃is nitro.

In some embodiments, R₃is oxo.

In some embodiments, one R₃is halo and the other R₃is cyano.

In some embodiments, one R₃is fluoro and the other R₃is cyano.

In some embodiments, one R₃is trifluoromethyl and the other R₃is cyano.

In some embodiments, one R₃is C₁-C₆haloalkyl and the other R₃is cyano.

In some embodiments, one R₃is C₁-C₆trifluoroalkyl and the other R₃is cyano.

In some embodiments, R₃is C₁-C₆alkyl. For example, R₃is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl.

In some embodiments, R₃is C₂-C₆alkenyl or C₂-C₆alkynyl. For example, in some embodiments, R₃is C₃alkenyl. For example, in some embodiments, R₃is C₃alkynyl.

In some embodiments, R₃is C₁-C₆haloalkyl. For example, in some embodiments, R₃is fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, chloromethyl, chloroethyl, chloropropyl, dichloromethyl, dichloroethyl, dichloropropyl, trichloromethyl, trichloroethyl, trichloropropyl, bromomethyl, bromoethyl, bromopropyl, dibromomethyl, dibromoethyl, dibromopropyl, tribromomethyl, tribromoethyl, tribromopropyl, iodomethyl, iodoethyl, iodopropyl, diiodomethyl, diiodoethyl, diiodopropyl, triiodomethyl, triiodoethyl, or triiodopropyl. In some embodiments, R₃is trifluoromethyl.

In some embodiments, R₃is C₃-C₈cycloalkyl. For example, in some embodiments, R₃is a C₃cycloalkyl. For example, in some embodiments, R₃is a C₅cycloalkyl. For example, in some embodiments, R₃is a C₆cycloalkyl. In some embodiments, R₃is cyclopropyl.

In some embodiments, R₃is aminocarbonyl.

In some embodiments, R₃is mono-C₁-C₆alkylaminocarbonyl or di-C₁-C₆alkylaminocarbonyl. For example, in some embodiments, R₃is methylaminocarbonyl. For example, in some embodiments, R₃is dimethylaminocarbonyl.

In some embodiments, R₃is C₁-C₆alkylsulfonyl. For example, in some embodiments, R₃is methylsulfonyl.

In some embodiments, R₃is aminosulfonyl.

In some embodiments, R₃is C₆-C₁₀aryl. For example, in some embodiments, R₃is phenyl. In some embodiments, C₆-C₁₀aryl is substituted with one or more groups selected from halo, C₁-C₆alkyl, and C₁-C₆alkoxyl. For example, in some embodiments, R₃is C₆-C₁₀aryl substituted with Cl, F, Br, or I. For example, in some embodiments, R₃is C₆-C₁₀aryl substituted with methyl. For example, in some embodiments, R₃is C₆-C₁₀aryl substituted with methoxyl. For example, in some embodiments, R₃is chlorophenyl. For example, in some embodiments, R₃is fluorophenyl. For example, in some embodiments, R₃is bromophenyl. For example, in some embodiments, R₃is iodophenyl. For example, in some embodiments, R₃is toluyl. For example, in some embodiments, R₃is methoxyphenyl.

In some embodiments, R₃is C₆-C₁₀aryloxyl.

In some embodiments, R₃is a 3 to 8-membered heterocycloalkyl or a 7 to 12-membered heterocycloalkyl.

In some embodiments, R₃is a 5 to 6-membered heteroaryl. For example, in some embodiments, R₃is selected from oxazolyl, pyridinyl, furanyl, thiazolyl, pyrrolyl, imidazolyl, and pyrazolyl. In some embodiments, the 5 to 6-membered heteroaryl is substituted with one or more methyl. For example, in some embodiments, R₃is selected from the group consisting of 2-methylthiazolyl, 1,2-dimethyl-pyrrolyl, 1-methyl-imidazolyl, and 1-methyl-pyrazolyl. In some embodiments, the 5 to 6-membered heteroaryl is substituted with one or more C₁-C₆haloalkyl. For example, in some embodiments, the 5 to 6-membered heteroaryl is substituted with one or more trifluoromethyl. For example, in some embodiments, R₃is 2-(trifluoromethyl)-2H-imidazolyl.

In some embodiments, R₃is a 7 to 12-membered heterocycloalkyl. For example, in some embodiments, R₃is 2,3-dihydrobenzofuranyl.

In some embodiments, R₃is —(CH₂)_mR₆. In some embodiments, R₃is —(CH₂)_mR₆and m is 1. In some embodiments, R₃is —(CH₂)_mR₆and m is 2. In some embodiments, R₃is —(CH₂)_mR₆and m is 3, 4, 5, or 6.

In some embodiments, where R₃is —(CH₂)_mR₆, R₆is C₆-C₁₀aryl. For example, in some embodiments, R₆is phenyl.

In some embodiments, where R₃is —(CH₂)_mR₆, R₆is C₆-C₁₀aryl substituted with C₁-C₆alkoxyl. In some embodiments, R₆is phenyl substituted with C₁-C₆alkoxyl. For example, in some embodiments, R₆is methoxyphenyl.

In some embodiments, where R₃is —(CH₂)_mR₆, R₆is di-C₁-C₆alkylamino. For example, in some embodiments R₆is dimethylamino, diethylamino, or dipropylamino. For example, in some embodiments R₆is methylethylamino, methylpropylamino, or ethylpropylamino. In some embodiments, R₆is dimethylamino.

In some embodiments, where R₃is —(CH₂)_mR₆, R₆is hydroxyl.

In some embodiments, R₃is QR₆.

In some embodiments, at least one R₃is QR₆.

In some embodiments, at least one R₃is QR₆, wherein Q is C₂-C₆alkynyl.

In some embodiments, Q is C₂-C₆alkynyl. For example, in some embodiments, Q is prop-1-ynyl.

In some embodiments, Q is a C₁-C₃alkyl. For example, in some embodiments, Q is methyl.

In some embodiments, Q is substituted with halogen or hydroxyl. For example, in some embodiments, Q is substituted with hydroxyl. For example, in some embodiments, Q is methanolyl. In some embodiments, Q is substituted with halo. For example, in some embodiments, Q is substituted with fluoro, chloro, iodo, or bromo. In some embodiments, Q is 1,1-difluoropropanyl.

In some embodiments, wherein R₃is QR₆, R₆is a 5-membered heterocycloalkyl. For example, in some embodiments, R₆is pyrrolidine.

In some embodiments, wherein R₃is QR₆, R₆is a 6-membered heteroaryl. For example, in some embodiments, R₆is pyridinyl.

In some embodiments, wherein R₃is QR₆, R₆is amino.

In some embodiments, wherein R₃is QR₆, R₆is di-C₁-C₆alkylamino. For example, in some embodiments, R₆is dimethylamino. In some embodiments, wherein R₃is QR₆, R₆is hydroxyl.

In some embodiments, wherein R₃is QR₆, R₆is C₁-C₆haloalkyl. For example, in some embodiments, R₆is trifluoromethyl.

In some embodiments, R₃is —NR₅R_5′.

In some embodiments where R₃is —NR₅R_5′, R₅is H and R_5′ is C₃-C₈cycloalkyl. For example, in some embodiments, R_5′ is a C₃cycloalkyl. For example, in some embodiments, R_5′ is a C₅cycloalkyl. For example, in some embodiments, R_5′ is a C₆cycloalkyl. In some embodiments, R_5′ is cyclopentyl.

In some embodiments where R₃is —NR₅R_5′, R₅is H and R_5′ is C₁-C₆alkyl. For example, R_5′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, R_5′ is methyl. In some embodiments, R_5′ is i-propyl.

In some embodiments where R₃is —NR₅R_5′, R₅is H and R_5′ is C₁-C₆alkenyl or C₁-C₆haloalkyl. For example, in some embodiments, R₅is C₃alkenyl.

In some embodiments where R₃is —NR₅R_5′, R₅is H and R_5′ is C₁-C₆alkylcarbonyl. For example, in some embodiments, R_5′ is ethanoyl.

In some embodiments, R₃is —OR₅.

In some embodiments where R₃is —OR₅, R₅is C₁-C₆alkyl. For example, in some embodiments, R₅is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, R₅is methyl.

In some embodiments where R₃is —OR₅, R₅is C₁-C₆alkenyl or C₁-C₆alkynyl.

In some embodiments where R₃is —OR₅, R₅is C₁-C₆haloalkyl.

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, n is 1 and R₃is cyano. In some embodiments, n is 1 or 2 and R₃is halo. In some embodiments, n is 2, one R₃is halo and the other R₃is cyano. In some embodiments, halo is selected from Cl, Br, and I. For example, in some embodiments, n is 2, one R₃is Cl and the other R₃is cyano. For example, in some embodiments, n is 2, one R₃is Br and the other R₃is cyano. For example, in some embodiments, n is 2, one R₃is I and the other R₃is cyano.

In some embodiments, R₆is selected from the group consisting of halo, hydroxyl, COOH, cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, heterocycloalkyl, amino, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

In some embodiments, R₆is halo, hydroxyl, COOH, or cyano.

In some embodiments, R₆is C₂-C₆alkenyl, C₂-C₆alkynyl.

In some embodiments, R₆is C₁-C₆alkoxyl. For example, in some embodiments, R₆is methoxyl, ethoxyl, or propyloxyl.

In some embodiments, R₆is C₃-C₈cycloalkyl. For example, in some embodiments, R₆is a C₃cycloalkyl. For example, in some embodiments, R₆is a C₅cycloalkyl. For example, in some embodiments, R₆is a C₆cycloalkyl. In some embodiments, R₆is cyclopropyl.

In some embodiments, R₆is C₆-C₁₀aryl or C₆-C₁₀aryloxyl.

In some embodiments, R₆is a 3 to 8-membered heterocycloalkyl.

In some embodiments, R₆is a 4-membered heterocycloalkyl. For example, R₆is oxetanyl.

In some embodiments, R₆is a 5-membered heterocycloalkyl. For example, in some embodiments, R₆is pyrrolidinyl or morpholinyl.

In some embodiments, R₆is 5 to 6-membered heteroaryl. For example, in some embodiments, R₆is pyridinyl, pyrimidinyl, furanyl, thiazolyl, imidazolyl, or pyrrolyl. In some embodiments, the 5 to 6-membered heteroaryl is substituted with one or more methyl. For example, in some embodiments, R₆is 2-methylthiazolyl or 1,2-dimethyl-1H-pyrrolyl.

In some embodiments, R₆is selected from the group consisting of halo, hydroxyl, COOH, cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, 3 to 8-membered heterocycloalkyl, amino, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

In some embodiments, R₆is amino, mono-C₁-C₆alkylamino, or di-C₁-C₆alkylamino.

In some embodiments, each amino, mono-C₁-C₆alkylamino, or di-C₁-C₆alkylamino is unsubstituted or substituted. In some embodiments, each amino, mono-C₁-C₆alkylamino, or di-C₁-C₆alkylamino is unsubstituted.

In some embodiments, R₈is H.

In some embodiments, R₈is halo.

In some embodiments, R₈is F.

In some embodiments, R₈is Cl.

In some embodiments, R₈is C₁-C₃alkyl

In some embodiments, R₈is CH₃.

In some embodiments, R₈is CH₂CH₃.

In some embodiments, R₉is H.

In some embodiments, R₉is halo.

In some embodiments, R₉is F.

In some embodiments, R₉is Cl.

In some embodiments, R₉is C₁-C₃alkyl

In some embodiments, R₉is CH₃.

In some embodiments, R₉is CH₂CH₃.

In some embodiments, at least one R₃is QR₆.

In some embodiments, R₃is QR₆.

In some embodiments, R₃is QR₆and Q is selected from the group consisting of C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl.

In some embodiments, R₃is QR₆and Q is C₃-C₆cycloalkyl.

In some embodiments, R₃is QR₆and Q is a C₃-C₆cycloalkyl selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl.

In some embodiments, R₃is QR₆and Q is C₃-C₆heterocycloalkyl.

In some embodiments, R₃is QR₆and Q is a C₃-C₆heterocycloalkyl selected from the group consisting of azetidinyl, oxtanyl, pyrrolidinyl, piperidinyl, piperazinyl, and tetrahydropyranyl.

In some embodiments, R₃is QR₆and Q is C₂-C₆alkynyl.

In some embodiments, R₃is

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In some embodiments, R₃is

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and R₆is selected from the group consisting of oxetanyl, azetidinyl, piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, and thiophenyl.

In some embodiments, R₃is

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and R₆is unsubstituted or substituted with an alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, aminosulfonyl, alkylsulfonyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, cycloalkyl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

In some embodiments, R₃is

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and R₆is unsubstituted or substituted with halogen or hydroxyl. For example, in some embodiments, R₆is substituted with hydroxyl. In some embodiments, R₆is substituted with halo. For example, in some embodiments, R₆is substituted with fluoro, chloro, iodo, or bromo.

In some embodiments, at least one R₃is QR₆and Q is selected from the group consisting of C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl.

In some embodiments, at least one R₃is QR₆and Q is C₃-C₆cycloalkyl.

In some embodiments, at least one R₃is QR₆and Q is a C₃-C₆cycloalkyl selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl.

In some embodiments, at least one R₃is QR₆and Q is C₃-C₆heterocycloalkyl.

In some embodiments, at least one R₃is QR₆and Q is a C₃-C₆heterocycloalkyl selected from the group consisting of azetidinyl, oxtanyl, pyrrolidinyl, piperidinyl, piperazinyl, and tetrahydropyranyl.

In some embodiments, at least one R₃is QR₆and Q is C₂-C₆alkynyl.

In some embodiments, at least one R₃is

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In some embodiments, at least one R₃is

embedded image

In some embodiments, at least one R₃is

embedded image

In some embodiments, at least one R₃is

embedded image

In some embodiments,

embedded image

is selected from:

embedded image

and tautomers thereof.

In some embodiments

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is selected from:

embedded image

and tautomers thereof.

In some embodiments

embedded image

is selected from

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In some embodiments, the SMARCA2 inhibitor is a compound of Table 2 below:

TABLE 2

SMARCA2 inhibitors of the present disclosure.

Compd.

Mass

No.
Structure
(u)

1

embedded image

314

2

embedded image

333

3

embedded image

354

4

embedded image

343

5

embedded image

368

6

embedded image

343

7

embedded image

329

8

embedded image

349

9

embedded image

367

10

embedded image

352

11

embedded image

388

12

embedded image

336

13

embedded image

246

14

embedded image

262

15

embedded image

315

16

embedded image

261

17

embedded image

300

18

embedded image

280

19

embedded image

326

20

embedded image

267

21

embedded image

327

22

embedded image

280

23

embedded image

261

24

embedded image

274

25

embedded image

318

26

embedded image

267

27

embedded image

247

28

embedded image

297

29

embedded image

251

30

embedded image

330

31

embedded image

315

32

embedded image

275

33

embedded image

277

34

embedded image

317

35

embedded image

311

36

embedded image

344

37

embedded image

286

38

embedded image

324

39

embedded image

300

40

embedded image

283

41

embedded image

326

42

embedded image

328

43

embedded image

317

44

embedded image

283

45

embedded image

329

46

embedded image

375

47

embedded image

362

48

embedded image

372

49

embedded image

329

50

embedded image

377

51

embedded image

372

52

embedded image

296

53

embedded image

368

54

embedded image

391

55

embedded image

246

56

embedded image

284

57

embedded image

390

58

embedded image

332

59

embedded image

342

60

embedded image

346

61

embedded image

342

62

embedded image

340

63

embedded image

284

64

embedded image

318

65

embedded image

297

66

embedded image

376

67

embedded image

355

68

embedded image

328

69

embedded image

284

70

embedded image

280

71

embedded image

343

72

embedded image

285

73

embedded image

297

74

embedded image

313

75

embedded image

371

76

embedded image

345

77

embedded image

327

78

embedded image

265

79

embedded image

317

80

embedded image

335

81

embedded image

353

82

embedded image

343

83

embedded image

333

84

embedded image

353

85

embedded image

400

86

embedded image

308

87

embedded image

347

88

embedded image

306

89

embedded image

357

90

embedded image

251

91

embedded image

311

92

embedded image

247

93

embedded image

247

94

embedded image

267

95

embedded image

311

96

embedded image

314

97

embedded image

300

98

embedded image

306

99

embedded image

267

100

embedded image

281

101

embedded image

371

102

embedded image

405

103

embedded image

318

104

embedded image

374

105

embedded image

331

106

embedded image

308

107

embedded image

284

108

embedded image

281

109

embedded image

335

110

embedded image

347

111

embedded image

359

112

embedded image

359

113

embedded image

390

114

embedded image

403

115

embedded image

280

116

embedded image

313

117

embedded image

345

118

embedded image

391

119

embedded image

459

120

embedded image

407

121

embedded image

404

122

embedded image

446

123

embedded image

342

124

embedded image

335

125

embedded image

360

126

embedded image

346

127

embedded image

362

128

embedded image

326

129

embedded image

353

130

embedded image

302

131

embedded image

396

132

embedded image

326

133

embedded image

350

134

embedded image

368

135

embedded image

404

136

embedded image

309

137

embedded image

363

138

embedded image

311

139

embedded image

344

140

embedded image

380

141

embedded image

389

142

embedded image

320

143

embedded image

356

144

embedded image

386

145

embedded image

321

146

embedded image

301

147

embedded image

284

148

embedded image

327

149

embedded image

360

150

embedded image

293

151

embedded image

347

152

embedded image

340

153

embedded image

350

154

embedded image

285

155

embedded image

303

156

embedded image

319

157

embedded image

318

158

embedded image

356

159

embedded image

336

160

embedded image

377

161

embedded image

339

162

embedded image

357

163

embedded image

393

164

embedded image

332

165

embedded image

285

166

embedded image

354

167

embedded image

318

168

embedded image

353

169

embedded image

372

170

embedded image

389

171

embedded image

309

172

embedded image

342

173

embedded image

387

174

embedded image

323

175

embedded image

258

176

embedded image

294

177

embedded image

317

178

embedded image

338

179

embedded image

295

180

embedded image

326

181

embedded image

299

182

embedded image

317

183

embedded image

258

184

embedded image

293

185

embedded image

331

186

embedded image

411

187

embedded image

326

188

embedded image

317

189

embedded image

335

190

embedded image

371

191

embedded image

333

192

embedded image

351

193

embedded image

360

194

embedded image

335

195

embedded image

369

196

embedded image

344

197

embedded image

362

198

embedded image

353

199

embedded image

275

200

embedded image

429

201

embedded image

369

202

embedded image

333

203

embedded image

318

204

embedded image

348

205

embedded image

317

206

embedded image

275

207

embedded image

380

208

embedded image

396

209

embedded image

279

210

embedded image

351

211

embedded image

401

212

embedded image

353

213

embedded image

324

214

embedded image

360

215

embedded image

360

216

embedded image

333

217

embedded image

307

218

embedded image

307

219

embedded image

369

220

embedded image

308

221

embedded image

344

222

embedded image

300

223

embedded image

316

224

embedded image

301

225

embedded image

343

226

embedded image

329

227

embedded image

316

228

embedded image

315

229

embedded image

327

230

embedded image

317

231

embedded image

309

232

embedded image

327

233

embedded image

317

234

embedded image

345

235

embedded image

309

236

embedded image

325

237

embedded image

379

238

embedded image

334

239

embedded image

302

240

embedded image

343

241

embedded image

343

242

embedded image

363

243

embedded image

308

244

embedded image

308

245

embedded image

328

246

embedded image

319

247

embedded image

355

248

embedded image

364

249

embedded image

387

250

embedded image

284

251

embedded image

337

252

embedded image

350

253

embedded image

304

254

embedded image

337

255

embedded image

373

256

embedded image

463

257

embedded image

455

258

embedded image

343

259

embedded image

321

260

embedded image

337

261

embedded image

447

262

embedded image

435

263

embedded image

444

264

embedded image

338

265

embedded image

354

266

embedded image

295

267

embedded image

331

268

embedded image

433

269

embedded image

352

270

embedded image

401

271

embedded image

352

272

embedded image

363

273

embedded image

340

274

embedded image

401

275

embedded image

331

276

embedded image

426

277

embedded image

384

278

embedded image

376

279

embedded image

323

280

embedded image

363

281

embedded image

420

282

embedded image

390

283

embedded image

350

284

embedded image

349

285

embedded image

362

286

embedded image

364

287

embedded image

384

288

embedded image

385

289

embedded image

417

290

embedded image

369

291

embedded image

377

292

embedded image

336

293

embedded image

344

294

embedded image

327

295

embedded image

336

296

embedded image

387

297

embedded image

372

298

embedded image

405

299

embedded image

390

300

embedded image

337

301

embedded image

397

302

embedded image

363

303

embedded image

328

304

embedded image

342

305

embedded image

410

306

embedded image

356

307

embedded image

397

308

embedded image

349

309

embedded image

398

310

embedded image

398

311

embedded image

365

312

embedded image

351

313

embedded image

362

314

embedded image

362

315

embedded image

376

316

embedded image

365

317

embedded image

368

318

embedded image

405

319

embedded image

401

320

embedded image

344

321

embedded image

351

322

embedded image

365

323

embedded image

355

324

embedded image

353

325

embedded image

371

326

embedded image

322

327

embedded image

460

328

embedded image

420

329

embedded image

438

330

embedded image

441

331

embedded image

401

332

embedded image

386

333

embedded image

441

334

embedded image

384

335

embedded image

400

336

embedded image

405

337

embedded image

371

338

embedded image

362

339

embedded image

405

340

embedded image

401

341

embedded image

383

342

embedded image

361

343

embedded image

417

345

embedded image

438

346

embedded image

439

TABLE 2a

SMARCA2 inhibitors of the present disclosure.

Compd.

No.
Structure
Mass (u)

1a

embedded image

355

2a

embedded image

336

3a

embedded image

280

4a

embedded image

376

5a

embedded image

ND

6a

embedded image

348

7a

embedded image

356

8a

embedded image

298

9a

embedded image

332

10a

embedded image

266

11a

embedded image

300

12a

embedded image

340

13a

embedded image

251

14a

embedded image

244

15a

embedded image

287

16a

embedded image

312

17a

embedded image

278

18a

embedded image

296

19a

embedded image

283

20a

embedded image

283

21a

embedded image

284

22a

embedded image

282

23a

embedded image

284

24a

embedded image

316

25a

embedded image

278

26a

embedded image

294

27a

embedded image

330

28a

embedded image

258

29a

embedded image

317

30a

embedded image

244

31a

embedded image

283

32a

embedded image

335

33a

embedded image

312

34a

embedded image

286

35a

embedded image

292

36a

embedded image

299

37a

embedded image

288

38a

embedded image

284

39a

embedded image

283

40a

embedded image

313

41a

embedded image

389

42a

embedded image

351

43a

embedded image

405

44a

embedded image

406

45a

embedded image

335

46a

embedded image

352

47a

embedded image

314

48a

embedded image

314

49a

embedded image

314

50a

embedded image

300

51a

embedded image

300

52a

embedded image

272

53a

embedded image

324

54a

embedded image

315

55a

embedded image

281

56a

embedded image

314

57a

embedded image

312

58a

embedded image

312

59a

embedded image

312

60a

embedded image

352

61a

embedded image

413

62a

embedded image

366

63a

embedded image

424

64a

embedded image

338

65a

embedded image

348

66a

embedded image

320

67a

embedded image

350

68a

embedded image

334

69a

embedded image

384

70a

embedded image

350

71a

embedded image

TABLE 2b

SMARCA2 inhibitors of the present disclosure.

Compd. No.
Structure
Mass (u)

1b

embedded image

285

2b

embedded image

277

3b

embedded image

263

4b

embedded image

311

5b

embedded image

311

6b

embedded image

277

7b

embedded image

277

8b

embedded image

295

9b

embedded image

295

10b

embedded image

295

11b

embedded image

235

12b

embedded image

249

13b

embedded image

283

14b

embedded image

283

15b

embedded image

269

16b

embedded image

269

17b

embedded image

347

18b

embedded image

338

19b

embedded image

338

20b

embedded image

329

21b

embedded image

350

22b

embedded image

370

23b

embedded image

392

TABLE 2c

SMARCA2 inhibitors of the present disclosure.

Compd.

Mass

No.
Structure
(u)

1c

embedded image

323

2c

embedded image

399

3c

embedded image

381

4c

embedded image

391

5c

embedded image

441

6c

embedded image

477

7c

embedded image

422

8c

embedded image

399

9c

embedded image

416

10c

embedded image

416

11c

embedded image

415

12c

embedded image

367

13c

embedded image

467

14c

embedded image

467

15c

embedded image

290

16c

embedded image

290

17c

embedded image

408

18c

embedded image

454

19c

embedded image

467

20c

embedded image

453

21c

embedded image

408

22c

embedded image

445

23c

embedded image

404

24c

embedded image

419

25c

embedded image

389

26c

embedded image

429

27c

embedded image

467

28c

embedded image

348

29c

embedded image

458

30c

embedded image

454

31c

embedded image

453

32c

embedded image

334

33c

embedded image

405

34c

embedded image

462

35c

embedded image

471

36c

embedded image

359

37c

embedded image

405

38c

embedded image

467

39c

embedded image

458

40c

embedded image

439

41c

embedded image

437

42c

embedded image

467

43c

embedded image

462

44c

embedded image

467

45c

embedded image

337

46c

embedded image

387

47c

embedded image

371

48c

embedded image

405

49c

embedded image

393

50c

embedded image

383

51c

embedded image

467

52c

embedded image

348

53c

embedded image

362

54c

embedded image

455

55c

embedded image

439

56c

embedded image

471

57c

embedded image

480

58c

embedded image

431

59c

embedded image

439

60c

embedded image

441

61c

embedded image

458

62c

embedded image

442

63c

embedded image

442

64c

embedded image

458

65c

embedded image

472

66c

embedded image

496

67c

embedded image

442

68c

embedded image

480

69c

embedded image

498

70c

embedded image

458

71c

embedded image

442

72c

embedded image

387

73c

embedded image

383

74c

embedded image

508

75c

embedded image

494

76c

embedded image

361

77c

embedded image

469

78c

embedded image

431

79c

embedded image

431

80c

embedded image

433

81c

embedded image

438

82c

embedded image

395

165c

embedded image

ND

167c

embedded image

ND

169c

embedded image

502

171c

embedded image

ND

173c

embedded image

451

175c

embedded image

485

177c

embedded image

408

179c

embedded image

429

83c

embedded image

427

84c

embedded image

430

85c

embedded image

375

86c

embedded image

494

87c

embedded image

467

88c

embedded image

467

89c

embedded image

467

90c

embedded image

467

91c

embedded image

467

92c

embedded image

397

93c

embedded image

408

94c

embedded image

423

95c

embedded image

440

96c

embedded image

396

97c

embedded image

530

98c

embedded image

515

99c

embedded image

530

100c

embedded image

401

101c

embedded image

454

102c

embedded image

454

103c

embedded image

467

104c

embedded image

453

105c

embedded image

458

106c

embedded image

422

107c

embedded image

473

108c

embedded image

401

109c

embedded image

338

110c

embedded image

453

111c

embedded image

487

112c

embedded image

388

113c

embedded image

427

114c

embedded image

394

115c

embedded image

408

116c

embedded image

444

117c

embedded image

469

118c

embedded image

432

119c

embedded image

498

120c

embedded image

484

121c

embedded image

498

122c

embedded image

471

123c

embedded image

498

124c

embedded image

453

125c

embedded image

473

126c

embedded image

512

127c

embedded image

442

128c

embedded image

494

129c

embedded image

495

130c

embedded image

495

131c

embedded image

481

132c

embedded image

442

133c

embedded image

439

134c

embedded image

429

135c

embedded image

359

136c

embedded image

428

137c

embedded image

492

138c

embedded image

467

139c

embedded image

459

140c

embedded image

492

141c

embedded image

491

142c

embedded image

490

143c

embedded image

495

144c

embedded image

441

145c

embedded image

492

146c

embedded image

496

147c

embedded image

482

148c

embedded image

498

149c

embedded image

498

150c

embedded image

505

151c

embedded image

463

152c

embedded image

468

153c

embedded image

458

154c

embedded image

498

155c

embedded image

393

156c

embedded image

405

157c

embedded image

389

158c

embedded image

423

159c

embedded image

472

160c

embedded image

427

161c

embedded image

ND

162c

embedded image

ND

163c

embedded image

ND

164c

embedded image

ND

166c

embedded image

ND

168c

embedded image

ND

170c

embedded image

493

172c

embedded image

485

174c

embedded image

485

176c

embedded image

525

178c

embedded image

432

TABLE 2d

SMARCA2 inhibitors of the present disclosure.

Compd.

No.
Structure
Mass (u)

1d

embedded image

311

2d

embedded image

338

3d

embedded image

346

4d

embedded image

340

5d

embedded image

386

6d

embedded image

346

7d

embedded image

317

8d

embedded image

304

9d

embedded image

265

10d

embedded image

274

11d

embedded image

274

12d

embedded image

311

13d

embedded image

274

14d

embedded image

328

15d

embedded image

296

16d

embedded image

315

17d

embedded image

259

18d

embedded image

318

19d

embedded image

318

20d

embedded image

285

21d

embedded image

372

22d

embedded image

332

23d

embedded image

339

24d

embedded image

351

25d

embedded image

331

26d

embedded image

331

27d

embedded image

353

28d

embedded image

345

29d

embedded image

335

30d

embedded image

345

31d

embedded image

335

32d

embedded image

312

33d

embedded image

400

34d

embedded image

380

35d

embedded image

414

36d

embedded image

442

37d

embedded image

322

38d

embedded image

322

39d

embedded image

355

40d

embedded image

395

41d

embedded image

346

42d

embedded image

346

43d

embedded image

313

44d

embedded image

322

45d

embedded image

440

46d

embedded image

401

47d

embedded image

435

48d

embedded image

350

49d

embedded image

385

50d

embedded image

383

51d

embedded image

321

52d

embedded image

391

53d

embedded image

438

54d

embedded image

638

55d

embedded image

485

56d

embedded image

403

57d

embedded image

502

58d

embedded image

493

59d

embedded image

412

60d

embedded image

468

61d

embedded image

468

62d

embedded image

458

63d

embedded image

458

64d

embedded image

463

65d

embedded image

468

66d

embedded image

458

67d

embedded image

485

68d

embedded image

445

69d

embedded image

378

70d

embedded image

458

71d

embedded image

432

72d

embedded image

418

73d

embedded image

431

74d

embedded image

429

75d

embedded image

392

76d

embedded image

428

77d

embedded image

415

78d

embedded image

412

79d

embedded image

421

80d

embedded image

385

81d

embedded image

342

82d

embedded image

401

83d

embedded image

392

84d

embedded image

388

85d

embedded image

404

86d

embedded image

412

87d

embedded image

368

88d

embedded image

394

89d

embedded image

455

90d

embedded image

483

91d

embedded image

478

92d

embedded image

465

93d

embedded image

448

94d

embedded image

386

95d

embedded image

483

96d

embedded image

477

97d

embedded image

531

98d

embedded image

449

99d

embedded image

493

100d

embedded image

451

101d

embedded image

447

102d

embedded image

436

103d

embedded image

462

104d

embedded image

422

105d

embedded image

422

106d

embedded image

430

107d

embedded image

430

108d

embedded image

444

109d

embedded image

446

110d

embedded image

512

111d

embedded image

456

112d

embedded image

403

113d

embedded image

458

114d

embedded image

447

115d

embedded image

477

116d

embedded image

441

117d

embedded image

421

118d

embedded image

472

119d

embedded image

482

120d

embedded image

459

121d

embedded image

500

122d

embedded image

476

123d

embedded image

441

124d

embedded image

354

125d

embedded image

460

126d

embedded image

442

127d

embedded image

442

128d

embedded image

500

129d

embedded image

459

130d

embedded image

443

131d

embedded image

426

132d

embedded image

458

133d

embedded image

445

134d

embedded image

445

135d

embedded image

457

136d

embedded image

445

137d

embedded image

421

138d

embedded image

426

139d

embedded image

418

140d

embedded image

458

141d

embedded image

485

142d

embedded image

472

143d

embedded image

481

144d

embedded image

459

145d

embedded image

499

146d

embedded image

416

In some embodiments, the compound is not:

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As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅or C₆alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅or C₆straight chain (linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅or C₆branched saturated aliphatic hydrocarbon groups. In some embodiments, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅or C₆alkyl groups. Examples of alkyl include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C₁-C₆for straight chain, C₃-C₆for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

As used herein, the term “cycloalkyl” refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C₃-C₁₂, C₃-C₁₀, or C₃-C₈). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. Bridged rings are also included in the definition of cycloalkyl, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0] bicyclodecane and [2.2.2]bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term “heterocycloalkyl” refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-yl, 7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-yl, 3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic non-aromatic rings, only one of the rings needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydroindolyl, benzo[d][1,3]dioxolyl, [1,3]dioxolo[4,5-b]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, and 4,5,6,6a-tetrahydrocyclopenta[b]pyrrolyl).

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

“Alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. In some embodiments, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.

In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆for branched chain). The term “C₂-C₆” includes alkenyl groups containing two to six carbon atoms. The term “C₃-C₆” includes alkenyl groups containing three to six carbon atoms.

The term “unsubstituted or substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, aminosulfonyl, alkylsulfonyl, sulfonamido, nitro, trifluoromethyl, cyano, cycloalkyl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety (i.e., aryl or heteroaryl).

“Alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. In some embodiments, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆for branched chain). The term “C₂-C₆” includes alkynyl groups containing two to six carbon atoms. The term “C₃-C₆” includes alkynyl groups containing three to six carbon atoms. As used herein, “C₂-C₆alkenylene linker” or “C₂-C₆alkynylene linker” is intended to include C₂, C₃, C₄, C₅or C₆chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. In some embodiments, C₂-C₆alkenylene linker is intended to include C₂, C₃, C₄, C₅and C₆alkenylene linker groups.

The term “unsubstituted or substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, aminosulfonyl, alkylsulfonyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, cycloalkyl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety (i.e., aryl or heteroaryl).

Other unsubstituted or substituted moieties (such as unsubstituted or substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. In some embodiments, substituted heterocycloalkyl, cycloalkyl, aryl, or heteroaryl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. In some embodiments, substituted heterocycloalkyl, cycloalkyl, aryl, or heteroaryl includes those substituted with one or more oxo groups, such as thiazol-2-onyl, pyrrolidin-3-onyl, piperidin-2-onyl, morpholin-3-onyl, pyridin-2(3H)-onyl, pyridin-3(4H)-onyl, pyridin-4(3H)-only, pyridazin-3(4H)-only, dihydro-2H-pyran-3(4H)-onyl, isoindolin-1-onyl 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onyl, and 2H-benzo[b][1,4]oxazin-3(4H)-only.

“Aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. Examples include phenyl, naphthalenyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.” As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)_p, where p=1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine, indazole, 1H-pyrazolo[3,4-b]pyridine. 1H-benzo[d]imidazole.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, aminosulfonyl, alkylsulfonyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety (i.e., aryl or heteroaryl). Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

As described herein, compounds of the application may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the application. It will be appreciated that the phrase “unsubstituted or substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an unsubstituted or substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The terms “unsubstituted or substituted”, “unsubstituted or substituted alkyl,” “unsubstituted or substituted “unsubstituted or substituted alkenyl,” “unsubstituted or substituted alkynyl”, “unsubstituted or substituted cycloalkyl,” “unsubstituted or substituted cycloalkenyl,” “unsubstituted or substituted aryl”, “unsubstituted or substituted heteroaryl,” “unsubstituted or substituted aralkyl”, “unsubstituted or substituted heteroaralkyl,” “unsubstituted or substituted heterocycloalkyl,” “optionally substituted”, “optionally substituted alkyl,” “optionally substituted “optionally substituted alkenyl,” “optionally substituted alkynyl”, “optionally substituted cycloalkyl,” “optionally substituted cycloalkenyl,” “optionally substituted aryl”, “optionally substituted heteroaryl,” “optionally substituted aralkyl”, “optionally substituted heteroaralkyl,” “optionally substituted heterocycloalkyl,” and any other optionally substituted and/or any other unsubstituted or substituted group as used herein, refer to groups that are optionally substituted and/or substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl, —C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl, C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl, —S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl, —SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl, —NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

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

The term “optionally substituted,” as used herein, means not being substituted (e.g., none of the one or more hydrogen atoms on the designated variable is replaced with any other group) or being substituted (e.g., any one or more hydrogen atoms on the designated variable is replaced with a suitable group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound).

Any of the substituents on compounds or moieties defined herein may be further substituted as described herein for the compounds or moieties constituting those substituents. For example, an alkyl substituent on any group can be “substituted alkyl” as described herein.

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

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

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. The term “perhalogenated” generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

As used herein, “nitro” means a group of the formula —NO₂.

The term “carbonyl” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. Carbonyl groups may be further substituted so as to include, e.g. alkylcarbonyl, arylcarbonyl or aminocarbonyl.

The term “alkylcarbonyl” refers to compounds and moieties which contain an alkyl group connected to a carbonyl (i.e., carbon connected with a double bond to an oxygen atom). The term includes compounds wherein the alkyl group connected to the carbonyl may be further substituted.

The term “aminocarbonyl” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl group. The term includes “alkylaminocarbonyl” and “dialkylaminocarbonyl” groups that include alkyl, alkenyl or alkynyl groups bound to a nitrogen atom which is bound to the carbon of a carbonyl group. It also includes “arylaminocarbonyl” groups that include aryl or heteroaryl moieties bound to a nitrogen atom that is bound to the carbon of a carbonyl group. The terms “alkylaminocarbonyl”, “alkenylaminocarbonyl”, “alkynylaminocarbonyl” and “arylaminocarbonyl” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. Substituents on aminocarbonyl groups may be further substituted.

The term “carboxyl” refers to —COOH or its C₁-C₆alkyl ester.

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

The term “aryloxy” or “aryloxyl” includes substituted and unsubstituted aryl groups covalently linked to an oxygen atom, where aryl is as defined herein. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

The term “alkylsulfonyl” includes compounds and moieties which contain an alkyl group connected with a single bond to a sulfonyl group (i.e., a sulfur atom connected with double bonds to two oxygen atoms. Examples of alkylsulfonyl groups include, but are not limited to methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, n-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl, s-pentylsulfonyl and n-hexylsulfonyl. The alkylsulfonyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, aminosulfonyl, alkylsulfonyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.

As used herein, “amine” or “amino” refers to —NH₂. Amino groups may be further substituted so as to include, e.g. alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino. “Alkylamino” includes groups of compounds wherein the nitrogen of —NH₂is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc. “Dialkylamino” includes groups wherein the nitrogen of —NH₂is bound to two alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. “Arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. “Aminoaryl” and “aminoaryloxy” refer to aryl and aryloxyl substituted with amino. “Alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. “Acylamino” includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The term “aminosulfonyl” includes compounds and moieties which contain an amino group connected with a single bond to a sulfonyl group (i.e., a sulfur atom connected with double bonds to two oxygen atoms. The term includes “alkylaminosulfonyl” or “dialkylaminosulfonyl” groups that include alkyl, alkenyl or alkynyl groups bound to a nitrogen atom which is bound to the sulfur of a sulfonyl group. It also includes “arylaminosulfonyl” groups that include aryl or heteroaryl moieties bound to a nitrogen atom that is bound to the sulfur of a sulfonyl group.

“Cyano” or “nitrile” refers to the group —CN.

Compounds of the present disclosure that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the present disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N→O or N⁺—O⁻). Furthermore, in other instances, the nitrogens in the compounds of the present disclosure can be converted to N-hydroxy or N-alkoxy compounds. In some embodiments, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R is substituted or unsubstituted C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. In addition, a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present disclosure.

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

A carbon atom bonded to four nonidentical substituents is termed a “chiral center.”

“Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

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

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

Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers thereof, it being understood that not all atropic isomers may have the same level of activity. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

“Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine. Examples of lactam-lactim tautomerism are as shown below.

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

The compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The substituted benzene compounds also include those salts containing quaternary nitrogen atoms.

Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

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

The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

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

Pharmaceutical Formulations

The disclosure also provides pharmaceutical compositions comprising a compound of the disclosure or pharmaceutically acceptable salts thereof, and one or more other therapeutic agents disclosed herein, mixed with pharmaceutically suitable carriers or excipient(s) at doses to treat or prevent a disease or condition as described herein. The pharmaceutical compositions of the disclosure can also be administered in combination with other therapeutic agents or therapeutic modalities simultaneously, sequentially, or in alternation.

Mixtures of compositions of the disclosure can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, some aspects of the disclosure relate to a pharmaceutical composition comprising a therapeutically effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof, one or more other therapeutic agents, and a pharmaceutically acceptable diluent or carrier.

A “pharmaceutical composition” is a formulation containing the compounds of the disclosure in a form suitable for administration to a subject. A compound of the disclosure and one or more other therapeutic agents described herein each can be formulated individually or in multiple pharmaceutical compositions in any combinations of the active ingredients. Accordingly, one or more administration routes can be properly elected based on the dosage form of each pharmaceutical composition. Alternatively, a compound of the disclosure and one or more other therapeutic agents described herein can be formulated as one pharmaceutical composition.

In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

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

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

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

A composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

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

In certain embodiments the therapeutically effective amount of each pharmaceutical agent used in combination will be lower when used in combination in comparison to monotherapy with each agent alone. Such lower therapeutically effective amount could afford for lower toxicity of the therapeutic regimen.

For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀(the dose therapeutically effective in 50% of the population) and LD₅₀(the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

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

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

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL Q (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

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

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

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

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

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

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

In therapeutic applications, the dosages of the SMARCA2 antagonists (e.g., inhibitors) described herein, other therapeutic agents described herein, compositions comprising a compound of the disclosure and one or more other therapeutic agents, or the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In some aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In some aspects, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m², and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The composition of the disclosure is capable of further forming salts. The composition of the disclosure is capable of forming more than one salt per molecule, e.g., mono-, di-, tri-. All of these forms are also contemplated within the scope of the claimed invention.

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

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

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates), of the same salt.

“Pharmaceutically acceptable salt” includes both acid and base addition salts.

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

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

The composition of the disclosure may also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester.

The composition, or pharmaceutically acceptable salts or solvates thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

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

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

A composition of the disclosure may comprise a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents, or a pharmaceutically acceptable salt thereof. The disclosure also provides for the administration of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents or a pharmaceutically acceptable salt thereof, as a co-formulation or in separate formulations, wherein the administration of formulations is simultaneous, sequential, or in alternation. In certain embodiments, the other therapeutic agents can be an agent that is recognized in the art as being useful to treat the disease or condition being treated by the composition of the disclosure. In some embodiments, the other therapeutic agent can be an agent that is not recognized in the art as being useful to treat the disease or condition being treated by the composition of the disclosure. In some aspects, the other therapeutic agent can be an agent that imparts a beneficial attribute to the composition of the disclosure (e.g., an agent that affects the viscosity of the composition). The beneficial attribute to the composition of the disclosure includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of a compound of Formula (I), (IA), (IB), (IC), (ID), or (IE) or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.

The therapeutic agents set forth below are for illustrative purposes and not intended to be limiting. The disclosure includes at least one other therapeutic agent selected from the lists below. The disclosure can include more than one other therapeutic agent, e.g., two, three, four, or five other therapeutic agents such that the composition of the disclosure can perform its intended function.

In some embodiments, the other therapeutic agent is an anticancer agent. In some embodiments, the anticancer agent is a compound that affects histone modifications, such as an HDAC inhibitor (such as Zolinza® or Farydak®). In certain embodiments, an anticancer agent is selected from the group consisting of chemotherapeutics (such as 2CdA, 5-FU, 6-Mercaptopurine, 6-TG, Abraxane™, Accutane®, Actinomycin-D, Adriamycin®, Alimta®, Alkeran® all-trans retinoic acid, amethopterin, Ara-C, Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, Clolar™, Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®, Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Etopophos®, Fludara®, FUDR®, Gemzar®, Gleevec®, hexamethylmelamine, Hycamtin®, Hydrea®, IDamycin®, Ifex®, Imbruvica®, ixabepilone, Ixempra®, L-asparaginase, Leukeran®, liposomal Ara-C, L-PAM, Lysodren, mafosfamide, Marqibo®, Matulane®, mithracin, Mitomycin-C, Myleran®, Navelbine®, Neutrexin®, nilotinib, Nipent®, Nitrogen Mustard, Novantrone®, Oncaspar®, Panretin®, Paraplatin®, Platinol®, prolifeprospan 20 with carmustine implant, Sandostatin®, Targretin®, Tasigna®, Taxotere®, Temodar®, TESPA, Toposar®, Treanda®, Trisenox®, Valstar®, Velban®, Vidaza™, vincristine sulfate, VM 26, Xeloda® and Zanosar®); biologics (such as Alpha Interferon, Bacillus Calmette-Guerin, Bexxar®, Campath®, Ergamisol®, Erlotinib, Herceptin®, Interleukin-2, Iressa®, lenalidomide, Mylotarg®, Ontak®, Pegasys®, Revlimid®, Rituxan®, Tarceva™, Thalomid®, Tykerb®, Velcade® and Zevalin™); corticosteroids, (such as dexamethasone sodium phosphate, DeltaSone® and Delta-Cortef®); glucocorticoid receptor agonists (such as Baycadron®, Maxidex®, Ozurdex®, Econopred®, Omnipred®, or Millipred®); hormonal therapies (such as Arimidex®, Aromasin®, Casodex®, Cytadren®, Eligard®, Eulexin®, Evista®, Faslodex®, Femara®, Halotestin®, Megace®, Nilandron®, Nolvadex®, Plenaxis™ and Zoladex®); and radiopharmaceuticals (such as Iodotope®, Metastron®, Phosphocol® and Samarium SM-153); immunomodulatory drugs (such as Pomalyst®, Revlimid® and Thalidomid®); proteasome inhibitors (such as Kyprolis®, Ninlaro® and Velcade®); bcl-2 inhibitors (such as Venclexta®).

Exemplary glucocorticoid receptor agonists include but are not limited to, dexamethasone (Baycadron®, Maxidex®, Ozurdex®), methylprednisolone (Depo-Medrol®, Solu-Medrol®), or prednisolone (Econopred®, Omnipred®, Millipred®).

Exemplary immunomodulatory drugs include, but are not limited to, lenalidomide (Revlimid®), pomalidomide (Pomalyst®) and thalidomide (Thalidomid®);

Exemplary proteasome inhibitors, include but are not limited to, bortezomib (Velcade®), carfilzomib (Kyprolis®) and ixazomib (Ninlaro®),

Exemplary Bcl-2 inhibitors include, but are not limited to, venetoclax (Venclexta®).

In some embodiments, the other therapeutic agent is a chemotherapeutic agent (also referred to as an anti-neoplastic agent or anti-proliferative agent), selected from the group including an alkylating agent; an antibiotic; an anti-metabolite; a detoxifying agent; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an mTOR inhibitor; a multi-kinase inhibitor; a serine/threonine kinase inhibitor; a tyrosine kinase inhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, an inhibitor of a molecular target or enzyme (e.g., a kinase or a protein methyltransferase), a cytidine analogue drug or any chemotherapeutic, anti-neoplastic or anti-proliferative agent listed in www.cancer.org/docroot/cdg/cdg_0.asp.

Exemplary alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan®; Neosar®); chlorambucil (Leukeran®); melphalan (Alkeran®); carmustine (BiCNU@); busulfan (Busulfex®); lomustine (CeeNU@); dacarbazine (DTIC-Dome®); oxaliplatin (Eloxatin®); carmustine (Gliadel®); ifosfamide (Ifex®); mechlorethamine (Mustargen); busulfan (Myleran®); carboplatin (Paraplatin®); cisplatin (CDDP®; Platinol®); temozolomide (Temodar®); thiotepa (Thioplex®); bendamustine (Treanda®); or streptozocin (Zanosar®).

Exemplary antibiotics include, but are not limited to, doxorubicin (Adriamycin®); doxorubicin liposomal (Doxil®); mitoxantrone (Novantrone®); bleomycin (Blenoxane®); daunorubicin (Cerubidine®); daunorubicin liposomal (DaunoXome®); dactinomycin (Cosmegen®); epirubicin (Ellence®); idarubicin (IDamycin®); plicamycin (Mithracin®); mitomycin (Mutamycin®); pentostatin (Nipent®); or valrubicin (Valstar®).

Exemplary anti-metabolites include, but are not limited to, fluorouracil (Adrucil®); capecitabine (Xeloda®); hydroxyurea (Hydrea®); mercaptopurine (Purinethol®); pemetrexed (Alimta); fludarabine (Fludara®); nelarabine (Arranon®); cladribine (Cladribine Novaplus®); clofarabine (Clolar®); cytarabine (Cytosar-U®); decitabine (Dacogen®); cytarabine liposomal (DepoCyt®); hydroxyurea (Droxia®); pralatrexate (Folotyn®); floxuridine (FUDR®); gemcitabine (Gemzar®); cladribine (Leustatin®); fludarabine (Oforta®); methotrexate (MTX®; Rheumatrex®); methotrexate (Trexall®); thioguanine (Tabloid®); TS-1 or cytarabine (Tarabine PFS®).

Exemplary detoxifying agents include, but are not limited to, amifostine (Ethyol®) or mesna (Mesnex®).

Exemplary interferons include, but are not limited to, interferon alfa-2b (Intron A®) or interferon alfa-2a (Roferon-A®).

Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin®); ofatumumab (Arzerra®); bevacizumab (Avastin®); rituximab (Rituxan®); cetuximab (Erbitux®); panitumumab (Vectibix®); tositumomab/iodinel31 tositumomab (Bexxar®); alemtuzumab (Campath®); ibritumomab (Zevalin®; In-111@; Y-90 Zevalin®); gemtuzumab (Mylotarg®); eculizumab (Soliris®) ordenosumab.

Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb®); cetuximab (Erbitux®); erlotinib (Tarceva®); panitumumab (Vectibix®); PKI-166; canertinib (CI-1033); matuzumab (Emd7200) or EKB-569.

Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin®); lapatinib (Tykerb®) or AC-480.

Histone Deacetylase Inhibitors include, but are not limited to, vorinostat (Zolinza®) and panobinostat (Farydak®).

Exemplary hormones include, but are not limited to, tamoxifen (Soltamox; Nolvadex®); raloxifene (Evista®); megestrol (Megace®); leuprolide (Lupron®; Lupron Depot®; Eligard®; Viadur®); fulvestrant (Faslodex®); letrozole (Femara®); triptorelin (Trelstar LA®; Trelstar Depot®); exemestane (Aromasin®); goserelin (Zoladex®); bicalutamide (Casodex®); anastrozole (Arimidex®); fluoxymesterone (Androxy®; Halotestin®); medroxyprogesterone (Provera®; Depo-Provera®); estramustine (Emcyt®); flutamide (Eulexin®); toremifene (Fareston®); degarelix (Firmagon®); nilutamide (Nilandron®); abarelix (Plenaxis®); or testolactone (Teslac®).

Exemplary mitotic inhibitors include, but are not limited to, paclitaxel (Taxol®; Onxol®; Abraxane®); docetaxel (Taxotere®); vincristine (Oncovin®; Vincasar PFS®); vinblastine (Velban®); etoposide (Toposar®; Etopophos®; VePesid®); teniposide (Vumon®); ixabepilone (Ixempra®); nocodazole; epothilone; vinorelbine (Navelbine®); camptothecin (CPT); irinotecan (Camptosar®); topotecan (Hycamtin®); amsacrine or lamellarin D (LAM-D).

Exemplary mTOR inhibitors include, but are not limited to, everolimus (Afinitor®) or temsirolimus (Torisel®); rapamune, ridaforolimus; or AP23573.

Exemplary VEGF/VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin®); sorafenib (Nexavar®); sunitinib (Sutent®); ranibizumab; pegaptanib; or vandetinib.

Exemplary microtubule targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastin, nocodazole, epothilones and navelbine.

Exemplary topoisomerase poison drugs include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.

Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxol.

Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferative agents include, but are not limited to, altretamine (Hexalen); isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin (Vesanoid®); azacitidine (Vidaza®); bortezomib (Velcade®) asparaginase (Elspar®); ibrutinib (Imbruvica®); levamisole (Ergamisol®); mitotane (Lysodren®); procarbazine (Matulane); pegaspargase (Oncaspar®); denileukin diftitox (Ontak®); porfimer (Photofrin®); aldesleukin (Proleukin®); lenalidomide (Revlimid®); bexarotene (Targretin®); thalidomide (Thalomid®); temsirolimus (Torisel®); arsenic trioxide (Trisenox®); verteporfin (Visudyn®); mimosine (Leucenol®); (1M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 M potassium oxonate), or lovastatin.

In further aspects, the other therapeutic agent is a chemotherapeutic agent or a cytokine such as G-CSF (granulocyte colony stimulating factor).

In yet further aspects, the other therapeutic agents can be standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP), Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molar ratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinotecan or Camptosar™), CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone or prednisolone), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone or prednisolone), CVP (cyclophosphamide, vincristine, and prednisone), hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisone), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

In other aspects, the other therapeutic agents can be an inhibitor of an enzyme, such as a receptor or non-receptor kinase. Receptor and non-receptor kinases are, for example, tyrosine kinases or serine/threonine kinases. Kinase inhibitors described herein are small molecules, polynucleic acids, polypeptides, or antibodies.

Exemplary kinase inhibitors include, but are not limited to, Bevacizumab (targets VEGF), BIBW 2992 (targets EGFR and Erb2), Cetuximab/Erbitux (targets Erb1), Imatinib/Gleevic (targets Bcr-Abl), Trastuzumab (targets Erb2), Gefitinib/Iressa (targets EGFR), Ranibizumab (targets VEGF), Pegaptanib (targets VEGF), Erlotinib/Tarceva (targets Erb1), Nilotinib (targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2/Her2), GW-572016/lapatinib ditosylate (targets HER2/Erb2), Panitumumab/Vectibix (targets EGFR), Vandetinib (targets RET/VEGFR), E7080 (multiple targets including RET and VEGFR), Herceptin (targets HER2/Erb2), PKI-166 (targets EGFR), Canertinib/CI-1033 (targets EGFR), Sunitinib/SU-11464/Sutent (targets EGFR and FLT3), Matuzumab/Emd7200 (targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR), PKC-412 (targets VEGR and FLT3), Vatalanib/Ptk787/ZK222584 (targets VEGR), CEP-701 (targets FLT3), SU5614 (targets FLT3), MLN518 (targets FLT3), XL999 (targets FLT3), VX-322 (targets FLT3), Azd0530 (targets SRC), BMS-354825 (targets SRC), SKI-606 (targets SRC), CP-690 (targets JAK), AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 (targets JAK), sorafenib/Nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3, and RET), Dasatinib/Sprycel (BCR/ABL and Src), AC-220 (targets Flt3), AC-480 (targets all HER proteins, “panHER”), Motesanib diphosphate (targets VEGF1-3, PDGFR, and c-kit), Denosumab (targets RANKL, inhibits SRC), AMG888 (targets HER3), and AP24534 (multiple targets including Flt3).

Exemplary serine/threonine kinase inhibitors include, but are not limited to, Rapamune (targets mTOR/FRAP1), Deforolimus (targets mTOR), Certican/Everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1), Eril/Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK), Seliciclib/CYC202/Roscovitrine (targets CDK), SNS-032/BMS-387032 (targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets PKC), Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K), VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase), Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 (targets MAP/MEK), GW681323 (targets MAP/MEK), CC-401 (targets INK), CEP-1347 (targets JNK), and PD 332991 (targets CDK).

Exemplary tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606 CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

In some embodiments, the other therapeutic agent is a SMARCA2 antagonist or inhibitor. Exemplary SMARCA2 inhibitors include BMCL 2968, I-BET151, JQ1, and PFI-3. Exemplary SMARCA2 antagonists include antisense RNA, shRNA, siRNA, CRISPR/Cas9, transcription activator-like effector nucleases (TALEN), Zinc Finger nucleases (ZFN), antibodies, antibody fragments and antibody mimetics.

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

A “subject” includes a mammal. The mammal can be e.g., any mammal, e.g., a human, primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. Preferably, the mammal is a human.

As used herein, a “subject in need thereof” is a subject that has cancer or a precancerous condition. In some embodiments, a subject in need thereof has cancer.

In some embodiments, a subject in need thereof is a subject having a disorder associated with a SMARCA4 mutation, a change in level of activity or function of SMARCA4, a change in level of SMARCA4 protein expression as compared to a control level, a change in level of SMARCA4 mRNA expression as compared to a control level, and/or an increased risk of developing such disorder relative to the population at large. In some embodiments, the disorder associated with a SMARCA4 mutation is a cancer. In some embodiments, the change in level of activity or function of SMARCA4 as compared to a control level is a decrease. In some embodiments, the change in level of SMARCA4 protein expression as compared to a control level is a decrease. In some embodiments, the change in level of SMARCA4 mRNA expression as compared to a control level is a decrease. In some embodiments, a subject in need thereof is a subject having a disorder associated with a SMARCA4 mutation, a decrease in level of activity or function of SMARCA4, a decrease in level of SMARCA4 protein expression as compared to a control level, a decrease in level of SMARCA4 mRNA expression as compared to a control level, and/or an increased risk of developing such disorder relative to the population at large

In some embodiments, a subject in need thereof is a subject having a disorder associated with a SMARCA4 mutation, decreased level of activity or function of SMARCA4, a decreased level of SMARCA4 protein expression, a decreased level of SMARCA4 mRNA expression compared to a control level, and/or a subject having an increased risk of developing such disorder relative to the population at large. In some embodiments, the subject or a cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4. In some embodiments, the SMARCA4 mutation is a change in at least one nucleotide as compared to the wild-type SMARCA4.

In some embodiments, the subject or a cell of the subject exhibits a decrease of SMARCA4 protein expression as compared to a control level. In some embodiments, the subject or a cell of the subject exhibits a loss of SMARCA4 protein expression as compared to a control level. In some embodiments, the subject or a cell of the subject exhibits a loss of SMARCA4 mRNA expression as compared to a control level. In some embodiments, the subject or a cell of the subject exhibits a decreased SMARCA4 activity as compared to a control level. In some embodiments, the subject or a cell of the subject exhibits a decreased SMARCA4 function as compared to a control level.

In some embodiments, the control level is a level of SMARCA4 protein expression, a level of SMARCA4 mRNA expression, a level of SMARCA4 activity or a level of SMARCA4 function in a subject or cell from a subject that does not have cancer. In some embodiments, the control level may be a level of SMARCA4 protein expression, a level of SMARCA4 mRNA expression, a level of SMARCA4 activity or a level of SMARCA4 function in a subject or cell from a subject belonging to a certain population, wherein the level is equal or about equal to the average level of protein expression, mRNA expression, activity or function of SMARCA4 observed in said population. In some embodiments, the control level may be a level of protein expression, mRNA expression, activity or function of SMARCA4 that is equal or about equal to the average level of protein expression, mRNA expression, activity or function of SMARCA4 in the population at large. In some embodiments, the control level is a level of SMARCA4 protein expression in a subject or cell from a subject that does not have cancer. In some embodiments, the control level is a level of SMARCA4 mRNA expression in a subject or cell from a subject that does not have cancer. In some embodiments, the control level is a level of SMARCA4 activity in a subject or cell from a subject that does not have cancer. In some embodiments, the control level is a level of SMARCA4 function in a subject or cell from a subject that does not have cancer.

The subject of the disclosure includes any human subject who has been diagnosed with, has symptoms of, or is at risk of developing a cancer or a precancerous condition. The subject of the disclosure includes any human subject expressing a mutant SMARCA4 gene. For example, a mutant SMARCA4 comprises one or more mutations, wherein the mutation is a substitution, a point mutation, a nonsense mutation, a missense mutation, a deletion, an insertion, or a translocation or any other SMARCA4 mutation described herein or otherwise known in the art to be associated with a loss of function of SMARCA4.

A subject in need thereof may have refractory or resistant cancer. “Refractory or resistant cancer” means cancer that does not respond to an established line of treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment. In some embodiments, the subject in need thereof has cancer recurrence following remission on most recent therapy. In some embodiments, the subject in need thereof received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In certain embodiments, the prior therapy is monotherapy. In certain embodiments, the prior therapy is combination therapy.

In some embodiments, a subject in need thereof may have a secondary cancer as a result of a previous therapy. “Secondary cancer” means cancer that arises due to or as a result from previous carcinogenic therapies, such as chemotherapy.

The subject may also exhibit decreased function or expression of SMARCA4, or loss of function of SMARCA4.

As used herein, the term “responsiveness” is interchangeable with terms “responsive”, “sensitive”, and “sensitivity”, and it is meant that a subject is showing therapeutic responses when administered a composition of the disclosure, e.g., tumor cells or tumor tissues of the subject undergo apoptosis and/or necrosis, and/or display reduced growing, dividing, or proliferation. This term is also meant that a subject will or has a higher probability, relative to the population at large, of showing therapeutic responses when administered a composition of the disclosure, e.g., tumor cells or tumor tissues of the subject undergo apoptosis and/or necrosis, and/or display reduced growing, dividing, or proliferation.

As used herein, “sample” means any biological sample derived from the subject, includes but is not limited to, cells, tissues samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), tumor cells, and tumor tissues. Preferably, the sample is selected from bone marrow, peripheral blood cells, blood, plasma and serum. Samples can be provided by the subject under treatment or testing. Alternatively samples can be obtained by the physician according to routine practice in the art.

As used herein, a “normal cell” is a cell that cannot be classified as part of a “cell proliferative disorder”. A normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease. Preferably, a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.

As used herein, “contacting a cell” refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell.

As used herein, “candidate compound” refers to a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, that has been or will be tested in one or more in vitro or in vivo biological assays, in order to determine if that compound is likely to elicit a desired biological or medical response in a cell, tissue, system, animal or human that is being sought by a researcher or clinician. A candidate compound is a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof. The biological or medical response can be the treatment of cancer. The biological or medical response can be treatment or prevention of a cell proliferative disorder. In vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

As used herein, “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.

A composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, can also be used to prevent a disease, condition, or disorder. As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition, or disorder.

As used herein, the term “alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. In some embodiments, the administration of pharmaceutical compositions of the disclosure leads to the elimination of a sign or symptom, however, elimination is not required. Effective dosages are expected to decrease the severity of a sign or symptom. For instance, a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.

As used herein, the term “severity” is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state. Alternatively, or in addition, severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art-recognized methods. Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes). Alternatively, or in addition, severity is meant to describe the tumor grade by art-recognized methods (see, National Cancer Institute, www.cancer.gov). Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute, www.cancer.gov). Furthermore, severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, www.cancer.gov).

In some aspects of the disclosure, severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized. Moreover, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe. In these situations, prolonging the life expectancy of the subject and/or reducing pain, decreasing the proportion of cancerous cells or restricting cells to one system, and improving cancer stage/tumor grade/histological grade/nuclear grade are considered alleviating a sign or symptom of the cancer.

As used herein the term “symptom” is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non-health-care professionals.

As used herein the term “sign” is also defined as an indication that something is not right in the body. But signs are defined as things that can be seen by a doctor, nurse, or other health care professional.

Cancer

A “cancer cell” or “cancerous cell” is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.

Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewing family of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilm's Tumor.

A “cell proliferative disorder of the hematologic system” is a cell proliferative disorder involving cells of the hematologic system. A cell proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A cell proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. Preferably, compositions of the disclosure may be used to treat a cancer selected from the group consisting of a hematologic cancer of the disclosure or a hematologic cell proliferative disorder of the disclosure. A hematologic cancer of the disclosure can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.

A “cell proliferative disorder of the lung” is a cell proliferative disorder involving cells of the lung. Cell proliferative disorders of the lung can include all forms of cell proliferative disorders affecting lung cells. Cell proliferative disorders of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in tissue and organs in the body other than the lung. Preferably, compositions of the disclosure may be used to treat lung cancer or cell proliferative disorders of the lung. Lung cancer can include all forms of cancer of the lung. Lung cancer can include malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer can include “scar carcinoma,” bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).

Cell proliferative disorders of the lung can include all forms of cell proliferative disorders affecting lung cells. Cell proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung. Cell proliferative disorders of the lung can include hyperplasia, metaplasia, and dysplasia of the lung. Cell proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Cell proliferative disorders of the lung can include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia. Individuals exposed to inhaled injurious environmental agents such as cigarette smoke and asbestos may be at increased risk for developing cell proliferative disorders of the lung. Prior lung diseases that may predispose individuals to development of cell proliferative disorders of the lung can include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

A “cell proliferative disorder of the colon” is a cell proliferative disorder involving cells of the colon. Preferably, the cell proliferative disorder of the colon is colon cancer. Preferably, compositions of the disclosure may be used to treat colon cancer or cell proliferative disorders of the colon. Colon cancer can include all forms of cancer of the colon. Colon cancer can include sporadic and hereditary colon cancers. Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma. Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.

Cell proliferative disorders of the colon can include all forms of cell proliferative disorders affecting colon cells. Cell proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. A cell proliferative disorder of the colon can include adenoma. Cell proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon. Prior colon diseases that may predispose individuals to development of cell proliferative disorders of the colon can include prior colon cancer. Current disease that may predispose individuals to development of cell proliferative disorders of the colon can include Crohn's disease and ulcerative colitis. A cell proliferative disorder of the colon can be associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC. An individual can have an elevated risk of developing a cell proliferative disorder of the colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.

A “cell proliferative disorder of the pancreas” is a cell proliferative disorder involving cells of the pancreas. Cell proliferative disorders of the pancreas can include all forms of cell proliferative disorders affecting pancreatic cells. Cell proliferative disorders of the pancreas can include pancreas cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysaplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas. Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer can also include pancreatic neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).

A “cell proliferative disorder of the prostate” is a cell proliferative disorder involving cells of the prostate. Cell proliferative disorders of the prostate can include all forms of cell proliferative disorders affecting prostate cells. Cell proliferative disorders of the prostate can include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, malignant growths or lesions of the prostate and metastatic lesions in tissue and organs in the body other than the prostate. Cell proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.

A “cell proliferative disorder of the skin” is a cell proliferative disorder involving cells of the skin. Cell proliferative disorders of the skin can include all forms of cell proliferative disorders affecting skin cells. Cell proliferative disorders of the skin can include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma and other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin. Cell proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.

A “cell proliferative disorder of the ovary” is a cell proliferative disorder involving cells of the ovary. Cell proliferative disorders of the ovary can include all forms of cell proliferative disorders affecting cells of the ovary. Cell proliferative disorders of the ovary can include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissue and organs in the body other than the ovary. Cell proliferative disorders of the ovary can include hyperplasia, metaplasia, and dysplasia of cells of the ovary.

A “cell proliferative disorder of the breast” is a cell proliferative disorder involving cells of the breast. Cell proliferative disorders of the breast can include all forms of cell proliferative disorders affecting breast cells. Cell proliferative disorders of the breast can include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast. Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

A cell proliferative disorder of the breast can be a precancerous condition of the breast. Compositions of the disclosure may be used to treat a precancerous condition of the breast. A precancerous condition of the breast can include atypical hyperplasia of the breast, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0 growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ). A precancerous condition of the breast can be staged according to the TNM classification scheme as accepted by the American Joint Committee on Cancer (AJCC), where the primary tumor (T) has been assigned a stage of T0 or Tis; and where the regional lymph nodes (N) have been assigned a stage of N0; and where distant metastasis (M) has been assigned a stage of M0.

The cell proliferative disorder of the breast can be breast cancer. Preferably, compositions of the disclosure may be used to treat breast cancer. Breast cancer includes all forms of cancer of the breast. Breast cancer can include primary epithelial breast cancers. Breast cancer can include cancers in which the breast is involved by other tumors such as lymphoma, sarcoma or melanoma. Breast cancer can include carcinoma of the breast, ductal carcinoma of the breast, lobular carcinoma of the breast, undifferentiated carcinoma of the breast, cystosarcoma phyllodes of the breast, angiosarcoma of the breast, and primary lymphoma of the breast. Breast cancer can include Stage I, II, IIIA, IIIB, IIIC and IV breast cancer. Ductal carcinoma of the breast can include invasive carcinoma, invasive carcinoma in situ with predominant intraductal component, inflammatory breast cancer, and a ductal carcinoma of the breast with a histologic type selected from the group consisting of comedo, mucinous (colloid), medullary, medullary with lymphocytic infiltrate, papillary, scirrhous, and tubular. Lobular carcinoma of the breast can include invasive lobular carcinoma with predominant in situ component, invasive lobular carcinoma, and infiltrating lobular carcinoma. Breast cancer can include Paget's disease, Paget's disease with intraductal carcinoma, and Paget's disease with invasive ductal carcinoma. Breast cancer can include breast neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).

Preferably, compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, may be used to treat breast cancer. A breast cancer that is to be treated can include familial breast cancer. A breast cancer that is to be treated can include sporadic breast cancer. A breast cancer that is to be treated can arise in a male subject. A breast cancer that is to be treated can arise in a female subject. A breast cancer that is to be treated can arise in a premenopausal female subject or a postmenopausal female subject. A breast cancer that is to be treated can arise in a subject equal to or older than 30 years old, or a subject younger than 30 years old. A breast cancer that is to be treated has arisen in a subject equal to or older than 50 years old, or a subject younger than 50 years old. A breast cancer that is to be treated can arise in a subject equal to or older than 70 years old, or a subject younger than 70 years old.

A breast cancer that is to be treated can be typed to identify a familial or spontaneous mutation in BRCA1, BRCA2, or p53. A breast cancer that is to be treated can be typed as having a HER2/neu gene amplification, as overexpressing HER2/neu, or as having a low, intermediate or high level of HER2/neu expression. A breast cancer that is to be treated can be typed for a marker selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, Ki-67, CA15-3, CA 27-29, and c-Met. A breast cancer that is to be treated can be typed as ER-unknown, ER-rich or ER-poor. A breast cancer that is to be treated can be typed as ER-negative or ER-positive. ER-typing of a breast cancer may be performed by any reproducible means. ER-typing of a breast cancer may be performed as set forth in Onkologie 27: 175-179 (2004). A breast cancer that is to be treated can be typed as PR-unknown, PR-rich, or PR-poor. A breast cancer that is to be treated can be typed as PR-negative or PR-positive. A breast cancer that is to be treated can be typed as receptor positive or receptor negative. A breast cancer that is to be treated can be typed as being associated with elevated blood levels of CA 15-3, or CA 27-29, or both.

A breast cancer that is to be treated can include a localized tumor of the breast. A breast cancer that is to be treated can include a tumor of the breast that is associated with a negative sentinel lymph node (SLN) biopsy. A breast cancer that is to be treated can include a tumor of the breast that is associated with a positive sentinel lymph node (SLN) biopsy. A breast cancer that is to be treated can include a tumor of the breast that is associated with one or more positive axillary lymph nodes, where the axillary lymph nodes have been staged by any applicable method. A breast cancer that is to be treated can include a tumor of the breast that has been typed as having nodal negative status (e.g., node-negative) or nodal positive status (e.g., node-positive). A breast cancer that is to be treated can include a tumor of the breast that has metastasized to other locations in the body. A breast cancer that is to be treated can be classified as having metastasized to a location selected from the group consisting of bone, lung, liver, or brain. A breast cancer that is to be treated can be classified according to a characteristic selected from the group consisting of metastatic, localized, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recurrent, and inoperable.

A compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, may be used to treat or prevent a cell proliferative disorder of the breast, or to treat or prevent breast cancer, in a subject having an increased risk of developing breast cancer relative to the population at large. A subject with an increased risk of developing breast cancer relative to the population at large is a female subject with a family history or personal history of breast cancer. A subject with an increased risk of developing breast cancer relative to the population at large is a female subject having a germ-line or spontaneous mutation in BRCA1 or BRCA2, or both. A subject with an increased risk of developing breast cancer relative to the population at large is a female subject with a family history of breast cancer and a germ-line or spontaneous mutation in BRCA1 or BRCA2, or both. A subject with an increased risk of developing breast cancer relative to the population at large is a female who is greater than 30 years old, greater than 40 years old, greater than 50 years old, greater than 60 years old, greater than 70 years old, greater than 80 years old, or greater than 90 years old. A subject with an increased risk of developing breast cancer relative to the population at large is a subject with atypical hyperplasia of the breast, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, or a stage 0 growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ).

A breast cancer that is to be treated can histologically graded according to the Scarff-Bloom-Richardson system, wherein a breast tumor has been assigned a mitosis count score of 1, 2, or 3; a nuclear pleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or 3; and a total Scarff-Bloom-Richardson score of between 3 and 9. A breast cancer that is to be treated can be assigned a tumor grade according to the International Consensus Panel on the Treatment of Breast Cancer selected from the group consisting of grade 1, grade 1-2, grade 2, grade 2-3, or grade 3.

A cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, Ti, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1. A cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. A cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pN0, PN0 (I−), PN0 (I+), PN0 (mol−), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

A cancer that is to be treated can include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than 5 centimeters in diameter. A cancer that is to be treated can be classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. A cancer that is to be treated can be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells). A cancer that is to be treated can be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells). A cancer that is to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer that is to be treated can be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy. A cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.

In some embodiments, a cancer that is to be treated is a cancer in which a member of the SWI/SNF complex, e.g., SMARCA4, is mutated, deleted and/or exhibits a loss of function (e.g., a decrease of enzymatic activity). For example, a cancer to be treated may be a cancer in which SMARCA4 is mutated. Non limiting examples of cancers in which SMARCA4 mutations occur include small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), bladder cancer, stomach cancer, lung cancer (e.g., non-small cell lung cancer), glioblastoma brain tumors (glioma, GBM), head and neck cancer, kidney cancer, uterine cancer, cervical cancer, and pancreatic cancer.

A cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. A cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division). A cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction.

Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects the nearby organs or structures. If a cancer spreads (metastasizes), then symptoms may appear in different parts of the body.

Treating cancer can result in a reduction in tumor volume. Preferably, after treatment, tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Tumor volume may be measured by any reproducible means of measurement.

Treating cancer can result in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, analog or derivative thereof. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, analog or derivative thereof. Preferably, the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. A decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

Treating cancer can result in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time.

Treating cancer can result in a decrease in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.

Treating or preventing a cell proliferative disorder can result in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. The rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

Treating or preventing a cell proliferative disorder can result in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. The proportion of proliferating cells can be equivalent to the mitotic index.

Treating or preventing a cell proliferative disorder can result in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. The size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.

Treating or preventing a cell proliferative disorder can result in a decrease in the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment, the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement. An abnormal cellular morphology can be measured by microscopy, e.g., using an inverted tissue culture microscope. An abnormal cellular morphology can take the form of nuclear pleiomorphism.

As used herein, the term “selectively” means tending to occur at a higher frequency in one population than in another population. The compared populations can be cell populations. Preferably, a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, acts selectively on a cancer or precancerous cell but not on a normal cell. Preferably, a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, acts selectively to modulate one molecular target (e.g., a target helicase, such as SMARCA2) but does not significantly modulate another molecular target (e.g., a different helicase, or a non-helicase enzyme, e.g., in the case of a SMARCA2 ATPase inhibitor, the ATPase activity of a different helicase, or a different protein having ATPase activity). A composition of the disclosure, e.g., a composition comprising SMARCA2 inhibitor, and one or more other therapeutic agents, such as prednisone, can modulate the activity of a molecular target (e.g., a target helicase). Modulating refers to stimulating or inhibiting an activity of a molecular target. Preferably, a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 2-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound. More preferably, a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound. The activity of a molecular target may be measured by any reproducible means. The activity of a molecular target may be measured in vitro or in vivo. For example, the activity of a molecular target may be measured in vitro by an enzymatic activity assay or a DNA binding assay, or the activity of a molecular target may be measured in vivo by assaying for expression of a reporter gene.

A composition of the disclosure, e.g., a composition comprising SMARCA2 inhibitor, and one or more other therapeutic agents, such as prednisone, can modulate the activity of a molecular target (e.g., a target helicase). Modulating refers to stimulating or inhibiting an activity of a molecular target. Preferably, a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 2-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound. More preferably, a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound. The activity of a molecular target may be measured by any reproducible means. The activity of a molecular target may be measured in vitro or in vivo. For example, the activity of a molecular target may be measured in vitro by an enzymatic activity assay or a DNA binding assay, or the activity of a molecular target may be measured in vivo by assaying for expression of a reporter gene.

A composition of the disclosure does not significantly modulate the activity of a molecular target if the addition of the compound does not stimulate or inhibit the activity of the molecular target by greater than 10% relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.

Administering a composition of the disclosure to a cell or a subject in need thereof can result in modulation (i.e., stimulation or inhibition) of an activity of a helicase of interest.

Administering a compound of the disclosure, e.g., a composition comprising aSMARCA2 inhibitor, and one or more other therapeutic agents, such as prednisone, to a cell or a subject in need thereof results in modulation (i.e., stimulation or inhibition) of an activity of an intracellular target (e.g., substrate). Several intracellular targets can be modulated with the compounds of the disclosure, including, but not limited to, helicases.

Activating refers to placing a composition of matter (e.g., protein or nucleic acid) in a state suitable for carrying out a desired biological function. A composition of matter capable of being activated also has an unactivated state. An activated composition of matter may have an inhibitory or stimulatory biological function, or both.

Elevation refers to an increase in a desired biological activity of a composition of matter (e.g., a protein or a nucleic acid). Elevation may occur through an increase in concentration of a composition of matter.

As used herein, “a cell cycle checkpoint pathway” refers to a biochemical pathway that is involved in modulation of a cell cycle checkpoint. A cell cycle checkpoint pathway may have stimulatory or inhibitory effects, or both, on one or more functions comprising a cell cycle checkpoint. A cell cycle checkpoint pathway is comprised of at least two compositions of matter, preferably proteins, both of which contribute to modulation of a cell cycle checkpoint. A cell cycle checkpoint pathway may be activated through an activation of one or more members of the cell cycle checkpoint pathway. Preferably, a cell cycle checkpoint pathway is a biochemical signaling pathway.

As used herein, “cell cycle checkpoint regulator” refers to a composition of matter that can function, at least in part, in modulation of a cell cycle checkpoint. A cell cycle checkpoint regulator may have stimulatory or inhibitory effects, or both, on one or more functions comprising a cell cycle checkpoint. A cell cycle checkpoint regulator can be a protein or not a protein.

Treating cancer or a cell proliferative disorder can result in cell death, and preferably, cell death results in a decrease of at least 10% in number of cells in a population. More preferably, cell death means a decrease of at least 20%; more preferably, a decrease of at least 30%; more preferably, a decrease of at least 40%; more preferably, a decrease of at least 50%; most preferably, a decrease of at least 75%. Number of cells in a population may be measured by any reproducible means. A number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are as shown in Li et al., Proc Natl Acad Sci USA. 100(5): 2674-8, 2003. In some aspects, cell death occurs by apoptosis.

Preferably, an effective amount of a composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, is not significantly cytotoxic to normal cells. A therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells. In some aspects, cell death occurs by apoptosis.

Contacting a cell with a composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, can induce or activate cell death selectively in cancer cells. Administering to a subject in need thereof a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, can induce or activate cell death selectively in cancer cells. Contacting a cell with a composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, can induce cell death selectively in one or more cells affected by a cell proliferative disorder. Preferably, administering to a subject in need thereof a composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, induces cell death selectively in one or more cells affected by a cell proliferative disorder.

The disclosure relates to a method of treating or preventing cancer by administering a composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, where administration of the composition of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, results in one or more of the following: prevention of cancer cell proliferation by accumulation of cells in one or more phases of the cell cycle (e.g. G1, G1/S, G2/M), or induction of cell senescence, or promotion of tumor cell differentiation; promotion of cell death in cancer cells via cytotoxicity, necrosis or apoptosis, without a significant amount of cell death in normal cells, antitumor activity in animals with a therapeutic index of at least 2. As used herein, “therapeutic index” is the maximum tolerated dose divided by the efficacious dose.

The present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

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

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

Compounds of the present disclosure can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this disclosure having any of the Formulae described herein may be prepared according to the procedures illustrated in Schemes 1-6 below, from commercially available starting materials or starting materials which can be prepared using literature procedures. Certain variables (such as R₁, R₂, R₅and A) in Schemes 1-6 are as defined in any Formula described herein, unless otherwise specified.

One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups.

One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3^rdedition, John Wiley & Sons: New York, 1999.

Preferred protecting groups include, but are not limited to:

For a hydroxyl moiety: TBS, benzyl, THP, Ac

For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allyl ester

For amines: Cbz, BOC, DMB

For diols: Ac (×2) TBS (×2), or when taken together acetonides

For thiols: Ac

For benzimidazoles: SEM, benzyl, PMB, DMB

For aldehydes: di-alkyl acetals such as dimethoxy acetal or diethyl acetyl.

In the reaction schemes described herein, multiple stereoisomers may be produced. When no particular stereoisomer is indicated, it is understood to mean all possible stereoisomers that could be produced from the reaction. A person of ordinary skill in the art will recognize that the reactions can be optimized to give one isomer preferentially, or new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC may be used to separate the isomers.

The following abbreviations are used throughout the specification and are defined below:

- ACN acetonitrile
- Ac acetyl
- AcOH acetic acid
- AlCl₃aluminum chloride
- BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)
- t-BuOK potassium t-butoxide
- tBuONa or t-BuONa sodium t-butoxide
- br broad
- BOC tert-butoxy carbonyl
- Cbz benzyloxy carbonyl
- CDCl₃CHCl₃chloroform
- CH₂Cl₂dichloromethane
- CH₃CN acetonitrile
- CsCO₃cesium carbonate
- CH₃NO₃nitromethane
- d doublet
- dd doublet of doublets
- dq doublet of quartets
- DCE 1,2 dichloroethane
- DCM dichloromethane
- Δ heat
- δ chemical shift
- DIEA N,N-diisopropylethylamine (Hunig's base)
- DMB 2,4 dimethoxy benzyl
- DMF N,N-Dimethylformamide
- DMSO Dimethyl sulfoxide
- DMSO-d6 deuterated dimethyl sulfoxide
- EA or EtOAc Ethyl acetate
- ES electrospray
- Et₃N triethylamine
- equiv equivalents
- g grams
- g relative centrifugal force (RCF) expressed in units of gravity
- h hours
- HATU Hexafluorophosphate azabenzotriazole tetramethyl uronium (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate)
- H₂O water
- HCl hydrogen chloride or hydrochloric acid
- HPLC High performance liquid chromatography
- Hz Hertz
- IPA isopropyl alcohol
- i-PrOH isopropyl alcohol
- J NMR coupling constant
- K₂CO₃potassium carbonate
- HI potassium iodide
- KCN potassium cyanide
- LCMS or LC-MS Liquid chromatography mass spectrum
- M molar
- m multiplet
- mg milligram
- MHz megahertz
- mL milliliter
- mm millimeter
- mmol millimole
- mol mole
- [M+1] molecular ion plus one mass unit
- m/z mass/charge ratio
- m-CPBA meta-chloroperbenzoic acid
- MeCN Acetonitrile
- MeOH methanol
- Mel Methyl iodide
- min minutes
- μm micron
- MsCl Mesyl chloride
- MW microwave irradiation
- N normal
- Na₂SO₄sodium sulfate
- NH₃ammonia
- NaBH(AcO)₃sodium triacetoxyborohydride
- NaI sodium iodide
- Na₂SO₄sodium sulfate
- NH₄C₁ammonium chloride
- NH₄HCO₃ammonium bicarbonate
- nm nanometer
- NBS N-bromosuccinimide
- NMP N-methylpyrrolidinone
- NMR Nuclear Magnetic Resonance
- Pd(OAc)₂palladium (II) acetate
- Pd/C Palladium on carbon
- Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium(0)
- PMB para methoxybenzyl
- ppm parts per million
- POCl₃phosphoryl chloride
- prep-HPLC preparative High Performance Liquid Chromatography
- PTSA para-toluenesulfonic acid
- p-TsOH para-toluenesulfonic acid
- RT retention time
- rt room temperature
- s singlet
- t triplet
- t-BuXPhos 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl
- TEA Triethylamine
- TFA trifluoroacetic acid
- TfO triflate
- THP tetrahydropyran
- TsOH tosic acid
- UV ultraviolet

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Scheme 1 shows a synthesis of the pyridone-carboxamide portion of the compounds disclosed herein following a general route. A pyridin-2-ol (A1) is converted to a 5-nitropyridin-2(1H)-one (A2) under standard nitration conditions, e.g., using a mixture of nitric acid (HNO₃) and sulfuric acid (H₂SO₄), followed by alkylation in the presence of a base, (e.g., NaH, DMF) to give N-alkylated 5-nitropyridin-2(1H)-one (A3). A3 is reduced to a 5-amino-pyridin-2(1H)-one (A4) using standard reduction reagents (e.g., Fe/NH₄Cl/MeOH—H₂O). Amide coupling, using e.g., a carbonyl chloride (Q=Cl) in the presence of a tertiary amine base (e.g. triethylamine, TEA; N,N-diisopropylethylamine, DIEA), or a carboxylic acid (Q=OH) in the presence of a coupling reagent (e.g., hexafluorophosphate azabenzotriazole tetramethyl uranium, HATU) yields the compound (A5).

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Scheme 2 shows a synthesis of the pyridone-carboxamide portion of the compounds when R₂is NR_5′R₅or OR₅. The 5-nitropyridin-2(1H)-one B3 is obtained following step 1 and step 2 as described in Scheme 1. Reaction of B3 with an amine in the presence of a catalyst (e.g., Pd(OAc)₂/Xantphos/Cs₂CO₃/dioxane) or with alcohol (R₅ZH) in the presence of a catalyst (e.g., CuI/t-BuOLi) yields intermediate B4. Step 4 and step 5 are the same as step 3 and step 4 in Scheme 1.

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Scheme 3 shows an exemplary synthesis of a A-COOH intermediate containing a cyano group following a general route. For example, a 4-haloheteroaryl-2-carboxylic acid (C1) is brominated using a bromination reagent (e.g. N-bromosuccinimide, NBS) in a suitable solvent (e.g. dimethylformamide, DMF). The resulting 5-bromo-4-haloheteroaryl-2-carboxylic acid (C2) is reacted with zinc cyanide (Zn(CN)₂) using a coupling catalyst (e.g., Pd(PPh₃)₄) in an appropriate solvent (e.g., DMF) to give a 5-cyano-4-haloheteroaryl-2-carboxylic acid (C3).

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Scheme 4 shows a synthesis of a A-COOH intermediate following a general route. For example, 5-haloheteroaryl-2-carboxylate (D1) is fluorinated using a fluorination reagent (e.g. 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), Selectfluor™) in a suitable solvent (e.g. CH₃CN). The resulting 5-halo-4-fluoroheteroaryl-2-carboxylate (D2) is hydrolized to 5-halo-4-fluoroheteroaryl-2-carboxylic acid (D3) using suitable reagent (e.g. lithium hydroxide) in an appropriate solvent (e.g., THF/H₂O).

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Scheme 5 shows a synthesis of a A-COOH intermediate following a general route. For example, a heteroaryl (E1) is carboxylated using CO₂and a suitable base (e.g., lithium diisopropylamide, LDA) to yield the heteroaryl carboxylic acid (E2).

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Scheme 6 shows a synthesis of a A-COOH intermediate when A is thiazole. For example, an amide (F1) is converted to a thioamide (F2) using an appropriate thionation reagent (e.g., P₂S₅). F2 is then reacted with ethyl 2-chloro-3-oxopropanoate in an appropriate solvent (e.g. tert-butanol) to yield a ethyl thiazole-5-carboxylate (F3). F3 is hydrolized to give a thiazole-5-carboxylic acid (E4) using suitable base (e.g. sodium hydroxide) in an appropriate solvent (e.g., ethanol).

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Scheme 7 shows a method for introducing a halogen substituent at the A-COOH intermediate. For example a heteroaryl-2-carboxylic acid (G1) is halogenated using an appropriate agent (e.g. N-chlorosuccinimide, NCS) in an appropriate solvent (e.g. dimethylformamide, DMF) to give a 5-halo-heteroaryl-2-carboxylic acid (G2).

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Scheme 8 shows a method for coupling the A-COOH intermediate to the pyridone carboxamide portion of the compounds herein, following a general route. For example, a heteroaryl-2-carboxylic acid (H1) is reacted with a 5-aminopyridin-2(1H)-one (H2) in the presence of a coupling reagent (e.g., hexafluorophosphate azabenzotriazole tetramethyl uranium, HATU) and an appropriate base (e.g. triethylamine, TEA; N,N-diisopropylethylamine, DIEA) in an appropriate solvent (e.g. dimethylformamide, DMF) to give the desired compound (H3).

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Scheme 9 shows a method for attaching an alkynyl linked group to the compounds herein. For example, a 4-bromo-N-(6-oxo-1,6-dihydropyridin-3-yl)heteroaryl-2-carboxamide (I1) is reacted with an ethynyl compound (I2) via a standard cross-coupling reaction (e.g., Sonogashira coupling) using appropriate catalysts (e.g., a palladium catalyst, e.g., dichlorobis(tricyclohexylphosphine)palladium and a copper catalyst, e.g., CuI) in the presence of a base (e.g., caesium carbonate) in an appropriate solvent (e.g., dimethyl sulfoxide, DMSO) (I3).

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Scheme 10 shows a method for attaching an aryl or alkynyl linked group to the compounds herein. For example, a N-(5-halo-6-oxo-1,6-dihydropyridin-3-yl)heteroaryl-2-carboxamide (K1) is reacted with an alkynyl compound or aryl boronate via a standard cross-coupling reaction (e.g., Sonogashira or Suzuki coupling) using appropriate catalysts (e.g., a palladium catalyst, e.g., dichlorobis(tricyclohexylphosphine)palladium and a copper catalyst, e.g., CuI) in the presence of a base (e.g., caesium carbonate) in an appropriate solvent (e.g., dimethyl sulfoxide, DMSO) to give the desired compound (K2).

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Scheme 11 shows a method for attaching a trifluoromethyl group to the compounds herein. For example, a 5-iodoheteroaryl-2-carboxylate (Li) is reacted with a trifluoromethylating agent (e.g., methyl 2,2-difluoro-2-(fluorodimethylidene-lambda6-sulfanyl)acetate) using appropriate catalysts (e.g., a copper catalyst, e.g., CuI) in an appropriate solvent (e.g., DMF/HMPA) to give the desired compound (L2).

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Scheme 11 shows a method for attaching a substituted alkyl group to the compounds herein. For example, a heteroaryl-2-carboxylate (M1) is reacted with an anhydride (M2) using appropriate catalysts (e.g., a ruthenium catalyst, e.g., tris(bipyridine)ruthenium(II) chloride) and an N-oxide (e.g., 4-phenylpyridine N-oxide) and blue light in an appropriate solvent (e.g., acetonitrile, ACN) to give the desired compound (M3).

Example 1: The compounds listed in Table 2, 2a, 2b, 2c, and 2d were synthesized by reaction schemes depicted in the general schemes above or by methods described below.

Synthesis of Compound 82c: 4-cyano-N-[1-(2,2-difluoroethyl)-5-fluoro-6-oxopyridin-3-yl]-5-(trifluoromethyl)thiophene-2-carboxamide

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Step 1: Synthesis of methyl 4-bromo-5-iodothiophene-2-carboxylate

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Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (20.00 mL), methyl 4-bromothiophene-2-carboxylate (6.00 g, 27.14 mmol, 1.00 equiv), LDA (2 mol/L) (30.05 mL, 60.10 mmol, 2.21 equiv) was added by dropwise at −78° C. after 40 min at this temperature, 12 (7.00 g, 27.58 mmol, 1.02 equiv) was added by dropwise in THF (5 mL). The resulting solution was stirred for 2 hr at −78° C. in a liquid nitrogen bath. The reaction progress was monitored by GCMS. The reaction was quenched by 5 mL of H₂O, The resulting mixture was concentrated. And the residue was dissolved by ethyl acetate (40 mL), washed by 20% NaHSO₃aqueous (3×15 ml) to remove excess iodine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 6.4 g (68%) of methyl 4-bromo-5-iodothiophene-2-carboxylate as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆.ppm) δ 7.69 (s, 1H), 3.83 (s, 3H).

Step 2: Synthesis of methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate

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Into a 100-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed DMF (9.00 mL), HMPA (9.00 mL), methyl 4-bromo-5-iodothiophene-2-carboxylate (2.00 g, 5.76 mmol, 1.00 equiv), methyl 2,2-difluoro-2-(fluorodimethylidene-lambda6-sulfanyl)acetate (2.36 g, 12.54 mmol, 2.18 equiv), CuI (570.00 mg, 2.99 mmol, 0.52 equiv), KF (1.00 g, 17.21 mmol, 2.99 equiv). The resulting solution was stirred for 2 hr at 70° C. in an oil bath. The reaction progress was monitored by GCMS. The reaction was quenched by 30 mL of H₂O, The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×10 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 1.4 g (90%) of methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate as yellow oil. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 7.77 (s, 1H), 3.83 (s, 3H)

Step 3: Synthesis of methyl 4-cyano-5-(trifluoromethyl)thiophene-2-carboxylate

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Into a 100-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed THE (5.00 mL), H₂O (5.00 mL), methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate (1.00 g, 3.45 mmol, 1.00 equiv), Zn(CN)₂(1.20 g, 10.56 mmol, 3.00 equiv), t-Buxphos Pd G3 (562.00 mg, 0.70 mmol, 0.20 equiv). The resulting solution was stirred for 2 hr at 80° C. in an oil bath. The reaction progress was monitored by GCMS. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 800 mg (98%) of methyl 4-cyano-5-(trifluoromethyl)thiophene-2-carboxylate as a yellow solid. ¹H NMR (300 MHz, Methanol-d₄, ppm) δ 8.12 (s, 1H), 3.84 (s, 3H).

Step 4: Synthesis of 4-cyano-5-(trifluoromethyl)thiophene-2-carboxylic acid

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Into a 100-mL 3-necked round-bottom flask, was placed THE (5.00 mL), H₂O (1.00 mL), methyl 4-cyano-5-(trifluoromethyl)thiophene-2-carboxylate (1.00 g, 4.25 mmol, 1.00 equiv), lithium hydroxide (140.00 mg, 5.84 mmol, 1.37 equiv). The resulting solution was stirred for 2 hr at 0° C. in a water/ice bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated. The pH was adjusted to 5-6 with HCl (1 mol/L). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 600 mg (63%) of 4-cyano-5-(trifluoromethyl)thiophene-2-carboxylic acid as a yellow solid. LCMS (ESI): RT=0.71 min, m z=220 [M−H]⁻;

Step 5: Synthesis of 4-cyano-N-[1-(2,2-difluoroethyl)-5-fluoro-6-oxopyridin-3-yl]-5-(trifluoromethyl)thiophene-2-carboxamide

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Into a 100-mL round-bottom flask, was placed DMF (5.00 mL), 4-cyano-5-(trifluoromethyl)thiophene-2-carboxylic acid (464.00 mg, 2.09 mmol, 1.00 equiv), 5-amino-1-(2,2-difluoroethyl)-3-fluoropyridin-2-one (490.00 mg, 2.55 mmol, 1.22 equiv), DIEA (812.00 mg, 6.28 mmol, 2.99 equiv), HATU (957.00 mg, 2.51 mmol, 1.20 equiv), The resulting solution was stirred for 2 hr at 25° C. The reaction progress was monitored by LCMS, The reaction was quenched by 20 mL of H₂O, The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified by C18 column with acetonitrile/water (40%). This resulted in 233.4 mg (28%) of 4-cyano-N-[1-(2,2-difluoroethyl)-5-fluoro-6-oxopyridin-3-yl]-5-(trifluoromethyl)thiophene-2-carboxamide as a white solid.

LCMS (ESI): RT=1.77 min, m z=396.1 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.71 (s, 1H), 8.37 (s, 1H), 8.00 (d, J=18.0 Hz, 1H), 7.71 (dd, J=11.4, 2.1 Hz, 1H), 6.54-6.18 (m, 1H), 4.58 (m, 2H).

Synthesis of Compound 125: 4-Chloro-N-(5-chloro-1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-cyanothiophene-2-carboxamide

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Step 1: 5-Bromo-4-chlorothiophene-2-carboxylic acid

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Into a 10-mL round-bottom flask was placed 4-chlorothiophene-2-carboxylic acid (5 g, 30.75 mmol, 1.00 equiv), NBS (10 g, 101.69 mmol, 1.80 equiv), and N,N-dimethylformamide (10 ml). The resulting solution was stirred for 12 h at 50° C. in an oil bath. The resulting mixture was poured into water and extracted by ethyl acetate (3×50 ml), the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column (mobile phase: ethyl acetate/petroleum ether (1:1)), and 6 g (81% yield) of 5-bromo-4-chlorothiophene-2-carboxylic acid.

LCMS (ESI): RT=0.49 min, m/z=241[M+1]⁺; 1H NMR (300 MHz, DMSO-d6, ppm) δ 13.8 (br, 1H), 7.71 (s, 1H).

Step 2: 4-Chloro-5-cyanothiophene-2-carboxylic acid

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Into a 20-mL round-bottom flask was placed 5-bromo-4-chlorothiophene-2-carboxylic acid (1 g, 4.14 mmol, 1.00 equiv), Zn(CN)₂(2.5 g, 20.6 mmol, 5.00 equiv), N,N-dimethylformamide (5 mL), and Pd(PPh₃)₄(1.25 g, 1.03 mmol, 0.25 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was poured into water and extract by ethyl acetate (3×20 ml). The organic layer was concentrated under vacuum to give crude product. The residue was applied onto a silica gel column (mobile phase: ethyl acetate/petroleum ether (1:1)) to give 0.6 g (77% yield) of 4-chloro-5-cyanothiophene-2-carboxylic acid as a white solid.

LCMS (ESI): RT=0.87 min, m/z=188[M+1]⁺

Step 1a: 3-Chloro-1-(2-fluoroethyl)-5-nitropyridin-2(1H)-one

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Into a 10-mL round-bottom flask was placed 3-chloro-5-nitro-1,2-dihydropyridin-2-one (5 g, 28.5 mmol, 1.00 equiv), NaH (2.2 g, 57 mmol, 2.00 equiv), 1-fluoro-2-iodoethane (10 g, 57 mmol, 2.00 equiv), and N,N-dimethylformamide (20 mL). The resulting solution was stirred for 12 h at 25° C. The reaction progress was monitored by LCMS. Then the mixture was poured into water and extracted by ethyl acetate (3×40 ml). The organic layers combined and concentrated. The residue was applied onto a silica gel column (mobile phase: ethyl acetate/petroleum ether (1:1)) to give 2 g (46% yield) of 5-amino-3-chloro-1-(2-fluoroethyl)-1,2-dihydropyridin-2-one as a white solid.

LCMS (ESI): RT=0.26 min, m/z=221[M+1]⁺¹H NMR (300 MHz, DMSO-d₆, ppm) δ 7.44-7.45 (m, 1H), 6.91-6.92 (m, 1H), 4.74 (t, J=4.7 Hz, 1H), 4.59 (t, J=4.6 Hz, 1H), 4.22 (t, J=4.7 Hz, 1H), 4.13 (t, J=4.7 Hz, 1H).

Step 2a: 5-Amino-3-chloro-1-(2-fluoroethyl)pyridin-2(1H)-one

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Into a 10-mL round-bottom flask was placed 3-chloro-1-(2-fluoroethyl)-5-nitro-1,2-dihydropyridin-2-one (5 g, 22.67 mmol, 1.00 equiv), Fe (6.3 g, 113.35 mmol, 5.00 equiv), NH₄Cl (6.3 g, 113.35 mmol, 5.00 equiv), methanol (2 mL), and water (1 mL). The resulting solution was stirred for 12 h at 60° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column (mobile phase: MeOH/DCM (1:10)). This resulted in 2 g (46% yield) of 5-amino-3-chloro-1-(2-fluoroethyl)-1,2-dihydropyridin-2-one as a white solid.

LCMS (ESI): (ES, m/z): RT=0.21 min, m/z=191[M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ7.34-7.35 (m, 1H), 6.81-6.82 (m, 1H), 4.86-4.87 (m, 2H), 4.71 (t, J=4.7 Hz, 1H), 4.51 (t, J=4.6 Hz, 1H), 4.16 (t, J=4.7 Hz, 1H), 4.06 (t, J=4.7 Hz, 1H).

Step 3: 4-Chloro-N-(5-chloro-1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-cyanothiophene-2-carboxamide (Compound 125)

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Into a 10-mL round-bottom flask was placed 4-chloro-5-cyanothiophene-2-carboxylic acid (5 g, 26.10 mmol, 1.00 equiv), 5-amino-3-chloro-1-(2-fluoroethyl)-1,2-dihydropyridin-2-one (4.98 g, 26.10 mmol, 1.00 equiv), HATU (11.8 g, 31.31 mmol, 1.20 equiv), DIEA (16.8 g, 130.5 mmol, 5.00 equiv), and N,N-dimethylformamide (10 mL). The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The resulting solution was extracted with 5×50 mL of ethyl acetate. The organic layer was concentrated under vacuum and the crude product 2.5 g (89%) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH₃CN/H₂O=20.0% increasing to CH₃CN/H₂O (0.05%)=50.0% within 10 min; Detector, UV 254 nm. This resulted in 695 mg (26% yield) of 4-chloro-N-[5-chloro-1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-cyanothiophene-2-carboxamide as a white solid.

LCMS (ESI): RT=0.49 min, m/z=359.8[M+1]⁺; ¹HNMR (300 MHz, Methanol-d₄, ppm) δ 8.20 (d, J=2.6 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 7.86 (s, 1H), 4.87-4.78 (m, 1H), 4.72-4.63 (m, 1H), 4.49-4.40 (m, 1H), 4.40-4.31 (m, 1H).

Synthesis of Compound 151: 2-Cyano-N-(5-fluoro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)thiazole-5-carboxamide

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Step 1: 3-Fluoro-5-nitro-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one

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Into a 100-mL round-bottom flask, was placed 3-fluoro-5-nitro-1,2-dihydropyridin-2-one (1.5 g, 9.49 mmol, 1.00 equiv), Cs₂CO₃(6.2 g, 19.03 mmol, 2.01 equiv), and N,N-dimethylformamide (20 mL), followed by the dropwise addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 g, 47.39 mmol, 4.99 equiv). The resulting solution was stirred for 3 h at 25° C. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of 50 mL of water. The resulting solution was extracted with 4×50 mL of dichloromethane. The organic layers combined were applied onto a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.3 g (57% yield) of 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-2-one as a yellow solid.

LCMS (ESI): RT=1.74 min, m z=241.0 [M+H]⁺;

Step 2: 5-Amino-3-fluoro-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one

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Into a 100-mL 3-necked round-bottom flask was placed 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-2-one (400 mg, 1.67 mmol, 1.00 equiv), methanol (2.5 mL), and Raney Ni (300 mg). This was followed by the dropwise addition of hydrazine hydrate (1 mL) while stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 180 mg (51% yield) of 5-amino-3-fluoro-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-2-one as a black solid.

LCMS (ESI): RT=0.80 min, m z=211.0 [M+H]⁺.

Step 3: 2-Cyano-N-(5-fluoro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)thiazole-5-carboxamide (Compound 151)

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Into a 8-mL vial was placed 5-amino-3-fluoro-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-2-one (150 mg, 0.71 mmol, 1.00 equiv), 2-cyano-1,3-thiazole-5-carboxylic acid (100 mg, 0.71 mmol, 1.00 equiv), HATU (370 mg, 1.06 mmol, 1.50 equiv), DIEA (254 mg, 2.13 mmol, 3.00 equiv), and N,N-dimethylformamide (2 mL). The resulting solution was stirred for 3 h at 25° C. The reaction progress was monitored by LCMS. The resulting mixture was quenched by 5 ml of ice/water and extracted by dichloromethane (3×10 mL). The organic layers were concentrated under vacuum. The crude product 120 mg (85%) was purified by Prep-HPLC with the following conditions: Column, X-bridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 10 mmol NH₄HCO₃and CH₃CN (10.0% CH₃CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm. This resulted in 28.5 mg (24% yield) of 2-cyano-N-[5-fluoro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl]-LCMS (ESI): RT=1.54 min, m z=346.9 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.78 (s, 1H), 8.03 (s, 1H), 7.71 (dd, J=11.2 Hz, 2.5 Hz, 1H), 5.04 (q, J=9.5 Hz, 2H) ppm.

Synthesis of Compound 297: N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-2-(trifluoromethyl)thiazole-5-carboxamide

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Step 1: 3-Fluoro-5-nitropyridin-2-ol

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Into a 2000-mL round-bottom flask was placed 3-fluoro-1,2-dihydropyridin-2-one (100 g, 884.22 mmol, 1.00 equiv), and con. H₂SO₄(700 mL), by the dropwise addition of fuming HNO₃(150 mL) while stirring at 80° C. The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The reaction was poured into 5000 mL of water/ice. The resulting solution was extracted with 3×2000 mL of ethyl acetate. The resulting mixture was concentrated under vacuum. The crude product was crystallized from ethyl acetate to give 40 g (30% yield) of 3-fluoro-5-nitro-1,2-dihydropyridin-2-one as a yellow solid.

LCMS (ESI): RT=0.49 min, m z=159 [M+H]⁺; ¹H NMR (300 MHz, Methanol-d₄ppm) δ 8.52 (dd, J=2.8, 1.1 Hz, 1H), 8.09 (dd, J=10.0, 2.8 Hz, 1H)

Step 2: 1-(2,2-Difluoroethyl)-3-fluoro-5-nitropyridin-2(1H)-one

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Into a 250-mL round-bottom flask was placed 3-fluoro-5-nitro-1,2-dihydropyridin-2-one (7 g, 12.60 mmol, 1.00 equiv), potassium carbonate (18.3 g, 37.61 mmol, 3.00 equiv), N,N-dimethylformamide (80 mL), and 1,1-difluoro-2-iodoethane (24.5 g, 37.61 mmol, 3.00 equiv). The resulting solution was stirred for 8 h at 80° C. The resulting solution was extracted with 3×500 mL of ethyl acetate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 4.7 g (71% yield) of 1-(2,2-difluoroethyl)-3-fluoro-5-nitro-1,2-dihydropyridin-2-one as yellow oil.

LCMS (ESI): RT=1.05 min, m z=223.0 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 9.13 (dd, J=2.9, 1.3 Hz, 1H), 8.27 (dd, J=9.8, 2.8 Hz, 1H), 6.60-6.15 (m, 1H), 4.71-4.57 (m, 2H)

Step 3: 5-Amino-1-(2,2-difluoroethyl)-3-fluoropyridin-2(1H)-one

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Into a 50-mL round-bottom flask was placed 1-(2,2-difluoroethyl)-3-fluoro-5-nitro-1,2-dihydropyridin-2-one (1.7 g, 7.65 mmol, 1.00 equiv), Fe (4.2 g, 76.65 mmol, 10.00 equiv), NH₄C₁(4.1 g, 76.65 mmol, 10.00 equiv), methanol (10 mL), and water (10 mL). The resulting solution was stirred for 2 h at 60° C., cooled to 25° C. and filtered. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with MeOH/DCM (1:10). This resulted in 700 mg (48% yield) of 5-amino-1-(2,2-difluoroethyl)-3-fluoro-1,2-dihydropyridin-2-one as a brown oil.

LCMS (ESI): RT=0.46 min, m/z=193.1 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 7.42-7.04 (m, 3H), 6.72 (s, 1H), 6.50-6.06 (m, 1H), 4.34-4.26 (m, 2H).

Step 4: N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-2-(trifluoromethyl)thiazole-5-carboxamide (Compound 297)

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Into a 25-mL round-bottom flask was placed 5-amino-1-(2,2-difluoroethyl)-3-fluoro-1,2-dihydropyridin-2-one (159 mg, 0.83 mmol, 1.20 equiv), HATU (210 mg, 0.56 mmol, 1.10 equiv), DIEA (190 mg, 1.53 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL), and 2-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid (100 mg, 0.51 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3×50 mL of ethyl acetate. The resulting mixture was concentrated under vacuum. The crude product 170 mg (90%) was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, CH₃CN/H₂O (0.05% TFA)=20.0% increasing to CH₃CN/H₂O (0.05% TFA)=30.0% within 8 min; Detector, UV 254 nm. This resulted in 108.6 mg (44% yield) of N-[1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl]-2-(trifluoromethyl)-1,3-thiazole-5-carboxamide as a light yellow solid.

LCMS (ESI): RT=1.66 min, m z=372.0 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 10.71 (s, 1H), 8.74 (d, J=1.3 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.67 (dd, J=11.3, 2.6 Hz, 1H), 6.53 (t, J=3.7 Hz, 1H), 4.57-4.46 (m, 2H).

Synthesis of Compound 298: 4-Chloro-N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)thiophene-2-carboxamide

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Step 1: 4-Chloro-5-(trifluoromethyl)thiophene-2-carboxylic acid

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Into a 50-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 1-chloro-2-(trifluoromethyl)cyclopentane (1 g, 5.794 mmol, 1.00 equiv), THE (5 mL), and LDA (0.31 mL, 6.95 mmol, 1.20 equiv) (2.5 mol/L in THF) at −78° C. (liquid nitrogen/ethanol). The resulting solution was stirred for 30 min at −78° C., then solid CO₂(excess) was added slowly and in batches. The resulting solution was stirred for an additional 2 h at 25° C., and the reaction was then quenched by the addition of 4 mL of HCl (2 mol/L). The resulting solution was extracted with 3×20 mL of dichloromethane and washed with 3×10 mL saturated NaCl solution. The organic layers combined and concentrated, and the solids were collected.

LCMS (ESI): RT=1.13 min, m/z=229 [M−H]⁺; ¹H NMR (400 MHz, DMSO-d₆ppm) δ 8.88 (bar, 1H), 7.31 (s, 1H).

Step 2: 4-Chloro-N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)thiophene-2-carboxamide (Compound 298)

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Into a 50-mL round-bottom flask was placed 4-chloro-5-(trifluoromethyl)thiophene-2-carboxylic acid (200 mg, 0.86 mmol, 1.00 equiv), 5-amino-1-(2,2-difluoroethyl)-3-fluoro-1,2-dihydropyridin-2-one (199.98 mg, 1.04 mmol, 1.2 equiv), HATU (428.73 mg, 1.12 mmol, 1.30 equiv), DIEA (336.29 mg, 2.60 mmol, 3.00 equiv), and N,N-dimethylformamide (2 mL). The resulting solution was stirred for 2 h at 25° C., and the reaction progress was monitored by LCMS. The resulting mixture was quenched by 10 ml of ice/water. The resulting solution was extracted with 3×15 mL of ethyl acetate. The resulting mixture was concentrated under vacuum. The crude product (160 mg; 85%) was purified by Prep-HPLC with the following conditions: Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH₄HCO₃) and ACN (40% Phase B up to 65% in 7 min); Detector, UV. This resulted in 72 mg (36% yield) of 4-chloro-N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)thiophene-2-carboxamide as a white solid.

LCMS (ESI): RT=2.439 min, m/z=405 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆ppm) δ 10.59 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 8.02 (t, J=2.1 Hz, 1H), 7.68 (dd, J=11.2, 2.6 Hz, 1H), 6.36 (t, J=3.7 Hz, 1H), 4.53 (td, J=15.1, 3.7 Hz, 2H).

Alternative Synthesis of Compound 298: 4-Chloro-N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)thiophene-2-carboxamide

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Step 1: Methyl 4-Chloro-5-(trifluoromethyl)thiophene-2-carboxylate

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Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-phenylpyridine N-oxide (58.43 g, 339.732 mmol, 2.00 equiv), methyl 4-chlorothiophene-2-carboxylate (30.00 g, 169.87 mmol, 1.00 equiv), tris(bipyridine)ruthenium(II) chloride (108.79 mg, 0.170 mmol, 0.001 equiv), ACN (300 mL), trifluoroacetic anhydride (78.49 g, 373.705 mmol, 2.20 equiv). The resulting solution was stirred for 8 hr at 25° C. under blue light. The solids were filtered out. The resulting solution was extracted with 4×300 mL of petroleum ether and concentrated. This resulted in 64 g (51%) of methyl 4-chloro-5-(trifluoromethyl)thiophene-2-carboxylate as red oil.

Step 2: 4-Chloro-5-(trifluoromethyl)thiophene-2-carboxylic acid

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Into a 1-L 3-necked round-bottom flask, was placed methyl 4-chloro-5-(trifluoromethyl)thiophene-2-carboxylate (64.00 g, 261.64 mmol, 1.00 equiv) and tetrahydrofuran (600 mL), and the resulting solution was stirred at 0° C. Then lithium hydroxide (18.80 g, 784.92 mmol, 3.00 equiv) and H₂O (200 mL) was added for 20 min. The resulting solution was allowed to react, with stirring, for an additional 4 hr at 25° C. The resulting solution was extracted with 50 mL of ethyl acetate The pH value of the solution was adjusted to 4-5 with HCl. The resulting solution was extracted with 3×150 mL of ethyl acetate, and the organic layer was evaporated. This resulted in 42 g (69%) of 4-chloro-5-(trifluoromethyl)thiophene-2-carboxylic acid as a dark red solid.

Step 3: 4-Chloro-N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)thiophene-2-carboxamide

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Into a 1-L round-bottom flask, was placed 4-chloro-5-(trifluoromethyl)thiophene-2-carboxylic acid (30.00 g, 130.10 mmol, 1.00 equiv), 5-amino-1-(2,2-difluoroethyl)-3-fluoropyridin-2-one (30.00 g, 156.12 mmol, 1.20 equiv), HATU (59.36 g, 156.12 mmol, 1.20 equiv), DIEA (50.44 g, 390.30 mmol, 3.00 equiv), DMF (288.46 mL). The resulting solution was stirred for 2 hr at 25° C. The resulting solution was extracted with 3×1.2 L of ethyl acetate The resulting mixture was washed with 2×1.2 L of Water. The resulting mixture was concentrated. The residue was applied onto a silica gel column with water:ACN (2:3). This resulted in 28.14 g (53%) of 4-chloro-N-[1-(2,2-difluoroethyl)-5-fluoro-6-oxopyridin-3-yl]-5-(trifluoromethyl)thiophene-2-carboxamide as a yellow solid.

LCMS: (ES, m z): RT=2.618 min, m z 404.95[M+H]⁺; H-NMR: ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.05 (d, J=1.5 Hz, 1H), 8.00 (t, J=2.0 Hz, 1H), 7.65 (dd, J=11.2, 2.5 Hz, 1H), 7.56 (s, 1H), 6.34 (t, J=3.7 Hz, 1H), 4.51 (td, J=15.1, 3.8 Hz, 2H).

Example 2
SMARCA2 ATPase and Chromatin Remodeling Assays

General Materials. Adenosine 5′-triphosphate disodium salt hydrate (ATP), Bicine, bovine skin gelatin (BSG), dimethylsulfoxide (DMSO), doxorubicin, glycerol, HEPES, NP-40, phenylmethanesulfonyl fluoride (PMSF), Tris-HCl, Tris(2-carboxyethyl)phosphine hydrochloride solution (TCEP) and Tween 20 were commercially available.

Substrates. Chicken erythrocyte mononucleosomes were prepared from fresh chicken blood collected into anticoagulant and filtered through cheesecloth. The filtered chicken blood was diluted in buffer A (10 mM Tris-HCl, pH 7.4, 10 mM NaCl, 3 mM MgCl₂) and centrifuged at 500 g for 15 minutes to collect the erythrocytes. Erythrocyte nuclei were harvested by resuspending the pellets in buffer A containing 0.3% NP-40 detergent. The mixture was stirred with a magnetic bar for 10 mins and centrifuged at 4000 g for 10 minutes. Resuspension, stirring and centrifugation was repeated twice more before the final nuclei pellet was resuspended in buffer A+0.3% NP-40 and stored at −80° C. until purification. For nucleosome purification, nuclei aliquots were rapidly thawed and washed five times with buffer B (10 mM Tris-HCl, pH 7.4, 1 mM CaCl₂), 1 mM PMSF) and collected by centrifugation at 2800 g for 10 minutes. Pellets were resuspended in buffer B and treated with 100 U/mL micrococcal nuclease for 40 minutes at 37° C. The reaction was terminated by the addition of 2 mM EDTA and was centrifuged at 2800 g for 10 minutes. The nuclei were then lysed by resuspending the pellet in 1 mM EDTA and 1 mM PMSF and passing the mixture through a 22G needle 4 to 5 times. The solution was then centrifuged at 15,000 g for 20 minutes and the supernatant was collected. The remaining pellet was lysed through the syringe twice more and the supernatants were pooled after centrifugation. The pooled supernatants were further purified by size exclusion chromatography (GE Sephacryl S300 HR 50/100) in buffer C (10 mM HEPES, pH 7.5, 10 mM KCl, 1 mM EDTA, 1 mM PMSF, 10% glycerol). Fractions were analyzed by agarose gel electrophoresis and SDS-PAGE and fractions containing mononucleosomes were pooled and stored at −80° C.

Molecular Biology: Full-length human SMARCA2 isoform 1 (P51531) transcript clone was amplified from a cDNA library incorporating an N-terminal HIS tag (MGSHHHHHHHHSG) fused directly to Ser2 of SMARCA2 and a C-FLAG tag (YKDDDDK) fused directly to Glu1590 of SMARCA2. The amplified gene was subcloned into pFastBacI (Life Technologies).

Protein Expression: Recombinant baculovirus were generated and protein over-expression was accomplished by infecting exponentially growing Sf21 insect cell culture at 1.24×10⁶cell/ml with an MOI of 0.1. Infections were carried out for 76 hours, harvested by centrifugation, and stored at −80° C. for purification.

Protein Purification:

Expressed full-length SMARCA2 was purified from cell paste by FLAG affinity chromatography followed by anion exchange chromatography. The protein was dialyzed into a storage buffer containing 25 mM HEPES, 300 mM KCl, 10% Glycerol, pH 7.9, 1 mM TCEP and 0.01% Tween-20. The purity of the protein was measured as 74% using micro-capillary based gel electrophoresis.

The predicted translation for the HIS-SMARCA2-FL-FLAG is set forth in SEQ ID NO: 1.

General Procedure for SMARCA2 and SMARCA4 ATPase Activity Assay

The SMARCA2 or SMARCA4 ATPase assays were identical. The SMARCA2 or SMARCA4 ATPase assays were performed in a buffer consisting of 20 mM Bicine (pH 7.5), 10 mM KCl, 1 mM MgCl₂, 1 mM TCEP, 0.005% BSG, and 0.002% Tween 20, prepared on the day of use. Compounds in 100% DMSO were 3-fold serially diluted to produce a 10 point curve for IC₅₀determination and 0.2 uL were transferred into polypropylene 384-well V-bottom plates (Greiner) using an Echo liquid handler (Labcyte). DMSO (0.2 uL) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 0.2 uL doxorubicin, a known DNA intercalator, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. The SMARCA2 or SMARCA4 enzyme (10 uL) was added to the compounds and allowed to incubate with the compounds for 30 min at room temperature. The SMARCA2 or SMARCA4 ATPase assay was initiated by the addition of 10 uL chicken mononucleosome and ATP mixture (final volume=20 uL). The final concentrations of the assay components were as follows: SMARCA2 or SMARCA4 was 5 nM, ATP was 250 uM, chicken mononucleosome was 10 nM, doxorubicin in the minimum signal control wells was 50 uM, and the DMSO concentration was 1%. 5 uL of the reaction mixture was transferred from the 384-well polypropylene plate to a white opaque polystyrene 384-well plate. At 60 minutes, the assays were terminated by the addition of 5 uL ADP-Glo™ Reagent (Promega). After 40 minutes, the luciferase reaction was initiated by the addition of 10 uL of Kinase Detection Reagent (Promega) and incubated for 1 hour. The ADP product generated from the SMARCA2 or SMARCA4 ATPase reaction was determined via luminescence intensity. The IC₅₀values for compounds of the disclosure are listed in Tables 3.1, 3a.1 and 3b.1 below (“A” means IC₅₀<100 nM; “B” means IC₅₀ranging between 100 nM and 1 μM; “C” means IC₅₀ranging between >1 μM and 10 μM; “D” means IC₅₀ranging between >10 μM and 50 μM; “E” means IC₅₀>50 μM; “-” or “ND” means not determined).

TABLE 3.1

SMARCA2 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA2

No.
IC₅₀

1
2.724

2
33.25

3
>50

4
>50

5
>50

6
>50

7
>50

8
>50

9
>50

10
>50

11
>50

12
>50

13
>50

14
>50

15
>50

16
>50

17
4.058

18
19.53

19
>50

20
>50

21
2.037

22
ND

23
ND

24
ND

25
ND

26
19.6

27
ND

28
ND

29
ND

30
ND

31
ND

32
>50

33
>50

34
28.5

35
>50

36
>50

37
>50

38
ND

39
ND

40
2.63

41
>50

42
12.6

43
1.261

44
>50

45
43.14

46
11.14

47
>50

48
14.08

49
>50

50
>50

51
46.4

52
>50

53
1.478

54
>50

55
>50

56
>50

57
>50

58
1.305

59
>50

60
16.7

61
>50

62
>50

63
>50

64
>50

65
28.4

66
>50

67
>50

68
8.552

69
2.517

70
16.7

71
>50

72
33.2

73
11.5

74
17.24

75
0.4365

76
>50

77
>50

78
>50

79
>50

80
0.2091

81
0.2229

82
14.79

83
20.8

84
0.1969

85
11.98

86
0.3646

87
>50

88
>50

89
>50

90
>50

91
>50

92
>50

93
>50

94
3.153

95
>50

96
>50

97
>50

98
>50

99
>50

100
>50

101
0.07411

102
4.124

103
0.356

104
0.192

105
27.83

106
0.4172

107
36.72

108
>50

109
0.1733

110
>50

111
>50

112
>50

113
14.07

114
9.415

115
>50

116
39.3

117
>50

118
>50

119
>50

120
>50

121
>50

122
>50

123
1.195

124
>50

125
0.03086

126
46.8

127
0.2516

128
0.07867

129
0.05117

130
0.147

131
0.1127

132
0.1425

133
0.3426

134
0.1485

135
0.2933

136
0.05772

137
0.02599

138
0.00642

139
0.01964

140
0.04671

141
0.09409

142
0.04745

143
0.1214

144
0.2452

145
3.014

146
1.017

147
17.13

148
0.01266

149
>50

150
0.02662

151
0.02043

152
0.1656

153
0.1472

154
1.93

155
0.1627

156
0.2346

157
1.5

158
1.85

159
0.1936

160
0.224

161
0.5535

162
0.1936

163
0.3094

164
0.3105

165
0.3434

166
2.723

167
0.6095

168
0.2755

169
0.3749

170
0.376

171
>50

172
0.238

173
0.03917

174
0.3883

175
2.04

176
0.0552

177
>50

178
30.83

179
>50

180
0.08455

181
0.1139

182
0.03553

183
>50

184
>50

185
>50

186
15.64

187
0.1584

188
0.0305

189
0.00909

190
0.0201

191
0.04589

192
0.01706

193
1.229

194
3.116

195
7.59

196
0.03824

197
0.2815

198
0.1073

199
>50

200
48.28

201
>50

202
>50

203
0.04068

204
1.26

205
3.489

206
0.3174

207
0.07293

208
0.123

209
>50

210
0.2066

211
2.309

212
8.522

213
17.87

214
29.9

215
0.07099

216
>50

217
>50

218
>50

219
>50

220
0.4877

221
1.452

222
1.31

223
18.38

224
>50

225
>50

226
>50

227
>50

228
>50

229
0.6015

230
>50

231
0.1417

232
0.02489

233
7.629

234
0.4783

235
0.05915

236
0.1247

237
0.201

238
0.2324

239
>50

240
0.6257

241
0.1119

242
0.03887

243
1.643

244
>50

245
2

246
1.349

247
2.027

248
21.01

249
0.03584

250
25.4

251
0.1306

252
>50

253
>50

254
5.813

255
16.73

256
6.339

257
19.12

258
>50

259
0.05115

260
0.01528

261
7.375

262
15.32

263
21.6

264
6.227

265
0.08147

266
>50

267
>50

268
16.65

269
5.187

270
>50

271
>50

272
>50

273
>50

274
>50

275
0.3813

276
28.68

277
>50

278
>50

279
24

280
>50

281
>50

282
>50

283
33.18

284
3.214

285
0.02722

286
9.485

287
1.277

288
>50

289
10.56

290
0.1359

291
>50

292
6.83

293
0.1268

294
0.1171

295
0.173

296
0.09398

297
0.07568

298
0.02411

299
>50

300
2.735

301
16.71

302
>50

303
>50

304
>50

305
>50

306
>50

307
0.9403

308
23.3

309
29.6

310
>50

311
>50

312
>50

313
>50

314
>50

315
>50

316
>50

317
>50

318
2.883

319
1.317

320
0.1514

321
0.1 > 505

322
>50

323
0.01923

324
0.03494

325
0.0355

326
3.778

327
0.8459

328
0.03836

329
0.03122

330
0.04223

331
0.1715

332
0.3313

333
0.4169

334
0.1817

335
7.464

336
1.241

337
0.03369

338
0.08896

339
0.9429

340
0.6948

341
0.6682

342
0.2777

343
0.02304

345
0.0165

346
0.1807

TABLE 3.2

SMARCA4 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA4

No.
IC₅₀

1
39.58

2
>50

3
>50

4
>50

5
>50

6
>50

7
>50

8
>50

9
>50

10
>50

11
>50

12
>50

13
>50

14
>50

15
>50

16
>50

17
26.59

18
>50

19
>50

20
>50

21
8.998

22
>50

23
>50

24
>50

25
>50

26
>50

27
>50

28
>50

29
>50

30
>50

31
>50

32
>50

33
>50

34
>50

35
>50

36
>50

37
>50

38
ND

39
ND

40
11.6

41
ND

42
ND

43
ND

44
>50

45
ND

46
ND

47
ND

48
>50

49
ND

50
ND

51
>50

52
>50

53
16.7

54
>50

55
>50

56
>50

57
>50

58
13.57

59
>50

60
34.69

61
>50

62
>50

63
>50

64
>50

65
>50

66
>50

67
>50

68
>50

69
11.69

70
>50

71
>50

72
>50

73
35.6

74
31.5

75
1.515

76
>50

77
>50

78
>50

79
>50

80
0.7578

81
0.7228

82
28.9

83
>50

84
1.119

85
34.69

86
0.6685

87
>50

88
>50

89
>50

90
>50

91
>50

92
>50

93
>50

94
11.5

95
>50

96
>50

97
>50

98
>50

99
ND

100
ND

101
0.2374

102
18.6

103
0.531

104
0.229

105
>50

106
0.8384

107
>50

108
>50

109
0.5589

110
>50

111
>50

112
>50

113
16.64

114
14.35

115
16.7

116
>50

117
>50

118
>50

119
>50

120
>50

121
>50

122
>50

123
11.6

124
>50

125
0.1082

126
>50

127
0.5268

128
0.1609

129
0.1959

130
0.4434

131
0.3033

132
0.2996

133
2.18

134
0.6305

135
1.996

136
0.1843

137
0.1113

138
0.01606

139
0.05408

140
0.1466

141
0.352

142
0.1626

143
0.3307

144
1.174

145
11.99

146
3.588

147
>50

148
0.0 > 5075

149
>50

150
0.09482

151
0.06741

152
0.6164

153
0.7145

154
8.08

155
0.5289

156
0.8838

157
11.05

158
13.73

159
0.7589

160
0.864

161
4.031

162
0.9398

163
1.168

164
1.343

165
1.074

166
16.64

167
2.863

168
1.27

169
1.415

170
2.428

171
>50

172
1.071

173
0.2159

174
1.475

175
5.603

176
0.2669

177
>50

178
37.7

179
>50

180
0.3828

181
0.3135

182
0.1265

183
>50

184
>50

185
>50

186
>50

187
0.616

188
0.1187

189
0.03368

190
0.08514

191
0.184

192
0.08741

193
8.933

194
21.88

195
29.8

196
0.1808

197
0.8309

198
0.283

199
>50

200
45.3

201
>50

202
>50

203
0.118

204
5.777

205
22.64

206
0.6487

207
0.3418

208
0.6322

209
>50

210
0.6936

211
27.51

212
>50

213
>50

214
>50

215
0.4915

216
>50

217
>50

218
>50

219
>50

220
1.932

221
6.277

222
10.16

223
>50

224
>50

225
>50

226
>50

227
>50

228
>50

229
1.884

230
>50

231
0.544

232
0.1109

233
36.4

234
1.741

235
0.2723

236
0.555

237
0.8631

238
0.8791

239
>50

240
2.391

241
0.6532

242
0.1677

243
11.72

244
>50

245
12.1

246
6.37

247
10.7

248
>50

249
0.2599

250
>50

251
0.6231

252
>50

253
>50

254
47.1

255
>50

256
21.35

257
23.74

258
>50

259
0.2278

260
0.06542

261
24.44

262
25.94

263
27.36

264
38.5

265
0.5903

266
>50

267
>50

268
41.79

269
24.85

270
>50

271
>50

272
>50

273
>50

274
>50

275
2.098

276
47.1

277
>50

278
>50

279
>50

280
>50

281
>50

282
>50

283
>50

284
30.65

285
0.08683

286
16.68

287
3.664

288
>50

289
42.6

290
0.6796

291
>50

292
8.482

293
0.2997

294
0.3865

295
0.7355

296
0.5195

297
0.448

298
0.1647

299
>50

300
5.961

301
>50

302
>50

303
>50

304
>50

305
>50

306
>50

307
3.273

308
>50

309
>50

310
>50

311
>50

312
>50

313
>50

314
>50

315
>50

316
>50

317
>50

318
13.48

319
16.62

320
0.5621

321
0.6345

322
>50

323
0.06831

324
0.1374

325
0.1626

326
17.17

327
1.511

328
0.108

329
0.1113

330
0.1169

331
0.9243

332
2.2

333
0.8413

334
0.3374

335
45.1

336
5.866

337
0.1042

338
0.3631

339
2.318

340
4.892

341
9.282

342
0.7385

343
0.1075

345
0.03789

346
0.6057

TABLE 3a.1

SMARCA2 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA2

No.
IC₅₀

1a
>50

2a
>50

3a
>50

4a
>50

5a
>50

6a
>50

7a
>50

8a
>50

9a
>50

10a
>50

11a
>50

12a
>50

13a
>50

14a
>50

15a
>50

16a
26.8

17a
>50

18a
>50

19a
>50

20a
>50

21a
>50

22a
>50

23a
>50

24a
>50

25a
>50

26a
>50

27a
>50

28a
>50

29a
>50

30a
>50

31a
>50

32a
>50

33a
>50

34a
>50

35a
>50

36a
>50

37a
>50

38a
>50

39a
>50

40a
>50

41a
>50

42a
13.17

43a
>50

44a
42.5

45a
>50

46a
42.7

47a
>50

48a
>50

49a
>50

50a
>50

51a
>50

52a
>50

53a
>50

54a
>50

55a
>50

56a
>50

57a
>50

58a
>50

59a
>50

60a
14.26

61a
>50

62a
44

63a
>50

64a
>50

65a
4.91

66a
32.1

67a
>50

68a
>50

69a
1.533

70a
8.001

71a
2.72

TABLE 3a.2

SMARCA4 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA4

No.
IC₅₀

1a
>50

2a
>50

3a
>50

4a
>50

5a
>50

6a
>50

7a
>50

8a
>50

9a
>50

10a
>50

11a
>50

12a
>50

13a
>50

14a
>50

15a
>50

16a
>50

17a
>50

18a
>50

19a
ND

20a
>50

21a
>50

22a
>50

23a
>50

24a
>50

25a
>50

26a
>50

27a
>50

28a
>50

29a
>50

30a
>50

31a
>50

32a
>50

33a
>50

34a
>50

35a
>50

36a
>50

37a
>50

38a
>50

39a
>50

40a
>50

41a
>50

42a
>50

43a
>50

44a
>50

45a
>50

46a
41.1

47a
>50

48a
>50

49a
>50

50a
>50

51a
>50

52a
>50

53a
>50

54a
>50

55a
>50

56a
>50

57a
>50

58a
>50

59a
>50

60a
46.7

61a
>50

62a
48.2

63a
>50

64a
>50

65a
27.02

66a
>50

67a
>50

68a
>50

69a
8.485

70a
25.09

71a
39.58

TABLE 3b.1

SMARCA2 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA2

No.
IC₅₀

1b
>50

2b
>50

3b
>50

4b
42

5b
>50

6b
>50

7b
>50

8b
>50

9b
43.7

10b
>50

11b
>50

12b
>50

13b
>50

14b
>50

15b
>50

16b
>50

17b
0.6448

18b
0.9172

19b
2.024

20b
2.456

21b
>50

22b
>50

23b
>50

TABLE 3b.2

SMARCA4 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA4

No.
IC₅₀

1b
>50

2b
>50

3b
>50

4b
>50

5b
>50

6b
>50

7b
>50

8b
>50

9b
>50

10b
>50

11b
>50

12b
>50

13b
>50

14b
>50

15b
>50

16b
>50

17b
4.783

18b
5.343

19b
12.62

20b
11.46

21b
>50

22b
>50

23b
>50

TABLE 3c.1

SMARCA2 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA2

No.
IC₅₀

1c
0.402

2c
24.57

3c
40

4c
6.982

5c
0.02851

6c
0.9006

7c
>50

8c
>50

9c
2.88

10c
3.351

11c
>50

12c
34.8

13c
>50

14c
>50

15c
>50

16c
>50

17c
>50

18c
>50

19c
>50

20c
>50

21c
0.2676

22c
0.03012

23c
0.1728

24c
11.28

25c
0.0142

26c
5.413

27c
>50

28c
>50

29c
25.4

30c
>50

31c
>50

32c
5.668

33c
8.902

34c
0.0938

35c
0.6984

36c
>50

37c
0.4822

38c
>50

39c
0.07798

40c
0.09954

41c
0.08268

42c
0.2033

43c
0.1304

44c
1.04

45c
0.09806

46c
>50

47c
0.06495

48c
25.3

49c
16.78

50c
2.615

51c
>50

52c
>50

53c
>50

54c
0.04523

55c
0.07784

56c
0.2968

57c
0.02089

58c
0.04472

59c
0.1321

60c
0.2515

61c
0.02665

62c
0.008047

63c
0.03335

64c
0.008785

65c
0.03367

66c
0.2362

67c
0.3706

68c
0.06714

69c
1.004

70c
0.2601

71c
0.09202

72c
0.21

73c
0.8471

74c
0.06751

75c
0.01997

76c
24.1

77c
6.555

78c
0.09829

79c
0.0568

80c
0.1614

81c
0.07982

82c
0.009882

83c
0.01943

84c
1.85

85c
0.08113

86c
0.01722

87c
>50

88c
>50

89c
>50

90c
>50

91c
>50

92c
0.1198

93c
>50

94c
>50

95c
0.603

96c
10.53

97c
0.0607

98c
0.1085

99c
0.04064

100c
6.813

101c
>50

102c
>50

103c
31.28

104c
22.4

105c
0.04069

106c
0.028

107c
0.05078

108c
0.08179

109c
0.06249

110c
>50

111c
0.01048

112c
>50

113c
0.03448

114c
30.54

115c
>50

116c
0.2063

117c
0.00522

118c
40.27

119c
6.172

120c
0.09094

121c
0.1911

122c
0.05203

123c
0.471

124c
0.01085

125c
0.05223

126c
0.235

127c
0.3518

128c
0.2108

129c
0.05131

130c
0.01657

131c
0.008677

132c
5. > 503

133c
0.01385

134c
0.00812

135c
39.5

136c
0.02625

137c
0.3004

138c
0.0288

139c
0.05994

140c
0.03397

141c
0.02796

142c
0.04993

143c
0.006077

144c
0.02011

145c
0.08168

146c
9.545

147c
5.24

148c
0.1464

149c
8.034

1 > 50c
0.008977

151c
0.02962

152c
4.688

153c
0.2113

154c
0.07113

155c
30.77

156c
0.3467

157c
0.4815

158c
2.519

159c
0.01672

160c
0.1911

161c
ND

162c
ND

163c
ND

164c
ND

165c
ND

166c
ND

167c
ND

168c
ND

169c
ND

170c
ND

171c
ND

172c
ND

173c
ND

174c
ND

175c
ND

176c
9.19

177c
0.0127

178c
0.02145

179c
ND

TABLE 3c.2

SMARCA4 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA4

No.
IC_>50

1c
>50

2c
>50

3c
>50

4c
18.07

5c
0.07592

6c
0.679

7c
>50

8c
>50

9c
7.82

10c
7.129

11c
>50

12c
>50

13c
>50

14c
>50

15c
>50

16c
>50

17c
>50

18c
>50

19c
>50

20c
>50

21c
0.5732

22c
0.06075

23c
0.2192

24c
38.7

25c
0.08 > 508

26c
6.274

27c
>50

28c
>50

29c
41.4

30c
>50

31c
>50

32c
12.46

33c
8.155

34c
0.2326

35c
0.9047

36c
>50

37c
2.492

38c
>50

39c
0.1432

40c
0.2586

41c
0.2499

42c
0.4773

43c
0.3291

44c
2.191

45c
0.2322

46c
>50

47c
0.177

48c
>50

49c
16.8

50c
22.1

51c
>50

52c
>50

53c
>50

54c
0.1656

55c
0.269

56c
1.036

57c
0.0999

58c
0.178

59c
0.3786

60c
0.492

61c
0.08666

62c
0.02684

63c
0.1004

64c
0.02972

65c
0.1542

66c
0.772

67c
0.8067

68c
0.1212

69c
3.766

70c
0.3854

71c
0.3036

72c
1.547

73c
2.93

74c
0.2449

75c
0.0545

76c
>50

77c
30.51

78c
0.2565

79c
0.1427

80c
0.4941

81c
0.1984

82c
0.06615

83c
0.06295

84c
28.9

85c
0.2334

86c
0.04513

87c
>50

88c
>50

89c
>50

90c
>50

91c
>50

92c
0.346

93c
>50

94c
>50

95c
5.708

96c
29.31

97c
0.1907

98c
0.2873

99c
0.08012

100c
27.6

101c
>50

102c
>50

103c
26

104c
29.6

105c
0.1715

106c
0.05335

107c
0.1416

108c
0.1997

109c
0.1586

110c
>50

111c
0.02651

112c
>50

113c
0.1109

114c
>50

115c
>50

116c
0.5475

117c
0.00699

118c
>50

119c
16.09

120c
0.2391

121c
0.3841

122c
0.1295

123c
1.074

124c
0.01774

125c
0.1655

126c
0.9569

127c
0.9 > 501

128c
0.823

129c
0.1432

130c
0.04404

131c
0.01374

132c
11.35

133c
0.0607

134c
0.0128

135c
35.8

136c
0.1174

137c
0.5582

138c
0.06568

139c
0.1861

140c
0.06326

141c
0.05981

142c
0.119

143c
0.008168

144c
0.06911

145c
0.2084

146c
15.3

147c
7.956

148c
0.4324

149c
16.08

150c
0.01452

151c
0.1108

152c
37.5

153c
0.4391

154c
0.1468

155c
36.16

156c
0.6595

157c
4.728

158c
8.236

159c
0.1053

160c
0.3841

161c
ND

162c
ND

163c
ND

164c
ND

165c
ND

166c
ND

167c
ND

168c
ND

169c
ND

170c
ND

171c
ND

172c
ND

173c
ND

174c
ND

175c
ND

176c
9.19

177c
0.07973

178c
0.06674

179c
ND

TABLE 3d.1

SMARCA2 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA2

No.
IC_>50

1d
>50

2d
>50

3d
>50

4d
32

5d
>50

6d
22.37

7d
>50

8d
>50

9d
>50

16d
16.7

17d
>50

18d
>50

19d
>50

20d
7.373

21d
16.67

22d
6.38

23d
12.46

24d
18.41

25d
>50

26d
>50

27d
>50

28d
>50

29d
>50

30d
>50

31d
48.1

32d
>50

33d
>50

34d
>50

35d
>50

36d
36.5

37d
>50

38d
>50

39d
>50

40d
>50

41d
>50

42d
27.62

43d
>50

44d
29.55

45d
>50

46d
>50

47d
25.1

48d
>50

49d
>50

50d
34.55

51d
>50

52d
34

53d
>50

54d
9.192

55d
0.0926

56d
0.09838

57d
0.05157

58d
0.06189

59d
0.03406

60d
0.018

61d
0.197

62d
0.02246

63d
0.1649

64d
0.1651

65d
2.361

66d
0. > 5053

67d
0.01463

68d
0.07249

69d
0.02658

70d
1.689

71d
0.5359

72d
0.4806

73d
0.0109

74d
0.4625

75d
0.9478

76d
1.314

77d
0.1597

78d
0.05755

79d
0.04318

80d
0.2235

81d
0.06701

82d
1.363

83d
0.465

84d
8.575

85d
0.104

86d
0.1007

87d
0.9784

88d
0.5765

89d
0.1869

90d
1.387

91d
0.0229

92d
0.03135

93d
0.04308

94d
1.768

95d
0.3339

96d
0.03815

97d
2.695

98d
0.03064

99d
0.1948

100d
0.00606

101d
0.166

102d
0.01936

103d
>50

104d
0.02997

105d
0.03141

106d
2.185

107d
0.5723

108d
0.5421

109d
1.064

110d
1.466

111d
1.704

112d
0.3449

113d
0.967

114d
0.1116

115d
0.03584

116d
0.2519

117d
22.4

118d
0.2446

119d
0.9615

120d
0.07005

121d
16.8

122d
0.2528

123d
0.5199

124d
>50

125d
0.03566

126d
1.578

127d
0.5862

128d
>50

129d
0.05838

130d
0.0309

131d
>50

132d
>50

133d
0.0461

134d
0.0188

135d
0.16

136d
0.0419

137d
>50

138d
1.68

139d
3.1

140d
0.772

TABLE 3d.2

SMARCA4 inhibition by compounds of the disclosure.

Compd.
FL-SMARCA4

No.
IC₅₀

1d
>50

2d
>50

3d
>50

4d
>50

5d
>50

6d
>50

7d
>50

8d
>50

9d
>50

16d
>50

17d
>50

18d
>50

19d
>50

20d
28.9

21d
>50

22d
28.9

23d
15.29

24d
>50

25d
>50

26d
>50

27d
>50

28d
>50

29d
>50

30d
>50

31d
>50

32d
>50

33d
>50

34d
>50

35d
>50

36d
>50

37d
>50

38d
>50

39d
>50

40d
>50

41d
>50

42d
>50

43d
>50

44d
>50

45d
>50

46d
>50

47d
>50

48d
>50

49d
>50

50d
>50

51d
>50

52d
>50

53d
>50

54d
28.44

55d
0.246

56d
0.5353

57d
0.1906

58d
0.102

59d
0.2676

60d
0.03627

61d
0.6545

62d
0.05706

63d
0.5178

64d
0.498

65d
7.794

66d
1.29

67d
0.03715

68d
0.2048

69d
0.1201

70d
4.751

71d
1.256

72d
1.308

73d
0.0327

74d
1.014

75d
11.25

76d
10.18

77d
0.4631

78d
0.3773

79d
0.3096

80d
1.138

81d
0.2414

82d
8.091

83d
2.393

84d
>50

85d
0.5962

86d
0.5118

87d
4.986

88d
3.966

89d
2.068

90d
2.713

91d
0.06983

92d
0.1553

93d
0.1473

94d
17.92

95d
1.06

96d
0.09733

97d
3.38

98d
0.1213

99d
0.2443

100d
0.008526

101d
0.2846

102d
0.04635

103d
>50

104d
0.08204

105d
0.09055

106d
5.629

107d
1.537

108d
1.778

109d
3.161

110d
4.615

111d
5.102

112d
2.136

113d
2.882

114d
0.3723

115d
0.09928

116d
0.6734

117d
>50

118d
0.5439

119d
2.224

120d
0.2012

121d
17.25

122d
0.8346

123d
1.578

124d
>50

125d
0.09292

126d
4.373

127d
1.446

128d
>50

129d
0.161

130d
0.132

131d
>50

132d
>50

133d
0.165

134d
0.0587

135d
0.334

136d
0.0852

137d
>50

138d
4.61

139d
6.7

140d
1.77

General Procedure for SMARCA2 FRET Nucleosome Remodeling Activity Assay

The SMARCA2 FRET nucleosome remodeling assay was performed in a buffer consisting of 20 mM Bicine (pH 7.5), 10 mM KCl, 0.15 mM MgCl₂, 1 mM TCEP, 0.005% BSG, and 0.002% Tween 20, prepared on the day of use. Compounds in 100% DMSO (0.2 uL) were transferred into black polystyrene low volume 384-well plates, producing a 10 point curve for IC₅₀determination. DMSO (0.2 uL) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 0.2 uL SMARCA2 control compound (Compound 138) was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. The SMARCA2 enzyme (8 uL) was added to the compounds by an electronic multichannel pipettor and allowed to incubate with the compounds for 30 min at room temperature. The SMARCA2 remodeling assay was initiated by the addition of 2 uL of a nucleosome remodeling assay substrate and ATP mixture (final volume=10 uL). The final concentrations of the assay components were as follows: SMARCA2 was 5 nM, ATP was 85 uM, nucleosome remodeling assay substrate was 6 nM, control compound (Compound 138) in the minimum signal control wells was 1 uM, and the DMSO concentration was 2%. The assays were terminated after 15 minutes by the addition of 2 uL EDTA (final concentration of 25 mM). The SMARCA2 remodeling activity was determined by measuring the fluorescence ratio of the Cy3 and Cy5 labels (□em=531 nm, □ex=579 and 685 nm). The remodeling of the nucleosome substrate causes an increase in the spacing between the Cy3 and Cy5 labels and therefore a reduction in FRET and an increase in Cy3/Cy5 fluorescence ratio.

Percent Inhibition Calculation

$% inh = 100 - (\frac{{signal}_{cmpd} - {signal}_{\min}}{{signal}_{\max} - {signal}_{\min}}) \times 100$

Where signal is luminescence intensity or Cy3/Cy5 ratio in the assay well, and min and max are the respective minimum and maximum signal controls.

Four-Parameter IC₅₀Fit

$Y = Bottom + \frac{(Top - Bottom)}{(1 + {(\frac{X}{{IC}_{50}})}^{Hill Coefficient})}$

Where Y is the % inhibition and X is the compound concentration and the top and bottom plateaus may occasionally be fixed at 100 or 0 respectively in a 3-parameter fit. The results are shown in Table 4 (“A” means IC₅₀<100 nM; “B” means IC₅₀ranging between 100 nM and 1 μM; “C” means IC₅₀ranging between >1 μM and 10 μM; “D” means IC₅₀ranging between >10 μM and 50 μM; “E” means IC₅₀>50 μM; “-” or “ND” means not determined).

TABLE 4

Results of remodeling assay

Cmpd.
SMARCA2

No.
Remodeling IC₅₀

1
7.115

101
0.314

125
0.06608

128
0.223

129
0.1141

131
0.171

136
0.0288

137
0.02904

138
0.01428

139
0.0253

140
0.089

141
0.399

142
0.06

143
0.168

144
1.269

145
5.059

146
2.573

148
0.02224

150
0.02174

151
0.02875

173
0.0758

176
0.0818

188
0.0222

189
0.0234

190
0.035

191
0.0653

192
0.0219

196
0.0181

249
0.07

260
0.0182

265
0.143

285
0.00922

290
0.407

295
0.499

298
0.0471

Example 3-Long Term Proliferation (LTP) Assay
Analysis of Cell Proliferation and Viability: Suspension Cell Lines

For assessment of cell proliferation and viability in cell lines cultured in suspension, exponentially growing cells were plated, in triplicate, in 96-well plates at a density previously determined to result in log linear phase growth throughout the assay period in a final volume of 150 μl. Cells were incubated in the presence of increasing concentrations of Compound 139 up to 10 μM. Viable cell number was determined every 3-4 days for up to 14 days via laser scanning imaging cytometry. On days of cell counts, growth media and Compound 139 were replaced and cells split back to the starting density. Total cell number is expressed as split-adjusted viable cells per well. For each cell line, IC₅₀values were determined from concentration-dependence curves at each time point. The IC₅₀values for the various lung cancer cell lines are summarized in FIG. 1, and Table below. The day 15 IC₅₀of compounds of the disclosure in A549 cells are summarized in Table 6. In both tables, “A” means IC₅₀<100 nM; “B” means IC₅₀ranging between 100 nM and 1 μM; “C” means IC₅₀ranging between >1 μM and 10 μM; “D” means IC₅₀ranging between >10 μM and 50 μM; “E” means IC₅₀>50 μM; “-” or “ND” means not determined).

TABLE 5

Summary of Inhibition of SMARCA2 in various cancer cell lines by compounds of the disclosure

Compd.
Compd.
Compd.
SMARCA4

Cell line
139 IC₅₀
298 IC₅₀
82c IC₅₀
Protein
Cancer Indication
Cancer Subtype

A549
0.316
0.142
0.259
Absent
Lung NSCLC
adenocarcinoma

CALU6
1.21
1.4
ND
Present
Lung NSCLC
undifferentiated

carcinoma

CORL105
0.095
0.715
0.17
Present
Lung NSCLC
adenocarcinoma

CORL23
1.7
1.4
ND
Present
Lung NSCLC
large cell

carcinoma

COV644
ND
5.6
ND
ND
Ovarian Cancer
NS

DLD1
ND
1.4
ND
Present
Colon Cancer
adenocarcinoma

HCC15
0.677
0.569
ND
Absent
Lung NSCLC
squamous cell

carcinoma

HCC44
1.266
3.3
ND
Present
Lung NSCLC
adenocarcinoma

HCT116
0.169
0.836
0.142
Present
Colon Cancer
NS

HS766T
1
10
ND
ND
Pancreatic Cancer
ductal carcinoma

HT1376
ND
0.385
ND
ND
Bladder Cancer
transitional cell

carcinoma

MIAPACA2
ND
0.871
ND
ND
Pancreatic Cancer
ductal carcinoma

NCIH1299
0.857
0.548
1.7
ND
Lung NSCLC
non small cell

carcinoma

NCIH1437
1.5
1.4
ND
Present
Lung NSCLC
adenocarcinoma

NCIH1563
2.3
1.1
ND
Present
Lung NSCLC
adenocarcinoma

NCIH1568
0.395
0.509
10
Absent
Lung NSCLC
adenocarcinoma

NCIH1573
0.504
0.701
ND
Absent
Lung NSCLC
adenocarcinoma

NCIH1581
ND
ND
10
Absent
Lung NSCLC
large cell

carcinoma

NCIH1693
0.101
0.202
ND
Absent
Lung NSCLC
adenocarcinoma

NCIH1975
10
10
ND
Present
Lung NSCLC
non small cell

carcinoma

NCIH2030
1.145
1.1
ND
Absent
Lung NSCLC
non small cell

carcinoma

NCIH2085
0.314
ND
10
Present
Lung NSCLC
adenocarcinoma

NCIH2122
2.8
3.9
ND
Present
Lung NSCLC
adenocarcinoma

NCIH23
1.1
0.891
ND
Absent
Lung NSCLC
non small cell

carcinoma

NCIH358
10
10
1.7
Present
Lung NSCLC
bronchioloalveolar

adenocarcinoma

NCIH358
10
5.1
ND
Present
Lung NSCLC
bronchioloalveolar

SMARCA2

adenocarcinoma

NCIH358
0.347
0.312
0.383
Absent
Lung NSCLC
bronchioloalveolar

SMARCA4

adenocarcinoma

NCIH441
5.2
5
ND
Present
Lung NSCLC
adenocarcinoma

NCIH460
10
10
10
Present
Lung NSCLC
large cell

carcinoma

NCIH522
10
10
9.7
Absent
Lung NSCLC
adenocarcinoma

NCIH596
8.8
10
ND
ND
Lung NSCLC
mixed

adenosquamous

carcinoma

NCIH810
0.174
0.946
ND
Present
Lung NSCLC
large cell

carcinoma

OV7
ND
0.154
ND
ND
Ovarian Cancer
NS

PANC1
10
0.223
ND
ND
Pancreatic Cancer
ductal carcinoma

RERFLCAI
0.061
0.135
0.026
Absent
Lung NSCLC
squamous cell

carcinoma

SW900
10
10
ND
Present
Lung NSCLC
squamous cell

carcinoma

HCC1588
0.906
ND
ND
Present
Lung NSCLC
squamous cell

carcinoma

NCIH1395
10
ND
ND
Present
Lung NSCLC
adenocarcinoma

NCIH1435
0.443
ND
ND
Present
Lung NSCLC
adenocarcinoma

NCIH1650
5
ND
ND
Present
Lung NSCLC
bronchioalveolar

carcinoma

NCIH1792
10
ND
ND
Present
Lung NSCLC
adenocarcinoma

NCIH1793
0.89
ND
ND
Present
Lung NSCLC
adenocarcinoma

NCIH1838
0.587
ND
ND
Present
Lung NSCLC
non-small cell lung

cancer

NCIH2126
5.5
ND
ND
Present
Lung NSCLC
adenocarcinoma

NCIH2342
2.5
ND
ND
Present
Lung NSCLC
non-small cell lung

cancer

NCIH838
10
ND
ND
Present
Lung NSCLC
adenocarcinoma

HCC827
10
ND
ND
Present
Lung NSCLC
adenocarcinoma

(bronchioalveolar

features)

TABLE 6

Day 15 IC₅₀of compounds of the disclosure in A549 cells

Cmpd.
Day 15

No.
IC₅₀

43
15.2

47
30

80
6.252

101
0.356

125
0.484

138
20

139
0.316

142
0.534

173
3.9

176
20

188
9.9

190
3.9

191
8.3

192
4.2

249
0.323

259
0.177

260
0.093

265
0.851

267
10

298
0.142

323
0.106

324
0.282

325
0.312

345
0.058

62c
0.089

64c
0.088

82c
0.259

96c
10

18d
30

Analysis of Cell Proliferation and Viability: Adherent Cell Lines Protocol 1

The following cell lines were evaluated in an adherent cell line proliferation assay described herein: A549, HCC15, COV434, NCIH460, NCIH358, NCIH358-SMARCA2, NCIH358-SMARCA, NCIH1703, NCIH838, NCIH322, NCIH2122, NCIH2023, NCIH1355, NCIH1693, NCIH441, NCIH2030, NCIH1573, NCIH1373, NCIH1650, and NCIH1693. Plating densities for each cell line were determined based on growth curves (measured by ATP viability) and density over a 7 day timecourse. On the day before compound treatment, cells were plated in either 96-well plates in triplicate (for the day 0-7 timecourse) or 6-well plates (for replating on day 7 for the remainder of the timecourse). On Day 0, cells were either untreated, DMSO-treated, or treated with increasing concentrations of Compound 139 up to 10 μM. Plates were read on Day 0, Day 4, and Day 7 using a luminescent cell viability assay, with compound/media being replenished on Day 4. On Day 7, the 6-well plates were trypsinized, centrifuged, and resuspended in fresh media for counting by Vi-Cell. Cells from each treatment were replated at the original density in 96-well plates in triplicate. Cells were allowed to adhere to the plate overnight, and cells were treated as on Day 0. On Day 7, 11 and 14, plates were read using a luminescent cell viability assay, with compound/media being replenished on Day 11. Averages of triplicates were used to plot proliferation over the timecourse, and calculate IC₅₀values.

Analysis of Cell Proliferation and Viability: Adherent Cell Lines Protocol 2

The following cell lines were evaluated in an adherent cell line proliferation assay described herein: NCIH522, CORL23, NCIH1693, NCIH1838, HCC1588, NCIH1435, NCIH2085, HCC827, NCIH1792, NCIH596, NCIH1568, NCIH1793, NCIH2126, CORL105, NCIH1573, NCIH1693, NCIH1395, HCC44, NCIH2126, NCIH520, NCIH1373, NCIH2172, NCIH23, HCT116, RERFLCAI, NCIH2347, NCIH2110, NCIH647, NCIH1437, AGS, KMS11, BT549, HUPT4, NCIH1048, TE10, and TE14. Cell densities were determined by growth curve as per protocol 1. For the proliferation assay, on Day 0, cells were either untreated, DMSO-treated, or treated with increasing concentrations of Compound 139 up to 10 μM. Plates were read on Day 0, Day 4, and Day 7 using luminescent cell viability assay. On Day 7, the 6-well plates were trypsinized, centrifuged, and resuspended in fresh media for counting by Vi-Cell. Cells from each treatment were replated at the original density in 96-well plates in triplicate. Cells were treated with compound as on Day 0. On Day 7, 11 and 14, plates were read using a luminescent cell viability assay. Averages of triplicates were used to plot proliferation over the timecourse, and calculate IC₅₀values.

Example 4—High-Throughput Proliferation (HTP) Assay for A549 and H383 Cells

Assay for A549 Cells

Thawing vials: A549 cells (ATCC #CCL-185™) were thawed from a cryovial containing approximately 1.6×10{circumflex over ( )}6 cells frozen in 70% F12K medium, 20% HI-FBS and 10% DMSO. Cells were thawed by submerging the bottom half of the vial in a 37° C. water bath and gently flicked until almost thawed. The cells were transferred into a 15 mL conical tube containing 9 mL of F12K medium+10% HI-FBS and then centrifuged at 200×g for 4 min before drawing off the media without disturbing the cell pellet in order to remove the DMSO. The cells were resuspended again in 15 mL of F12K fresh complete media+10% HI-FBS and grown up in a T75 flask at 37° C. with 5% CO₂Incubator. Viability was measured to obtain baseline.

Frozen stock vials preparation: The cell culture was transferred to a 50 mL conical tube, spun down to remove medium, and resuspended at 1-2×10{circumflex over ( )}6 cells/mL in complete medium containing 10% DMSO. The culture was then stored for 24 hours at −80 degree C., (with the initial rate of freezing is −1 degree C. per minute in a freezing container), then transferred and stored in liquid nitrogen.

Routine subculture: Sub-confluent cultures (70-80%) were split every 4 days, seeding out at 1-2×10{circumflex over ( )}6 cells/75 cm².

Day 0: Assay ready plates were prepared by dispensing 50 nL of compound or DMSO in the appropriate wells of 384-well white CulturPlates using Echo550. Using the Multiflo, A549 cells were plated at 50 μL/well in F12K complete media+10% HI-FBS+1% pen/strep at cell density determined [1,250 cells/mL (62.5 cells/well)] from growth curve.

Treated cells were incubated at 37° C., 5% CO₂, relative humidity >90% for 7 days. CellTiter-Glo (CTG) ATP detection reagent was prepared according to manufacturer's specifications. Cell assay plates were removed from the incubator and brought to room temperature (RT). Using the MultiDrop liquid handler, 30 μL of CTG were added per well. Plates were placed on the multidrop dispenser shake for 5 seconds at room temperature (RT). Plates were incubated for 30 minutes in the dark at RT before measuring luminescence using the Envison2104.

Data analysis: Using the DMSO control wells as the 0% inhibition (high signal) control and the 10 μM Doxorubicin control wells as the 100% inhibition (low signal) control, percent inhibition EC₅₀s (inflection point) and IC₅₀s were calculated for the compound dose responses.

Assay for H358 Cells

Thawing vials: H358 cells (ATCC #CRL-5807™) were thawed from a cryovial containing approximately 1.6×10{circumflex over ( )}6 cells frozen in 70% RPMI 1640 medium, 20% HI-FBS and 10% DMSO. Cells were thawed by submerging the bottom half of the vial in a 37° C. water bath and gently flicked until almost thawed. The cells were removed and transferred into a 15 mL conical tube containing 9 mL RPMI 1640 medium+10% HI-FBS and then centrifuged 200×g for 4 min before drawing off the media without disturbing the cell pellet to remove the DMSO. The cells were resuspended again in 15 mL of RPMI 1640 fresh complete media+10% HI-FBS and grown up in a T75 flask at 37° C. with 5% CO₂Incubator. Viability was measured to obtain baseline.

Preparing frozen stock vials: Cell density was counted in a stock flask. The culture was transferred to a 50 mL conical tube and spun down to remove medium, and then resuspend at 1-2×10{circumflex over ( )}6 cells/mL in complete medium containing 10% DMSO and transferred to a 1 mL per vial.

Routine subculture: Sub-confluent cultures (70-80%) were split every 4 days, seeding out at 1-2×10{circumflex over ( )}6 cells/75 cm².

Day 0: Assay ready plates were prepared by dispensing 50 nL of compound stock or DMSO in the appropriate wells of 384-well white CulturPlates using Echo550. Using the Multiflo, H358 cells at 50 μL/well were plated in RPMI 1640 complete media+10% HI-FBS+1% pen/strep at cell density determined [20,000 cells/mL (1,000 cells/well)] from growth curve. Treated cells were inclubated at 37° C., 5% CO₂, relative humidity >90% for 7 days. CellTiter-Glo (CTG) ATP detection reagent was prepared according to manufacturer's specifications. Cell assay plates were removed from incubator and bring to room temperature (RT).

Using the MultiDrop liquid handler, 30 μL of CTG were added per well. Plates were placed on the multidrop dispenser shake for 5 seconds at RT. Plates were incubated for 30 minutes in the dark at RT before measuring luminescence using the Envison2104.

Data analysis: Using the DMSO control wells as the 0% inhibition (high signal) control and the 10 uM Doxorubicin control wells as the 100% inhibition (low signal) control, percent inhibition EC₅₀s (inflection point) and IC₅₀s were calculated for the compound dose responses.

TABLE 7

Inhibition of SMARCA2 by compounds of

the disclosure in A549 and H358 cells

A549
H358

Compd.
SMARCA2
SMARCA2

No.
IC₅₀
IC₅₀

80
11.48
ND

101
2.272
ND

125
1.16
ND

129
0.9044
ND

138
20
ND

139
0.868
ND

140
1.25
ND

142
1.342
ND

148
20
ND

173
*13.1
ND

176
20
ND

182
20
ND

188
*18.1
ND

189
9.689
ND

190
11.99
ND

191
*13.4
ND

192
20
ND

196
0.597
ND

203
20
ND

207
0.8922
ND

220
20
ND

222
20
ND

223
20
ND

231
20
ND

232
*15.53
ND

234
20
ND

235
20
ND

236
20
ND

237
20
ND

238
*7.27
ND

240
20
ND

242
17.4
ND

249
0.734
ND

251
5.465
ND

259
2.46
ND

260
0.5281
ND

265
7.302
ND

275
20
ND

285
0.934
ND

297
2.09
>10

298
0.6816
>10

302
>10
ND

323
0.3127
ND

330
>10
*8.74

336
>10
ND

337
0.7693
ND

338
3.209
ND

339
>10
ND

340
>10
ND

342
*9.49
>10

343
0.4919
>10

345
0.3549
>10

346
5.238
>10

5c
1.155
>10

22c
0.664
>10

25c
0.6135
>10

34c
1.456
>10

35c
3.703
8.761

37c
9.05
>10

39c
1.37
>10

40c
2.833
>10

41c
4.269
>10

42c
5.082
>10

43c
2.938
>10

45c
4.256
>10

47c
1.406
>10

48c
>10
>10

54c
1.923
>10

55c
3.777
>10

56c
4.4
*9.02

57c
3.611
>10

58c
1.495
>10

59c
1.187
2.03

60c
>10
>10

61c
1.507
>10

62c
0.5485
>10

63c
2.286
>10

64c
0.3745
>10

65c
4.319
>10

66c
>10
>10

67c
>10
>10

68c
5.907
>10

70c
6.249
9.156

71c
1.949
>10

72c
4.495
>10

73c
*6.01
>10

74c
3.927
>10

75c
1.78
>10

78c
1.574
>10

79c
1.294
>10

80c
3.976
>10

81c
2.011
>10

82c
0.5889
>10

83c
3.471
>10

85c
2.371
>10

86c
1.727
>10

92c
2.326
>10

95c
>10
>10

96c
>10
>10

97c
3.781
>10

98c
3.295
>10

99c
1.703
>10

111c
1.948
>10

113c
*4.03
>10

116c
*3.79
>10

117c
1.823
1.489

120c
>10
>10

121c
>10
>10

122c
4.603
>10

123c
3.98
>10

124c
1.075
7.229

125c
4.456
>10

126c
4.01
>10

127c
>10
>10

128c
5.13
3.89

129c
>10
>10

130c
1.211
>10

131c
>10
>10

134c
0.909
3.887

136c
0.7338
>10

139c
0.6393
0.5504

140c
>10
>10

141c
6.017
>10

142c
3.211
4.65

143c
0.4582
>10

144c
1.679
>10

145c
>10
>10

146c
>10
>10

147c
>10
>10

148c
4.248
>10

149c
>10
>10

150c
0.9317
>10

151c
0.8886
4.855

153c
>10
6.952

154c
>10
>10

155c
>10
>10

157c
3.35
9.72

158c
0.6875
6.645

160c
0.7865
7.144

177c
1.37
>10

178c
>10
>10

55d
>10
>10

56d
6.245
>10

57d
>10
>10

58d
>10
>10

59d
2.08
>10

60d
3.65
>10

61d
4.331
>10

62d
>10
>10

63d
>10
>10

64d
3.808
>10

65d
>10
>10

67d
2.115
>10

68d
2.406
>10

69d
2.042
>10

70d
1.963
9.845

71d
2.384
4.088

72d
5.756
>10

73d
1.811
>10

74d
1.649
2.44

75d
>10
>10

76d
>10
>10

77d
7.438
>10

78d
6.373
>10

79d
3.649
>10

80d
>10
>10

81d
2.37
>10

82d
*4.73
>10

83d
>10
>10

84d
>10
>10

85d
4.171
>10

86d
3.953
*8.56

87d
>10
>10

88d
>10
>10

89d
5.625
>10

90d
>10
>10

91d
>10
>10

92d
1.987
>10

93d
3.927
>10

95d
>10
>10

96d
4.435
>10

97d
>10
>10

98d
2.931
>10

99d
6.684
>10

100d
4.347
6.245

101d
3.74
>10

102d
1.046
>10

103d
>10
>10

104d
4.367
>10

105d
4.295
>10

106d
>10
>10

107d
>10
>10

108d
>10
>10

109d
>10
>10

110d
>10
>10

111d
>10
>10

112d
*9.96
>10

113d
>10
>10

114d
2.728
>10

115d
2.085
>10

116d
*8.92
>10

117d
1.96
2.274

118d
*7.18
>10

119d
>10
>10

120d
2.12
>10

121d
5.025
7.38

122d
8.444
>10

123d
>10
>10

124d
>10
>10

125d
>10
>10

126d
>10
>10

127d
>10
>10

128d
3.239
4.05

129d
2.173
>10

130d
3.369
6.747

131d
>10
>10

132d
7.985
>10

133d
2.89
>10

134d
1.33
>10

135d
2.38
>10

136d
2.22
>10

137d
>10
>10

138d
>10
>10

139d
>10
>10

140d
7.18
>10

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Unless specifically stated or obvious from context, as used herein, the terms “a,” “an,” and “the” are understood to be singular or plural. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.

Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. Where names of cell lines or genes are used, abbreviations and names conform to the nomenclature of the American Type Culture Collection (ATCC) or the National Center for Biotechnology Information (NCBI), unless otherwise noted or evident from the context.

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Example 5—Compound 82c Efficacy Study in the Treatment of Subcutaneous A549 Xenograft Model

The efficacy of compound 82c was studied in vivo for the treatment of A549 subcutaneous xenograft model in BALB/c nude mice. Seventy-five BALB/c nude female mice were injected cell A549 at 1×10⁷per mouse.

Fifty mice were selected and assigned into five groups using randomized block design based upon their tumor volumes and 10 mice per group. The 5 groups were treated p.o. with vehicle (0.5% NaCMC 0.1% Tween pH4), compound 82c 5 mg/kg BIDx21, 12.5 mg/kg BIDx10/QDx11, 25 mg/kg BIDx7/QDx14 and 50 mg/kg QDx10/3 days off/30 mg/kg QDx8.

All mice from 12.5 mg/kg BID were adjusted from BID to QD from treatment Day 11 until to the end of the study. #36˜#40 mice from group 25 mg/kg BID were compound administration holiday due to mice body weight loss. All mice from group 25 mg/kg BID were adjusted from BID to QD from treatment Day 8. All mice from group 50 mg/kg QD were compound administration holiday from Day 11 to Day 13 due to mice body weight loss and this group was adjusted from 50 mg/kg to 30 mg/kg until the end of the study.

Tumor Inoculation. Each mouse was inoculated subcutaneously at the right flank with A549 tumor cells (1×10⁷cells/mouse) in 0.2 mL of base media (F12K) for tumor development. The treatments were started when the tumor size reached 126.94 mm³for the tumor efficacy study (Day 14 post inoculation). Fifty tumor-bearing mice were block randomized into 5 groups with 10 mice in each. Test article administration and animal numbers in each group are shown in Table 7.

TABLE 7

Tumor weights, volumes, and TGI of different treatment groups, day 21

Tumor
Weight-
Tumor
Volume-

Weight (g),
based
Volume (mm{circumflex over ( )}3),
based

Group
Treatment
Day 21
TGI(%)^#
Day 21
TGI(%)^†

1
Vehicle
1.465 ± 0.141
—
1553.16 ± 161.44
—

BID×21

2
Compound 82c
0.773 ± 0.052
47.23*
737.75 ± 78.79
57.01*

5 mg/kg

BID×21

3
Compound 82c
0.609 ± 0.063
58.44*
579.14 ± 59.39
68.31*

12.5 mg/kg

BID×10 QD×11

4
Compound 82c
0.509 ± 0.077
65.26*
469.53 ± 70.97
75.87*

25 mg/kg

BID×7 QD×14

5
Compound 82c
0.496 ± 0.058
66.17*
461.87 ± 60.61
76.56*

50 mg/kg QD×10

3 days off

30 mg/kg QD×8

Note:

^#TGI(%) = (1 − TW_treatment/TW_control)) × 100%. TGI(%) > 58% was considered to be effective.

^†TGI(%) = (1 − (TVtreatment − Dx − TVtreatment − D1)/(TVcontrol − Dx − TVcontrol − D1)) × 100%. TGI(%) > 58% was considered to be effective.

*P < 0.001. P < 0.05 was considered to be statistically significant; P < 0.01 was considered to be statistically extremely significant.

Tumor Measurements and Endpoints. The major endpoint was tumor growth delay or cure. Tumor size was measured twice weekly in two dimensions using a caliper, and the volume was expressed in mm³using the formula: V=0.5 a×b²where a and b were the long and short diameters of the tumor, respectively. The tumor size was then used for calculations of T/C (%) values. T/C (%) was calculated according to the following equation: T/C (%)=T_RTV/C_RTV×1000/9 T_RTV=TV_treatment-Dn/TV_treatment-D1, C_RTV=TV_control-Dn/TV_control-D1, T/C (%)<42%, it was considered to be effective. The tumor size was then used for calculations of TGI (%) values. TGI (%) was calculated according to the following equation: TGI (%)=(1−(TV_Treatment/Dx−TV_Treatment/D1)/(TV_Control/Dx−TV_Control/D1))×100%, TGI□58 means this medicine is effective. The tumor weight was then used for calculations of TGI (%) values. TGI (%) was calculated according to the following equation: TGI (%)=(1−TW_Treatment/TW_Control)×100%

Statistical Analysis. Summary statistics, including mean and the standard error of the mean (SEM), were provided for the tumor volumes of each group at each time point. Statistical analyses of difference in tumor volumes among the groups were conducted on Day 21 after the last dose. Statistical analysis of difference in tumor volume and tumor weight among the groups was conducted. All data was analyzed using GraphPad Prism software. P<0.05 was considered to be statistically significant. A two-way ANOVA combined with Bonferroni post-test was performed to compare tumor volumes among vehicle and all treatment groups. A one-way ANOVA combined with Dunnett's Multiple Comparison Test to compare tumor weight among vehicle and all treatment groups. Results of the experiments are shown in FIGS. 2-5.

It is to be understood that the disclosure encompasses all variations, combinations, and permutations in which one or more limitation, element, clause, or descriptive term, from one or more of the claims or from one or more relevant portion of the description, is introduced into another claim. For example, a claim that is dependent on another claim can be modified to include one or more of the limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a composition, it is to be understood that methods of making or using the composition according to any of the methods of making or using disclosed herein or according to methods known in the art, if any, are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.

Where elements are presented as lists, e.g., in Markush group format, it is to be understood that every possible subgroup of the elements is also disclosed, and that any element or subgroup of elements can be removed from the group. It is also noted that the term “comprising” is intended to be open and permits the inclusion of additional elements or steps. It should be understood that, in general, where an embodiment, product, or method is referred to as comprising particular elements, features, or steps, embodiments, products, or methods that consist, or consist essentially of, such elements, features, or steps, are provided as well. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed.

Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in some embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. For purposes of brevity, the values in each range have not been individually spelled out herein, but it will be understood that each of these values is provided herein and may be specifically claimed or disclaimed. It is also to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range.

In addition, it is to be understood that any particular embodiment of the present disclosure may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the invention, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects are excluded are not set forth explicitly herein.

Exemplary Embodiments

Embodiment 0. In some aspects, the present disclosure features a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

X₁and X₂are each independently selected from —CH and N;

Y is selected from the group consisting of a bond, —NH, —C(O), C₁-C₆alkyl, —C(CH₃)₂—O—, and —CH₂—NH—CH₂—;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 1. A compound of Formula (IA):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 2. A compound of compound Formula (IA) or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 3. A compound of Formula (IB):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

R₇is selected from the group consisting of H and C₁-C₆alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted

Embodiment 4. A compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

R₇is selected from the group consisting of H and C₁-C₆alkyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 5. A compound of Formula (IC):

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or a pharmaceutically acceptable salt thereof, wherein

A is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 6. A compound of Formula (IC) or a pharmaceutically acceptable salt thereof, wherein

A is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 7. A compound of Formula (ID):

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or a pharmaceutically acceptable salt thereof, wherein

A is a heteroaryl, heterocycloalkyl, aryl, or a cycloalkyl;

each Q is independently selected from the group consisting of C₁-C₃alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, and C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

provided that at least one R₃is QR₆, wherein Q is C₂-C₆alkynyl.

Embodiment 8. A compound of Formula (IE)

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or a pharmaceutically acceptable salt thereof, wherein

A is a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;

wherein Q is C₁-C₃alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4; and

each alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted.

Embodiment 9. The compound of any one of Embodiments 0-9, wherein each alkyl, alkoxyl, alkenyl, alkynyl, alkylcarbonyl, or alkylsulfonyl is unsubstituted or substituted with one or more substituents from the group consisting of halo, amino, alkoxyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.

Embodiment 10. The compound of any one of Embodiments 0-9, wherein each cycloalkyl, aryl, aryloxyl, heterocycloalkyl, or heteroaryl is unsubstituted or substituted with one or more substituents from the group consisting of halo, alkyl, haloalkyl, alkoxyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.

Embodiment 11. The compound of any one of Embodiments 0-10, wherein each aminocarbonyl, or aminosulfonyl is unsubstituted or substituted with one or more substituents from the group consisting of halo, alkyl, alkoxyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.

Embodiment 12. The compound of any one of Embodiments 0-11, wherein each cycloalkyl is independently a C₃-C₁₄cycloalkyl.

Embodiment 13. The compound of any one of Embodiments 0-12, wherein each cycloalkyl is independently a C₃-C₈cycloalkyl.

Embodiment 14. The compound of any one of Embodiments 0-13, wherein each aryl is independently a C₆-C₁₀aryl.

Embodiment 15. The compound of any one of Embodiments 0-14, wherein each heteroaryl is independently a 5 to 6 membered heteroaryl.

Embodiment 16. The compound of any one of Embodiments 0-15, wherein each heterocycloalkyl is independently a 3 to 8-membered heterocycloalkyl.

Embodiment 17. The compound of any one of Embodiments 0-15, wherein each heterocycloalkyl is independently a 7 to 12-membered heterocycloalkyl.

Embodiment 17a. The compound of any one of Embodiments 0-17, wherein X₁and X₂are each independently selected from —CH and N.

Embodiment 17b. The compound of Embodiment 17a, wherein X₁is —CH.

Embodiment 17c. The compound of Embodiment 17a, wherein X₁is N.

Embodiment 17d. The compound of any one of Embodiments 0-17a, wherein X₂is —CH.

Embodiment 17e. The compound of any one of Embodiments 0-17a, wherein X₂is —N.

Embodiment 17f The compound of any one of Embodiments 0-17e, wherein Y is selected from the group consisting of a bond, —NH, —C(O), C₁-C₆alkyl, —C(CH₃)₂—O—, and —CH₂—NH—CH₂—;

Embodiment 17 g. The compound of Embodiment 17f, wherein Y is a bond.

Embodiment 17h. The compound of Embodiment 17f, wherein Y is —NH.

Embodiment 17i. The compound of Embodiment 17f, wherein Y is —C(O).

Embodiment 17j. The compound of Embodiment 17f, wherein Y is a C₁-C₆alkyl.

Embodiment 17k. The compound of Embodiment 17j, wherein Y is CH₃.

Embodiment 17l. The compound of Embodiment 17j, wherein Y is CH₂—CH₃.

Embodiment 17m. The compound of Embodiment 17f, wherein Y is —C(CH₃)₂—O—,

Embodiment 17n. The compound of Embodiment 17f, wherein Y is —CH₂—NH—CH₂—.

Embodiment 17o. The compound of any one of Embodiments 0-17n, wherein R₇is selected from the group consisting of H, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, C₁-C₆alkylcarbonyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, C₆-C₁₀aryloxyl, heterocycloalkyl, heteroaryl, and —(CH₂)_mR_4′.

Embodiment 17p. The compound of any one of Embodiments 0-17n, R₈and R_9′ are each independently selected from the group consisting of H, halo, and C₁-C₃alkyl.

Embodiment 18. The compound of any one of Embodiments 0-17p, wherein A is a 6 membered heteroaryl.

Embodiment 19. The compound of any one Embodiments 0-17n, wherein A is a 7-12 membered heteroaryl.

Embodiment 20. The compound of any one Embodiments 0-17n, wherein A is a 3 to 8-membered heterocycloalkyl having 1 to 4 heteroatoms selected from N, O, and S.

Embodiment 21. The compound of Embodiment 17, wherein A is a monocyclic heterocycloalkyl.

Embodiment 22. The compound of any one Embodiments 0-17n, wherein A is a 7 to 12-membered heterocycloalkyl having 1 to 4 heteroatoms selected from N, O, and S.

Embodiment 23. The compound of any one Embodiments 0-17n, wherein A is a 10-membered heterocycloalkyl having 1 to 4 heteroatoms selected from N, O, and S.

Embodiment 24. The compound of Embodiment 22 or 23, wherein A is a bicyclic heterocycloalkyl.

Embodiment 25. The compound of any one Embodiments 0-17n, wherein A is C₃-C₁₄cycloalkyl.

Embodiment 26. The compound of Embodiment 25, wherein A is C₃-C₈cycloalkyl.

Embodiment 27. The compound of Embodiment 26, wherein A is a C₃cycloalkyl.

Embodiment 28. The compound of Embodiment 27, wherein A is cyclopropyl.

Embodiment 29. The compound of Embodiment 26, wherein A is a C₄cycloalkyl.

Embodiment 30. The compound of Embodiment 26, wherein A is a C₅cycloalkyl.

Embodiment 31. The compound of Embodiment 26, wherein A is a C₆cycloalkyl.

Embodiment 32. The compound of any one of Embodiments 0-31, wherein R₃is selected from the group consisting of halo, hydroxyl, COOH, cyano, nitro, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, 4 to 7-membered heterocycloalkyl, 5 to 12-membered heterocycloalkyl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylcarbonylamino, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

Embodiment 33. The compound of any one of Embodiments 0-32, wherein R₆is selected from the group consisting of halo, hydroxyl, COOH, cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxyl, 4 to 7-membered heterocycloalkyl, —NR₅R_5′.

Embodiment 34. The compound of any one of Embodiments 0-33, wherein A is selected from thiazolyl, isothiazolyl, thiazol-2-onyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,4-triazolyl, and 1,2,3-triazolyl.

Embodiment 35. The compound of any one of Embodiments 0-34, wherein A is selected from thiazolyl, thiophenyl, pyrrolyl, and pyrazolyl.

Embodiment 36. The compound of any one of Embodiments 0-35, wherein A is thiazolyl or thiophenyl.

Embodiment 37. The compound of any one of Embodiments 0-36, wherein A is N-substituted pyrrolyl.

Embodiment 38. The compound of any one of Embodiments 0-37, wherein R₁is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, C₃-C₈cycloalkyl, and —(CH₂)_mR₄.

Embodiment 39. The compound of Embodiment 38, wherein R₁is selected from the group consisting of H, C₁-C₆alkyl, or C₁-C₆haloalkyl.

Embodiment 40. The compound of Embodiment 39, wherein R₁is methyl, ethyl, halomethyl or haloethyl.

Embodiment 41. The compound of Embodiment 40, wherein R₁is fluoroalkyl.

Embodiment 42. The compound of Embodiment 41, wherein R₁is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

Embodiment 43. The compound of Embodiment 38, wherein R₁is C₃-C₈cycloalkyl.

Embodiment 44. The compound of Embodiment 43, wherein R₁is cyclopropyl.

Embodiment 45. The compound of Embodiment 38, wherein R₁is C₆-C₁₀aryl.

Embodiment 46. The compound of Embodiment 45, wherein R₁is phenyl.

Embodiment 47. The compound of Embodiment 38, wherein R₁is —(CH₂)_mR₄.

Embodiment 48. The compound of Embodiment 47, wherein R₄is selected from the group consisting of C₁-C₆alkoxyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

Embodiment 49. The compound of Embodiment 47, wherein R₄is hydroxyl.

Embodiment 50. The compound of Embodiment 48, wherein R₄is mono-C₁-C₆alkylamino.

Embodiment 51. The compound of Embodiment 50, wherein R₄is methylamino.

Embodiment 52. The compound of Embodiment 48, wherein R₄is di-C₁-C₆alkylamino.

Embodiment 53. The compound of Embodiment 46, wherein R₄is dimethylamino.

Embodiment 54. The compound of Embodiment 47, wherein R₄is C₁-C₆alkoxyl.

Embodiment 55. The compound of Embodiment 54, wherein R₄is methoxyl.

Embodiment 56. The compound of Embodiment 47, wherein R₄is C₆-C₁₀aryl.

Embodiment 57. The compound of Embodiment 56, wherein R₄is phenyl.

Embodiment 58. The compound of Embodiment 47, wherein R₄is C₃-C₈cycloalkyl.

Embodiment 59. The compound of Embodiment 58, wherein R₄is cyclopropyl.

Embodiment 60. The compound of Embodiment 47, wherein R₄is a 5-membered heteroaryl.

Embodiment 61. The compound of Embodiment 60, wherein R₄is pyrazolyl or imidazolyl.

Embodiment 62. The compound of Embodiment 47, wherein R₄is a 5-membered heterocycloalkyl.

Embodiment 63. The compound of Embodiment 62, wherein R₄is pyrrolidinyl.

Embodiment 64. The compound of any one of Embodiments 47-63, wherein m is 1.

Embodiment 65. The compound of any one of Embodiments 47-63, wherein m is 2.

Embodiment 66. The compound of any one of Embodiments 47-63, wherein m is 3, 4, 5, or 6.

Embodiment 67. The compound of any one of Embodiments 0-65, wherein R₂is selected from the group consisting of H, halo, cyano, C₁-C₆alkyl, —(CH₂)_mR₄, —NR₅R_5′, —OR₅, —C(O)NH₂, and —NO₂.

Embodiment 68. The compound of Embodiment 67, wherein R₂is H.

Embodiment 69. The compound of Embodiment 67, wherein R₂is cyano.

Embodiment 69a. The compound of Embodiment 67, wherein R₂is —C(O)NH₂.

Embodiment 69b. The compound of Embodiment 67, wherein R₂is —NO₂.

Embodiment 70. The compound of Embodiment 67, wherein R₂is halo.

Embodiment 71. The compound of Embodiment 70, wherein R₂is F, Cl, or Br.

Embodiment 72. The compound of Embodiment 67, wherein R₂is C₁-C₆alkyl.

Embodiment 73. The compound of Embodiment 72, wherein R₂is methyl, ethyl, or propyl.

Embodiment 74. The compound of Embodiment 67, wherein R₂is —(CH₂)m R₄.

Embodiment 75. The compound of Embodiment 74, wherein R₄is C₆-C₁₀aryl.

Embodiment 76. The compound of Embodiment 75, wherein R₄is phenyl.

Embodiment 77. The compound of Embodiment 74, wherein R₄is a 5-membered heteroaryl.

Embodiment 78. The compound of Embodiment 77, wherein R₄is 1-methyl-pyrazolyl.

Embodiment 79. The compound of Embodiment 67, wherein R₂is —NR₅R_5′, R₅is H and R_5′ is C₁-C₆alkyl.

Embodiment 80. The compound of Embodiment 67, wherein R₂is —NR₅R_5′, and R₅and R_5′ are both C₁-C₆alkyl.

Embodiment 81. The compound of Embodiment 67, wherein R₂is —NR₅R_5′, R₅is H and R_5′ is —(CH₂)_mR_4′.

Embodiment 82. The compound of Embodiment 56, wherein R₄′ is C₁-C₆alkoxyl.

Embodiment 83. The compound of Embodiment 82, wherein R₄′ is methoxyl.

Embodiment 84. The compound of Embodiment 81, wherein R₄′ is di-C₁-C₆alkylamino.

Embodiment 85. The compound of Embodiment 84, wherein R₄′ is dimethylamino.

Embodiment 86. The compound of Embodiment 81, wherein R₄′ is a 6-membered heteroaryl.

Embodiment 87. The compound of Embodiment 86, wherein R₄′ is pyridinyl.

Embodiment 88. The compound of Embodiment 81, wherein R₄′ is a 6-membered heterocycloalkyl.

Embodiment 89. The compound of Embodiment 88, wherein R₄′ is morpholinyl.

Embodiment 90. The compound of Embodiment 81, wherein R₄′ is a 5-membered heteroaryl.

Embodiment 91. The compound of Embodiment 90, wherein R₄′ is 1-methylpyrazolyl.

Embodiment 92. The compound of Embodiment 90, wherein R₄′ is imidazolyl

Embodiment 93. The compound of Embodiment 81, wherein R₄′ is a 5-membered heterocyclyl.

Embodiment 94. The compound of Embodiment 93, wherein R₄′ is pyrrolidinyl.

Embodiment 95. The compound of Embodiment 67, wherein R₂is —OR₅and R₅is —(CH₂)_mR₄′.

Embodiment 96. The compound of Embodiment 95, wherein R₄′ is selected from the group consisting of C₁-C₆alkoxyl, mono-C₁-C₆alkylamino, and di-C₁-C₆alkylamino.

Embodiment 97. The compound of Embodiment 96, wherein R₄′ is C₁-C₆alkoxyl.

Embodiment 98. The compound of Embodiment 97, wherein R₄′ is methoxyl.

Embodiment 99. The compound of Embodiment 96, wherein R₄′ is mono-C₁-C₆alkylamino.

Embodiment 100. The compound of Embodiment 99, wherein R₄′ is methylamino.

Embodiment 101. The compound of Embodiment 96, wherein R₄′ is di-C₁-C₆alkylamino.

Embodiment 102. The compound of Embodiment 101, wherein R₄′ is dimethylamino.

Embodiment 103. The compound of Embodiment 95, wherein R₄′ is a 6-membered heterocycloalkyl.

Embodiment 104. The compound of Embodiment 103, wherein R₄′ is 1-methylpiperazine or morpholinyl.

Embodiment 105. The compound of any one of Embodiments 74-104, wherein m is 1.

Embodiment 106. The compound of any one of Embodiments 74-104 wherein m is 2.

Embodiment 107. The compound of any one of Embodiments 0-106, wherein R₃is selected from the group consisting of halo, cyano, nitro, oxo, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, 5 to 6-membered heteroaryl, 5 to 12-membered heterocycloalkyl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

Embodiment 108. The compound of Embodiment 107, wherein R₃is selected from the group consisting of halo, cyano, nitro, oxo, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, 5 to 12-membered heterocycloalkyl, aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, di-C₁-C₆alkylaminocarbonyl, C₁-C₆alkylsulfonyl, aminosulfonyl, QR₆, —(CH₂)_mR₆, —NR₅R_5′, and —OR₅.

Embodiment 109. The compound of Embodiment 107, wherein R₃is halo.

Embodiment 110. The compound of Embodiment 107, wherein R₃is cyano.

Embodiment 111. The compound of Embodiment 107, wherein R₃is nitro.

Embodiment 112. The compound of Embodiment 107, wherein R₃is oxo.

Embodiment 113. The compound of Embodiment 107, wherein R₃is C₁-C₆alkenyl.

Embodiment 114. The compound of Embodiment 107, wherein R₃is C₁-C₆haloalkyl.

Embodiment 115. The compound of Embodiment 114, wherein R₃is trifluoromethyl.

Embodiment 116. The compound of Embodiment 107, wherein R₃is aminocarbonyl, mono-C₁-C₆alkylaminocarbonyl, or di-C₁-C₆alkylaminocarbonyl.

Embodiment 117. The compound of Embodiment 107, wherein R₃is methylaminocarbonyl.

Embodiment 118. The compound of Embodiment 107, wherein R₃is dimethylaminocarbonyl.

Embodiment 119. The compound of Embodiment 107, wherein R₃is C₁-C₆alkylsulfonyl.

Embodiment 120. The compound of Embodiment 107, wherein R₃is aminosulfonyl.

Embodiment 121. The compound of Embodiment 107, wherein R₃is methylsulfonyl.

Embodiment 122. The compound of Embodiment 107, wherein R₃is C₆-C₁₀aryl.

Embodiment 123. The compound of Embodiment 122, wherein R₃is phenyl.

Embodiment 124. The compound of Embodiment 122 or 123, wherein the C₆-C₁₀aryl is substituted with one or more C₁-C₆alkyl, halogen, or C₁-C₆alkoxyl.

Embodiment 125. The compound of Embodiment 107, wherein R₃is C₃-C₈cycloalkyl.

Embodiment 126. The compound of Embodiment 125, wherein R₃is cyclopropyl.

Embodiment 127. The compound of Embodiment 107, wherein R₃is a 5 to 6-membered heteroaryl.

Embodiment 128. The compound of Embodiment 127, wherein R₃is selected from oxazolyl, pyridinyl, furanyl, thiazolyl, pyrrolyl, imidazolyl, and pyrazolyl.

Embodiment 129. The compound of Embodiment 127 or 128, wherein the 5 to 6-membered heteroaryl is substituted with one or more methyl.

Embodiment 130. The compound of Embodiment 127 or 128, wherein the 5 to 6-membered heteroaryl is substituted with one or more C₁-C₆haloalkyl.

Embodiment 131. The compound of Embodiment 130, wherein the 5 to 6-membered heteroaryl is substituted with trifluoromethyl.

Embodiment 132. The compound of Embodiment 129, wherein R₃is selected from the group consisting of 2-methylthiazolyl, 1,2-dimethyl-pyrrolyl, 1-methyl-imidazolyl, and 1-methyl-pyrazolyl.

Embodiment 133. The compound of Embodiment 107, wherein R₃is 5 to 12-membered heterocycloalkyl.

Embodiment 134. The compound of Embodiment 134, wherein R₃is 2,3-dihydrobenzofuranyl.

Embodiment 135. The compound of Embodiment 107, wherein R₃is —(CH₂)_mR₆.

Embodiment 136. The compound of Embodiment 135, wherein R₆is hydroxyl.

Embodiment 137. The compound of Embodiment 135, wherein R₆is C₆-C₁₀aryl.

Embodiment 138. The compound of Embodiment 137, wherein C₆-C₁₀aryl is substituted with C₁-C₆alkoxyl.

Embodiment 139. The compound of Embodiment 137 or 138, wherein C₆-C₁₀aryl is phenyl.

Embodiment 140. The compound of any one of Embodiments 135-139, wherein m is 1.

Embodiment 141. The compound of Embodiment 107, wherein R₃is QR₆.

Embodiment 142. The compound of Embodiment 141, wherein R₆is a 4, 5 or 6-membered heterocyclyl.

Embodiment 143. The compound of Embodiment 142, wherein R₆is oxetanyl, pyrrolidinyl, or morpholinyl.

Embodiment 144. The compound of Embodiment 141, wherein R₆is a 5 or 6-membered heteroaryl.

Embodiment 145. The compound of Embodiment 144, wherein R₆is pyridinyl, pyrimidinyl, furanyl, thiazolyl, imidazolyl, or pyrrolyl.

Embodiment 146. The compound of Embodiment 141, wherein R₆is amino.

Embodiment 147. The compound of Embodiment 141, wherein R₆is di-C₁-C₆alkylamino.

Embodiment 148. The compound of Embodiment 147, wherein R₆is dimethylamino.

Embodiment 149. The compound of Embodiment 141, wherein R₆is hydroxyl.

Embodiment 150. The compound of Embodiment 142, wherein R₆is C₁-C₆haloalkyl.

Embodiment 151. The compound of Embodiment 150, wherein R₆is trifluoromethyl.

Embodiment 152. The compound of any one of Embodiments 141-151, wherein Q is prop-1-ynyl.

Embodiment 153. The compound of any one of Embodiments 141-151, wherein Q is a C₁-C₃alkyl.

Embodiment 154. The compound of Embodiment 153, wherein Q is substituted with OH.

Embodiment 155. The compound of Embodiment 153, wherein Q is substituted with halo.

Embodiment 156. The compound of Embodiment 155, wherein Q is substituted with fluoro. Embodiment 157. The compound of Embodiment 153 or 154, wherein Q is methyl.

Embodiment 158. The compound of Embodiment 107, wherein R₃is —NR₅R_5′.

Embodiment 159. The compound of Embodiment 158, wherein R₅is H and R_5′ is C₃-C₈cycloalkyl.

Embodiment 160. The compound of Embodiment 159, wherein R_5′ is cyclopentyl.

Embodiment 161. The compound of Embodiment 158, wherein R₅is H and R_5′ is C₁-C₆alkyl.

Embodiment 162. The compound of Embodiment 161, wherein R_5′ is methyl.

Embodiment 163. The compound of Embodiment 161, wherein R_5′ is i-propyl.

Embodiment 164. The compound of Embodiment 158, wherein R₅is H and R_5′ is C₁-C₆alkylcarbonyl.

Embodiment 165. The compound of Embodiment 164, wherein R_5′ is ethanoyl.

Embodiment 166. The compound of Embodiment 107, wherein R₃is OR₅.

Embodiment 167. The compound of Embodiment 166, wherein R₅is C₁-C₆alkyl.

Embodiment 168. The compound of Embodiment 167, wherein the C₁-C₆alkyl is methyl.

Embodiment 169. The compound of any one of the preceding Embodiments, wherein n is 2 or 3.

Embodiment 170. The compound of Embodiment 107, wherein n is 1 and R₃is cyano.

Embodiment 171. The compound of Embodiment 107, wherein n is 1 or 2 and R₃is halo.

Embodiment 172. The compound of Embodiment 107, wherein n is 2, one R₃is halo and the other R₃is cyano.

Embodiment 173. The compound of any Embodiment 107, 171, or 172, wherein halo is selected from Cl, Br, and I.

Embodiment 174. The compound of Embodiment 1, wherein A is thiazolyl.

Embodiment 175. The compound of Embodiment 1, wherein A is thiophenyl.

Embodiment 176. The compound of Embodiment 174 or 175, wherein n is 1 and R₃is cyano.

Embodiment 177. The compound of Embodiment 174 or 175, wherein n is 2 and R₃is selected from halo and cyano.

Embodiment 178. The compound any one of Embodiments 174 or 177, wherein n is 2 and each R₃is halo.

Embodiment 179. The compound of Embodiment 177 or 178, wherein halo is chloro or fluoro.

Embodiment 180. The compound of Embodiment 9, wherein

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Embodiment 181. The compound of any one of Embodiments 174-180, wherein R₁is haloalkyl.

Embodiment 182. The compound of Embodiment 181, wherein R₁is fluoroalkyl.

Embodiment 183. The compound of Embodiment 182, wherein R₁is fluoroethyl or difluoroethyl.

Embodiment 184. The compound of any one of Embodiments 174-183, wherein R₂is halo.

Embodiment 185. The compound of Embodiment 184, wherein R₂is fluoro.

Embodiment 186. The compound of any one of Embodiments 0-185, wherein each amino, alkylamino or dialkylamino is unsubstituted or substituted.

Embodiment 187. The compound of any one of Embodiments 0-185, wherein each amino, alkylamino or dialkylamino is unsubstituted.

Embodiment 188. A compound selected from Table 2, Table 2a, Table 2b, Table 2c, Table 2d, and pharmaceutically acceptable salts thereof.

Embodiment 189. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a any one of Embodiments 0-188 to the subject or a cell of the subject.

Embodiment 190. A compound of any one of Embodiments 0-188 for use in the treatment of cancer in a cell or subject.

Embodiment 191. A compound of any one of Embodiments 0-188 for use as a medicament for the treatment of cancer in a cell or subject.

Embodiment 192. The use of a compound of any one of Embodiments 0-188 in the manufacture of a medicament for the treatment of cancer in a cell or subject.

Embodiment 193. The use, compound for use or method of any one of Embodiments 189-192, wherein the subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Embodiment 194. The use, compound for use or method of any one of Embodiments 189-192, wherein the subject or a cell of the subject comprises a biomarker of sensitivity to a SMARCA2 antagonist.

Embodiment 195. The use, compound for use or method of Embodiment 194, wherein the biomarker is a decreased activity or function of SMARCA4.

Embodiment 196. The use, compound for use or method of Embodiment 194, wherein the biomarker is loss of function of SMARCA4.

Embodiment 197. The use, compound for use or method of any one of Embodiments 189-192, wherein the subject has a cancer characterized by loss of function of SMARCA4.

Embodiment 198. The use, compound for use or method of any one of Embodiments 189-192, wherein said subject or cell of the subject exhibits a decreased activity or function of SMARCA4 when compared to a control level of the activity or the function of SMARCA4. In some embodiments, the subject or cell of the subject exhibits a SMARCA4 mutation as compared to wild-type SMARCA4.

Embodiment 199. The use, compound for use or method of Embodiment 198, wherein the control level is the level of activity or function of SMARCA4 in a subject that does not have cancer.

Embodiment 200. A method of modulating (e.g., inhibiting) an activity of SMARCA2, comprising contacting SMARCA2 enzyme with a compound of any one of Embodiments 1-188.

Embodiment 201. The compound of any one of Embodiments 0-188 for use in inhibiting an activity of SMARCA2, wherein the compound is contacted with a SMARCA2 enzyme.

Embodiment 202. The compound of any one of Embodiments 0-188 for use as a medicament for inhibiting an activity of SMARCA2, wherein the medicament is contacted with a SMARCA2 enzyme.

Embodiment 203. The compound of any one of Embodiments 0-188 for use in the manufacture of a medicament for inhibiting an activity of SMARCA2, wherein the medicament is to be contacted with a SMARCA2 enzyme.

	Number	Date	Country
	62702481	Jul 2018	US
	62815208	Mar 2019	US

PYRIDIN-2-ONE COMPOUNDS USEFUL AS SMARCA2 ANTAGONISTS

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