Combinations comprising alkyne substituted quinazoline derivatives and their use in the treatment of cancer

Abstract

The present disclosure relates to combinations comprising Compound No. 1 or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent. The present disclosure also relates to uses of the combinations, e.g., in treating or preventing cancer.

Description

COMBINATIONS COMPRISING ALKYNE SUBSTITUTED QUINAZOLINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application Nos. 63 / 609,635, filed on December 13, 2023, and 63 / 550,377, filed on February 6, 2024, the contents of each of which are incorporated by reference herein in their entirety for all purposes.BACKGROUND

[0002] Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal rowth factor receptor (EGFR) and Erb-2, also named HER2 in humans). ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies.

[0003] There is a need for prevention or treatment of cancer in patients, e.g., with these oncogenic mutations. The present disclosure addresses this need.SUMMARY

[0004] In some aspects, the present disclosure provides a combination comprising: (i) Compound No. 1 or a pharmaceutically acceptable salt thereof, and (ii) an additional therapeutic agent.

[0005] In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor in a subject, comprising administering to the subject a combination disclosed herein (or a composition thereof).

[0006] In some aspects, the present disclosure provides a combination disclosed herein (or a composition thereof) for use in inhibiting an oncogenic variant of an ErbB receptor in a subject.

[0007] In some aspects, the present disclosure provides use of a combination disclosed herein (or a composition thereof) in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor in a subject.

[0008] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a combination disclosed herein (or a composition thereof).

[0009] In some aspects, the present disclosure provides a combination disclosed herein (or a composition thereof) for use in treating or preventing cancer in a subject.

[0010] In some aspects, the present disclosure provides use of a combination disclosed herein (or a composition thereof) in the manufacture of a medicament for treating or preventing cancer in a subject.

[0011] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1 or a pharmaceutically acceptable salt thereof at a daily dosage of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0012] In some aspects, the present disclosure provides Compound No. 1 or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject in need thereof at a daily dosage of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0013] In some aspects, the present disclosure provides use of Compound No. 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof at a daily dosage of about 75±20 mg, about 75± 10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0014] In some aspects, the present disclosure provides a pharmaceutical composition for treating or preventing cancer, comprising Compound No. 1 or a pharmaceutically acceptable salt thereof at a daily dosage of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0015] In some aspects, the present disclosure provides a pharmaceutical kit for treating or preventing cancer, comprising Compound No. 1 or a pharmaceutically acceptable salt thereof at a daily dosage of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited hereinare not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0017] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.DETAILED DESCRIPTIONCombinations, Compositions, Methods, and Uses of the Present Disclosure

[0018] In some aspects, the present disclosure provides a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0019] In some aspects, the present disclosure provides a pharmaceutical composition comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0020] In some aspects, the present disclosure provides a combination therapy comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0021] In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor in a subject, comprising administering to the subject a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0022] In some aspects, the present disclosure provides a combination for use in inhibiting an oncogenic variant of an ErbB receptor in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0023] In some aspects, the present disclosure provides use of a combination in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0024] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0025] In some aspects, the present disclosure provides a combination disclosed herein for use in treating or preventing cancer in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0026] In some aspects, the present disclosure provides use of a combination in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0027] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1 or a pharmaceutically acceptable salt thereof at a dosage (e.g., a daily dosage) of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0028] In some aspects, the present disclosure provides Compound No. 1 or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject in need thereof at a dosage (e.g., a daily dosage) of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±I mg (e.g., about 75 mg).

[0029] In some aspects, the present disclosure provides use of Compound No. 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof at a dosage (e.g., a daily dosage) of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0030] In some aspects, the present disclosure provides a pharmaceutical composition for treating or preventing cancer, comprising Compound No. 1 or a pharmaceutically acceptable salt thereof at a dosage (e.g., a daily dosage) of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0031] In some aspects, the present disclosure provides a pharmaceutical kit for treating or preventing cancer, comprising Compound No. 1 or a pharmaceutically acceptable salt thereofat a dosage (e g., a daily dosage) of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).Compound No. 1

[0032] It is understood that, as used herein, the term “Compound No. 1” refers to a compound having the following structure:(Compound No. 1).

[0033] In some embodiments, Compound No. 1 is Compound No. 1 A or Compound No. IB.

[0034] In some embodiments, Compound No. 1 is Compound No. 1 A.

[0035] In some embodiments, Compound No. 1 is Compound No. IB.

[0036] It is understood that the term “Compound No. 1A,” as used herein, refers to a compound having the following structure:

[0037] It is understood that the term “Compound No. IB,” as used herein, refers to a compound having the following structure:(Compound No. IB)Additional Therapeutic Agents

[0038] In some embodiments, the additional therapeutic agent comprises BLU-701, Carboplatin (e.g., sold as Paraplatin®), Pemetrexed (e.g., sold as Alimta®), Pembrolizumab (e.g., sold as Keytruda"). or any combination thereof.

[0039] In some embodiments, the additional therapeutic agent comprises BLU-701.

[0040] In some embodiments, the additional therapeutic agent comprises Carboplatin (e.g., sold as Paraplatin®).

[0041] In some embodiments, the additional therapeutic agent comprises Pemetrexed (e.g., sold as Alimta®).

[0042] In some embodiments, the additional therapeutic agent comprises Pembrolizumab (e.g., sold as Keytruda®)

[0043] In some embodiments, the additional therapeutic agent comprises a checkpoint inhibitor.

[0044] In some embodiments, the additional therapeutic agent comprises a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, or any combination thereof.

[0045] In some embodiments, the additional therapeutic agent comprises a PD-1 inhibitor.

[0046] In some embodiments, the additional therapeutic agent comprises Pembrolizumab (e.g., sold as Keytruda®), Nivolumab (e.g., sold as Opdivo®), Cemiplimab (e.g., sold as Libtayo®), or any combination thereof.

[0047] In some embodiments, the additional therapeutic agent comprises Pembrolizumab (e.g., sold as Keytruda®).

[0048] In some embodiments, the additional therapeutic agent comprises Nivolumab (e.g., sold as Opdivo®).

[0049] In some embodiments, the additional therapeutic agent comprises Cemiplimab (e.g., sold as Libtayo®).

[0050] In some embodiments, the additional therapeutic agent comprises PD-L1 inhibitor.

[0051] In some embodiments, the additional therapeutic agent comprises Atezolizumab (e.g., sold as Tecentriq®), Avelumab (e.g., sold as Bavencio®), Durvalumab (e.g., sold as Imfinzi®), or any combination thereof.

[0052] In some embodiments, the additional therapeutic agent comprises Atezolizumab (e.g., sold as Tecentriq®).

[0053] In some embodiments, the additional therapeutic agent comprises Avelumab (e.g., sold as Bavencio®).

[0054] In some embodiments, the additional therapeutic agent comprises Durvalumab (e.g., sold as Imfinzi®).

[0055] In some embodiments, the additional therapeutic agent comprises CTLA-4 inhibitor.

[0056] In some embodiments, the additional therapeutic agent comprises Ipilimumab (e.g., sold as Yervoy®), Tremelimumab (e.g., sold as Imjuno®), or any combination thereof.

[0057] In some embodiments, the additional therapeutic agent comprises Ipilimumab (e.g., sold as Yervoy®).

[0058] In some embodiments, the additional therapeutic agent comprises Tremelimumab (e.g., sold as Imjuno®).

[0059] In some embodiments, the additional therapeutic agent comprises LAG-3 inhibitor.

[0060] In some embodiments, the additional therapeutic agent comprises Relatlimab, Nivolumab (e.g., sold as Opdivo®), Opdualag (e.g., Relatlimab and Novolumab), or any combination thereof.

[0061] In some embodiments, the additional therapeutic agent comprises Relatlimab.

[0062] In some embodiments, the additional therapeutic agent comprises Nivolumab (e.g., sold as Opdivo®).

[0063] In some embodiments, the additional therapeutic agent comprises Opdualag (e.g., Relatlimab and Novolumab).Suitable Subjects and Diseases / Disorders

[0064] In some embodiments, the subject is a mammal.

[0065] In some embodiments, the subject is a human.

[0066] In some embodiments, the subject is a mouse.

[0067] In some embodiments, cancer is a solid tumor.

[0068] In some embodiments, the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.

[0069] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof. In some embodiments, the cancer is glioblastoma (GBM).

[0070] In some embodiments, the cancer is glioblastoma (GBM) and the cancer is characterized by overexpression of EGFR.

[0071] In some embodiments, the cancer is methylated glioblastoma. In some embodiments, the cancer is unmethylated glioblastoma.

[0072] In some embodiments, the cancer is recurrent glioblastoma.

[0073] In some embodiments, the cancer is relapsed glioblastoma.

[0074] In some embodiments, the cancer is glioblastoma and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0075] In some embodiments, the cancer is relapsed glioblastoma and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0076] In some embodiments, the cancer is recurrent glioblastoma and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0077] In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or any subtype thereof.

[0078] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0079] In some embodiments, the cancer is recurrent non-small cell lung cancer (NSCLC).

[0080] In some embodiments, the cancer is relapsed non-small cell lung cancer (NSCLC).

[0081] In some embodiments, the cancer is NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0082] In some embodiments, the cancer is recurrent NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0083] In some embodiments, the cancer is relapsed NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0084] In some embodiments, the cancer is advanced or metastatic NSCLC .

[0085] In some embodiments, the cancer is advanced or metastatic NSCLC and the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR.

[0086] In some embodiments, the cancer is NSCLC, wherein the cancer has metastasized to the central nervous system (CNS).

[0087] In some embodiments, the cancer is advanced or metastatic NSCLC, wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the cancer has metastasized to the central nervous system (CNS).

[0088] In some embodiments, the cancer is advanced or metastatic NSCLC, wherein the cancer, or a tumor or cell thereof, expresses at least one oncogenic variant of EGFR, and wherein the cancer has not metastasized to the central nervous system (CNS).

[0089] In some embodiments, the cancer is NSCLC, wherein the cancer has not metastasized to cerebrospinal fluid (CSF).

[0090] In some embodiments, the cancer is NSCLC, wherein the cancer has metastasized to cerebrospinal fluid (CSF).

[0091] In some embodiments, the cancer is glioblastoma, wherein the cancer has not metastasized to cerebrospinal fluid (CSF).

[0092] In some embodiments, the cancer is glioblastoma, wherein the cancer has metastasized to cerebrospinal fluid (CSF).

[0093] In some embodiments, the cancer is NSCLC, wherein the cancer has not metastasized to the brain.

[0094] In some embodiments, the cancer is NSCLC, wherein the cancer has metastasized to the brain.

[0095] In some embodiments, the subject has a central nervous system (CNS) disease.

[0096] In some embodiments, the subject does not have any CNS disease.

[0097] In some embodiments, the subject has a leptomeningeal disease.

[0098] In some embodiments, the subject does not have any leptomeningeal disease.

[0099] In some embodiments, the cancer is NSCLC and the subject has leptomeningeal disease.

[0100] In some embodiments, the cancer is glioblastoma and the subject has leptomeningeal disease.

[0101] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor.

[0102] It is understood that an oncogenic variant of an ErbB receptor is an ErbB receptor protein that comprises at least one oncogenic mutation and that is produced as the result of the expression of a gene encoding the ErbB receptor that comprises at least one oncogenic mutation.

[0103] As would be appreciated by the skilled artisan, in the context of a gene (e.g. a gene encoding an ErbB receptor), an oncogenic mutation can include, but is not limited to a mutationthat results in the substitution of one amino acid for another at a specific position within an ErbB receptor, a mutation that results in an insertion of one or more amino acids between two positions within an ErbB receptor, a mutation that results in the deletion of one more amino acids between two positions within an ErbB receptor, and mutation that results in a fusion of an ErbB receptor or portion thereof, with another protein, or portion thereof. As would be appreciated by the skilled artisan, in the context of a gene, an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion.

[0104] As would be appreciated by the skilled artisan, in the context of a protein (e.g. an ErbB receptor), an oncogenic mutation can include, but is not limited to, the substitution of one amino acid for another at a specific position within an ErbB receptor, an insertion of one or more amino acids between two positions within an ErbB receptor, a deletion of one more amino acids between two positions within an ErbB receptor, and a fusion of an ErbB receptor, or portion thereof, with another protein, or portion thereof.

[0105] In some embodiments, the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

[0106] In some embodiments, the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor.

[0107] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.

[0108] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR)

[0109] In some embodiments, the ErbB receptor is a HER2 receptor.

[0110] In some embodiments, the ErbB receptor is a HER3 receptor.

[0111] In some embodiments, the ErbB receptor is a HER4 receptor.

[0112] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).

[0113] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0114] In some embodiments, the oncogenic variant of EGFR comprises an allosteric mutation.

[0115] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor.

[0116] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0117] In some embodiments, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[0118] In some embodiments, the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation.

[0119] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant II (EGFR-Vii) mutation.

[0120] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant VI (EGFR-Vvi) mutation.Administrations

[0121] In some embodiments, Compound No. 1 or the pharmaceutically acceptable salt thereof is administered.

[0122] In some embodiments, Compound No. 1 is administered.

[0123] In some embodiments, the pharmaceutically acceptable salt of Compound No. 1 is administered.

[0124] In some embodiments, Compound No. 1A or the pharmaceutically acceptable salt thereof is administered.

[0125] In some embodiments, Compound No. 1 A is administered.

[0126] In some embodiments, the pharmaceutically acceptable salt of Compound No. 1A is administered.

[0127] In some embodiments, Compound No. IB or the pharmaceutically acceptable salt thereof is administered.

[0128] In some embodiments, Compound No. IB is administered.

[0129] In some embodiments, the pharmaceutically acceptable salt of Compound No. IB is administered.

[0130] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three or more times daily.

[0131] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered once daily.

[0132] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered twice daily.

[0133] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered three or more times daily.

[0134] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of: about 15±10 mg, about 15±5 mg, about 15±4 mg, about 15±3 mg, about 15±2 mg, or about 15±1 mg (e.g., about 15 mg); about 25±10 mg, about 25±5 mg, about 25±4 mg, about 25±3 mg, about 25±2 mg, or about 25±1 mg (e.g., about 25 mg); about 50±10 mg, about 50±5 mg, about 50±4 mg, about 50±3 mg, about 50±2 mg, or about 50±l mg (e.g., about 50 mg); about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg); about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±l mg (e.g., about 100 mg); about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±l mg (e.g., about 150 mg); about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±l mg (e.g., about 200 mg); about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±l mg (e.g., about 300 mg); about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±l mg (e.g., about 400 mg); about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±l mg (e.g., about 500 mg); about 600±50 mg, about 600±40 mg, about 600±30 mg, about 600±20 mg, about 600±10 mg, about 600±5 mg, about 600±4 mg, about 600±3 mg, about 600±2 mg, or about 600±l mg (e.g., about 600 mg); about 800±50 mg, about 800±40 mg, about 800±30 mg, about 800±20 mg, about 800±10 mg, about 800±5 mg, about 800±4 mg, about 800±3 mg, about 800±2 mg, or about 800±l mg (e.g., about 800 mg); or about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, about 1000±10 mg, about 1000±5 mg, about 1000±4 mg, about 1000±3 mg, about 1000±2 mg, or about 1000±l mg (e.g., about 1000 mg).

[0135] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 15±10 mg, about 15±5 mg, about 15±4 mg, about 15±3 mg, about 15±2 mg, or about 15±1 mg (e.g., about 15 mg).

[0136] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 25±10 mg, about 25±5 mg, about 25±4 mg, about 25±3 mg, about 25±2 mg, or about 25±1 mg (e.g., about 25 mg).

[0137] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 50±10 mg, about 50±5 mg, about 50±4 mg, about 50±3 mg, about 50±2 mg, or about 50±l mg (e.g., about 50 mg).

[0138] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0139] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±l mg (e.g., about 100 mg).

[0140] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±l mg (e.g., about 150 mg).

[0141] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±l mg (e.g., about 200 mg).

[0142] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±l mg (e.g., about 300 mg).

[0143] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a dailydosage) of about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±l mg (e.g., about 400 mg).

[0144] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±l mg (e.g., about 500 mg).

[0145] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 600±50 mg, about 600±40 mg, about 600±30 mg, about 600±20 mg, about 600±10 mg, about 600±5 mg, about 600±4 mg, about 600±3 mg, about 600±2 mg, or about 600±l mg (e.g., about 600 mg).

[0146] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 800±50 mg, about 800±40 mg, about 800±30 mg, about 800±20 mg, about 800±10 mg, about 800±5 mg, about 800±4 mg, about 800±3 mg, about 800±2 mg, or about 800±l mg (e.g., about 800 mg).

[0147] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, about 1000±10 mg, about 1000±5 mg, about 1000±4 mg, about 1000±3 mg, about 1000±2 mg, or about 1000±l mg (e.g., about 1000 mg).

[0148] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of: about 60±10 mg / kg, about 60±5 mg / kg, about 60±4 mg / kg, about 60±3 mg / kg, about 60±2 mg / kg, or about 60±l mg / kg (e.g., about 60 mg / kg); about 180±20 mg / kg, about 180±10 mg / kg, about 180±5 mg / kg, about 180±4 mg / kg, about 180±3 mg / kg, about 180±2 mg / kg, or about 180±l mg / kg (e.g., about 180 mg / kg); about 600±50 mg / kg, about 600±40 mg / kg, about 600±30 mg / kg, about 600±20 mg / kg, about 600± 10 mg / kg, about 600±5 mg / kg, about 600±4 mg / kg, about 600±3 mg / kg, about 600±2 mg / kg, or about 600±l mg / kg (e.g., about 600 mg / kg); or about 1800±50 mg / kg, about 1800±40 mg / kg, about 1800±30 mg / kg, about 1800±20mg / kg, about 1800±10 mg / kg. about 1800±5 mg / kg, about 1800±4 mg / kg, about 1800±3 mg / kg, about 1800±2 mg / kg, or about 1800±l mg / kg (e.g., about 1800 mg / kg).

[0149] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 60±10 mg / kg, about 60±5 mg / kg, about 60±4 mg / kg, about 60±3 mg / kg, about 60±2 mg / kg, or about 60±l mg / kg (e.g., about 60 mg / kg).

[0150] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 180±20 mg / kg, about 180±10 mg / kg, about 180±5 mg / kg, about 180±4 mg / kg, about 180±3 mg / kg, about 180±2 mg / kg, or about 180±l mg / kg (e.g., about 180 mg / kg).

[0151] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 600±50 mg / kg, about 600±40 mg / kg, about 600±30 mg / kg, about 600±20 mg / kg, about 600±10 mg / kg, about 600±5 mg / kg, about 600±4 mg / kg, about 600±3 mg / kg, about 600±2 mg / kg, or about 600±l mg / kg (e.g., about 600 mg / kg).

[0152] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered at a dosage (e.g., a daily dosage) of about 1800±50 mg / kg, about 1800±40 mg / kg, about 1800±30 mg / kg, about 1800±20 mg / kg, about 1800±10 mg / kg, about 1800±5 mg / kg, about 1800±4 mg / kg, about 1800±3 mg / kg, about 1800±2 mg / kg, or about 1800±l mg / kg (e.g., about 1800 mg / kg).

[0153] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of: about 15±10 mg, about 15±5 mg, about 15±4 mg, about 15±3 mg, about 15±2 mg, or about 15±1 mg (e.g., about 15 mg); about 25±10 mg, about 25±5 mg, about 25±4 mg, about 25±3 mg, about 25±2 mg, or about 25±1 mg (e.g., about 25 mg); about 50±10 mg, about 50±5 mg, about 50±4 mg, about 50±3 mg, about 50±2 mg, or about 50±l mg (e.g., about 50 mg); about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg) about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±l mg (e.g., about 100 mg);about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±l mg (e.g., about 150 mg); about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±l mg (e.g., about 200 mg); about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±l mg (e.g., about 300 mg); about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±l mg (e.g., about 400 mg); about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±l mg (e.g., about 500 mg); about 600±50 mg, about 600±40 mg, about 600±30 mg, about 600±20 mg, about 600±10 mg, about 600±5 mg, about 600±4 mg, about 600±3 mg, about 600±2 mg, or about 600±l mg (e.g., about 600 mg); about 800±50 mg, about 800±40 mg, about 800±30 mg, about 800±20 mg, about 800±10 mg, about 800±5 mg, about 800±4 mg, about 800±3 mg, about 800±2 mg, or about 800±l mg (e.g., about 800 mg); or about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, about 1000±10 mg, about 1000±5 mg, about 1000±4 mg, about 1000±3 mg, about 1000±2 mg, or about 1000±l mg (e.g., about 1000 mg).

[0154] In some embodiments, Compound No. 1 (e.g., Compound No. 1 A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 15±10 mg, about 15±5 mg, about 15±4 mg, about 15±3 mg, about 15±2 mg, or about 15=1=1 mg (e.g., about 15 mg).

[0155] In some embodiments, Compound No. 1 (e.g., Compound No. 1 A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 25±10 mg, about 25±5 mg, about 25±4 mg, about 25±3 mg, about 25±2 mg, or about 25±1 mg (e.g., about 25 mg).

[0156] In some embodiments, Compound No. 1 (e.g., Compound No. 1 A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 50±10 mg, about 50±5 mg, about 50±4 mg, about 50±3 mg, about 50±2 mg, or about 50±l mg (e.g., about 50 mg).

[0157] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0158] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 100±20 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±l mg (e.g., about 100 mg).

[0159] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 150±20 mg, about 150±10 mg, about 150±5 mg, about 150±4 mg, about 150±3 mg, about 150±2 mg, or about 150±l mg (e.g., about 150 mg).

[0160] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 200±20 mg, about 200±10 mg, about 200±5 mg, about 200±4 mg, about 200±3 mg, about 200±2 mg, or about 200±l mg (e.g., about 200 mg).

[0161] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 300±20 mg, about 300±10 mg, about 300±5 mg, about 300±4 mg, about 300±3 mg, about 300±2 mg, or about 300±l mg (e.g., about 300 mg).

[0162] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 400±50 mg, about 400±40 mg, about 400±30 mg, about 400±20 mg, about 400±10 mg, about 400±5 mg, about 400±4 mg, about 400±3 mg, about 400±2 mg, or about 400±l mg (e.g., about 400 mg).

[0163] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 500±50 mg, about 500±40 mg, about 500±30 mg, about 500±20 mg, about 500±10 mg, about 500±5 mg, about 500±4 mg, about 500±3 mg, about 500±2 mg, or about 500±l mg (e.g., about 500 mg).

[0164] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 600±50 mg, about 600±40 mg, about 600±30 mg, about 600±20 mg,about 600±10 mg, about 600±5 mg, about 600±4 mg, about 600±3 mg, about 600±2 mg, or about 600±l mg (e.g., about 600 mg).

[0165] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 800±50 mg, about 800±40 mg, about 800±30 mg, about 800±20 mg, about 800±10 mg, about 800±5 mg, about 800±4 mg, about 800±3 mg, about 800±2 mg, or about 800±l mg (e.g., about 800 mg).

[0166] In some embodiments, Compound No. 1 (e.g., Compound No. 1 A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, about 1000±10 mg, about 1000±5 mg, about 1000±4 mg, about 1000±3 mg, about 1000±2 mg, or about 1000±l mg (e.g., about 1000 mg).

[0167] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of: about 60±10 mg / kg, about 60±5 mg / kg, about 60±4 mg / kg, about 60±3 mg / kg, about 60±2 mg / kg, or about 60±l mg / kg (e.g., about 60 mg / kg); about 180±20 mg / kg, about 180±10 mg / kg, about 180±5 mg / kg, about 180±4 mg / kg, about 180±3 mg / kg, about 180±2 mg / kg, or about 180±l mg / kg (e.g., about 180 mg / kg); about 600±50 mg / kg, about 600±40 mg / kg, about 600±30 mg / kg, about 600±20 mg / kg, about 600± 10 mg / kg, about 600±5 mg / kg, about 600±4 mg / kg, about 600±3 mg / kg, about 600±2 mg / kg, or about 600±l mg / kg (e.g., about 600 mg / kg); or about 1800±50 mg / kg, about 1800±40 mg / kg, about 1800±30 mg / kg, about 1800±20 mg / kg, about 1800±10 mg / kg, about 1800±5 mg / kg, about 1800±4 mg / kg, about 1800±3 mg / kg, about 1800±2 mg / kg, or about 1800±l mg / kg (e.g., about 1800 mg / kg).

[0168] In some embodiments, Compound No. 1 (e.g., Compound No. 1 A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 60±10 mg / kg, about 60±5 mg / kg, about 60±4 mg / kg, about 60±3 mg / kg, about 60±2 mg / kg, or about 60±l mg / kg (e.g., about 60 mg / kg).

[0169] In some embodiments, Compound No. 1 (e.g., Compound No. 1 A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 180±20 mg / kg, about 180± 10 mg / kg, about 180±5 mg / kg, about 180±4 mg / kg, about 180±3 mg / kg, about 180±2 mg / kg, or about 180±l mg / kg (e.g., about 180 mg / kg).

[0170] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 600±50 mg / kg, about 600±40 mg / kg, about 600±30 mg / kg, about 600±20 mg / kg, about 600±10 mg / kg, about 600±5 mg / kg, about 600±4 mg / kg, about 600±3 mg / kg, about 600±2 mg / kg, or about 600±l mg / kg (e.g., about 600 mg / kg).

[0171] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered one or more times daily at a daily dosage of about 1800±50 mg / kg, about 1800±40 mg / kg, about 1800±30 mg / kg, about 1800±20 mg / kg, about 1800±10 mg / kg, about 1800±5 mg / kg, about 1800±4 mg / kg, about 1800±3 mg / kg, about 1800±2 mg / kg, or about 1800±l mg / kg (e.g., about 1800 mg / kg).

[0172] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

[0173] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered without any drug holiday.

[0174] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered by an enteral administration.

[0175] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered by an oral administration.

[0176] In some embodiments, the additional therapeutic agent is administered once daily, twice daily, or three or more times daily.

[0177] In some embodiments, the additional therapeutic agent is administered once daily.

[0178] In some embodiments, the additional therapeutic agent is administered twice daily.

[0179] In some embodiments, the additional therapeutic agent is administered three or more times daily.

[0180] In some embodiments, the additional therapeutic agent is administered with one or more drug holidays.

[0181] In some embodiments, the additional therapeutic agent is administered without any drug holiday.

[0182] In some embodiments, the additional therapeutic agent is administered by an enteral administration.

[0183] In some embodiments, the additional therapeutic agent is administered by an oral administration.

[0184] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously, sequentially, or in alternation.

[0185] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously.

[0186] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially.

[0187] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered in temporal proximity.

[0188] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof is administered prior to administering the additional therapeutic agent .

[0189] In some embodiments, the additional therapeutic agent is administered prior to administering Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof.

[0190] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered in alternation.

[0191] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered in separate formulations.

[0192] In some embodiments, Compound No. 1 (e.g., Compound No. 1A or Compound No. IB) or the pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered in a co-formulation.Pharmaceutical Compositions and Kits

[0193] In some aspects, the present disclosure provides a pharmaceutical composition comprising a combination described herein.

[0194] In some aspects, the present disclosure provides a pharmaceutical composition comprising a combination described herein, and one or more pharmaceutically acceptable carriers or excipients.

[0195] In some aspects, the present disclosure provides a pharmaceutical composition comprising a combination described herein, and one or more of a pharmaceutically acceptable carrier, an excipient, a diluent, a binder, or a filler.

[0196] In some aspects, the present disclosure provides a pharmaceutical kit comprising a combination described herein.

[0197] In some aspects, the present disclosure provides a pharmaceutical kit comprising a combination described herein, and an instruction for using the kit.

[0198] The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0199] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), powder-in-capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0200] 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 com 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.

[0201] 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.

[0202] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0203] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), 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, sorbitol, 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.

[0204] 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 arevacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0205] In some embodiments, the active compounds are prepared with pharmaceutically acceptable excipients 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. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable excipients.

[0206] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository' for rectal dosing).Exemplary Embodiments

[0207] Exemplary Embodiment No. 1. A combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0208] Exemplary Embodiment No. 2. A pharmaceutical composition comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0209] Exemplary Embodiment No. 3. A method of inhibiting an oncogenic variant of an ErbB receptor in a subject, comprising administering to the subject a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0210] Exemplary Embodiment No. 4. A combination for use in inhibiting an oncogenic variant of an ErbB receptor in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0211] Exemplary Embodiment No. 5. Use of a combination in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0212] Exemplary Embodiment No. 6. A method of treating or preventing cancer in a subject, comprising administering to the subject a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0213] Exemplary Embodiment No. 7. A combination disclosed herein for use in treating or preventing cancer in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0214] Exemplary Embodiment No. 8. Use of a combination in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

[0215] Exemplary Embodiment No. 9. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject Compound No. 1 or the pharmaceutically acceptable salt thereof at a daily dosage of: about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0216] Exemplary Embodiment No. 10. Use of Compound No. 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered at a daily dosage of: about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

[0217] Exemplary Embodiment No. 11. The combination, method, or use of any one of the preceding embodiments, wherein the subject is a human.

[0218] Exemplary Embodiment No. 12. The combination, method, or use of any one of the preceding embodiments, wherein the cancer is a solid tumor.

[0219] Exemplary Embodiment No. 13. The combination, method, or use of any one of the preceding embodiments, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.

[0220] Exemplary Embodiment No. 14. The combination, method, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma (GBM) or any subtype thereof.

[0221] Exemplary Embodiment No. 15. The combination, method, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma (GBM).Definitions

[0222] Unless explicitly indicated otherwise, the terms “approximately” and “about” are synonymous. In some embodiments, “approximately” and “about” refer to the recited amount, value, dose, or duration ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1%, or ± 0.5%. In some embodiments, “approximately” and “about” refer to the listed amount or duration ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, or ± 2%. In some embodiments, “approximately” and “about” refer to the listed amount, value, dose, or duration ± 5%. In some embodiments, “approximately” and “about” refer to the listed amount, value, dose, or duration ± 2%. In some embodiments, “approximately” and “about” refer to the listed amount, value, dose, or duration ± 1%.

[0223] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a 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).

[0224] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0225] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in a solid state (e.g., a 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.

[0226] It is to be understood that the present disclosure provides methods for the preparation of the formulations described herein. The present disclosure also provides detailed methods for preparation of various formulations of the present disclosure according to the following Examples.

[0227] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein, as well as use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0228] It is to be understood that, unless otherwise stated, any description of a method of prevention includes use of the compounds to provide such prevention as is described herein, as well as use of the compounds to prepare a medicament to prevent such condition. The prevention includes prevention in human or non-human animals including rodents and other disease models.

[0229] As used herein, the term “subject” is interchangeable with the term “subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g. , a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human.

[0230] As used herein, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after theadministration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the another therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disorder, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease, disorder, or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered. In some embodiments, “temporal proximity” means within 15 minutes, within 30 minutes, or within an hour. In some embodiments, multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may change during a treatment cycle or within a dosing regimen. In some embodiments, two therapeutic agents are administered in temporal proximity such that maximal gastrointestinal and systemic exposure to both therapeutic agents occurs at about the same time.

[0231] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0232] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0233] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0234] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0235] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0236] As used herein, the term “pharmaceutically acceptable salts'’ refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. In some embodiments, the pharmaceutically acceptable salt of a compound (e.g., a (3-lactam compound or probenecid described herein) is also a prodrug of the compound. 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, gly colly arsanilic, 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, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0237] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1 : 1, or any ratio other than 1: 1, e.g., 3: 1, 2:1, 1:2, or 1 :3.

[0238] It is to be understood that all references to compounds include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same compound.

[0239] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0240] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including ty pe, 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.

[0241] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0242] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.EQUIVALENTS

[0243] It is to be understood that 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.

Claims

CLAIMSWhat is claimed is:

1. A combination comprising:(i) Compound No. 1:or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

2. A pharmaceutical composition comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

3. A method of inhibiting an oncogenic variant of an ErbB receptor in a subject, comprising administering to the subject a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

4. A combination for use in inhibiting an oncogenic variant of an ErbB receptor in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

5. Use of a combination in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

6. A method of treating or preventing cancer in a subject, comprising administering to the subject a combination comprising:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

7. A combination disclosed herein for use in treating or preventing cancer in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

8. Use of a combination in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the combination comprises:(i) Compound No. 1 or a pharmaceutically acceptable salt thereof; and(ii) an additional therapeutic agent.

9. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject Compound No. 1 or the pharmaceutically acceptable salt thereof at a daily dosage of: about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

10. Use of Compound No. 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof, wherein Compound No. 1 or the pharmaceutically acceptable salt thereof is administered at a daily dosage of: about 75±20 mg, about 75±10 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg).

11. The combination, method, or use of any one of the preceding claims, wherein the subject is a human.

12. The combination, method, or use of any one of the preceding claims, wherein the cancer is a solid tumor.

13. The combination, method, or use of any one of the preceding claims, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a nonsmall cell lung cancer (NSCLC), or any subtype thereof.

14. The combination, method, or use of any one of the preceding claims, wherein the cancer is glioblastoma (GBM) or any subtype thereof.

15. The combination, method, or use of any one of the preceding claims, wherein the cancer is glioblastoma (GBM).

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