Methods of treating cancer using isoquinoline or 6-aza-quinoline derivatives

Abstract

The present disclosure relates to methods of treating or preventing cancer using compounds of Formula (0): or a pharmaceutically acceptable salt thereof. The present disclosure also relates to pharmaceutical compositions and pharmaceutical kits suitable for said treatment or prevention. # imgabs0 #

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority and the benefit of U.S. Provisional Application No. 63 / 416,305, filed on October 14, 2022; U.S. Provisional Application No. 63 / 431,997, filed on December 12, 2022; U.S. Provisional Application No. 63 / 449,757, filed on March 3, 2023; and U.S. Provisional Application No. 63 / 472,037, filed on June 9, 2023, which are hereby incorporated by reference in their entirety.

[0003] Reference to Electronic Sequence Listing

[0004] The content of the electronic sequence listing (ASET - 041_001WO_SeqList_ST26.xml; size 23,649 bytes; and creation date: October 12, 2023) is hereby incorporated by reference in its entirety. Background Art

[0005] Specific mutations in the human gene BRAF, which encodes the protein B - Raf, drive oncogenic activity in a variety of different cancers. Targeted inactivation of mutant B - Raf proteins by the administration of protein kinase inhibitors has been used to treat many different cancers in patients. However, there is a subset of patients who either show no response to the administration of these treatments, eventually relapse, or experience secondary lesions / pathway rebounds. More specifically, many existing B - Raf - targeted kinase inhibitors either show low specificity for B - Raf, resulting in undesirable off - target effects, or only target specific subsets of BRAF / B - Raf mutations. Thus, there has been a long - standing need in the art for new therapies that target specific oncogenic forms of B - Raf produced by mutations or alterations in the BRAF gene. The present disclosure provides compositions and methods for preventing or treating cancer in patients having oncogenic mutations in the BRAF gene and B - Raf protein. Summary of the Invention

[0006] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of the present disclosure (e.g., in a therapeutically effective amount).

[0007] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a compound of the present disclosure (e.g., in a therapeutically effective amount).

[0008] In some aspects, the present disclosure provides a compound of the present disclosure for treating or preventing cancer in a subject.

[0009] In some aspects, the present disclosure provides a compound of the present disclosure for treating cancer in a subject.

[0010] In some aspects, the present disclosure provides the use of a compound of the present disclosure for preparing a medicament for treating or preventing cancer in a subject.

[0011] In some aspects, the present disclosure provides the use of a compound of the present disclosure for preparing a medicament for treating cancer in a subject.

[0012] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0013] In some aspects, the present disclosure provides a method for treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and one or more additional therapeutic agents (e.g., in a therapeutically effective amount).

[0014] In some aspects, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and one or more additional therapeutic agents (e.g., in a therapeutically effective amount).

[0015] In some aspects, the present disclosure provides a combination for treating or preventing cancer in a subject, the combination comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0016] In some aspects, the present disclosure provides a combination for treating cancer in a subject, the combination comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0017] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and one or more additional therapeutic agents for preparing a medicament for treating or preventing cancer in a subject.

[0018] In some aspects, the present disclosure provides a compound of the present disclosure for use in combination with one or more additional therapeutic agents for treating or preventing cancer in a subject.

[0019] In some aspects, the present disclosure provides a compound of the present disclosure for use in combination with one or more additional therapeutic agents for treating cancer in a subject.

[0020] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and one or more additional therapeutic agents for preparing a medicament for treating or preventing cancer in a subject.

[0021] In some aspects, the present disclosure provides a combined use, the combination comprising a compound of the present disclosure and one or more additional therapeutic agents, for use in the preparation of a medicament for treating cancer in a subject.

[0022] 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 this specification, unless the context clearly dictates otherwise, the singular forms also include the plural forms. 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. It is not admitted that the references cited herein are prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between the chemical structure and the name of the compounds disclosed herein, the chemical structure shall prevail.

[0023] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a diagram depicting a protocol of an exemplary study of a compound of the present disclosure.

[0025] Figure 2 is a diagram depicting the anti-tumor activity of a compound of the present disclosure ("Compound") in combination with binimetinib in mice with KRAS G12D NSCLC patient-derived xenograft (PDX) models.

[0026] Figure 3 is a diagram depicting the anti-tumor activity of a compound of the present disclosure ("Compound") in combination with binimetinib in mice with a melanoma cell line carrying the BRAF V600E mutation. DETAILED DESCRIPTION

[0027] The present disclosure relates to methods of using a compound and its pharmaceutically acceptable salts and stereoisomers for treating or preventing cancers associated with B-Raf oncogenic activity, as well as compositions and kits suitable for such methods.

[0028] BRAF is a human gene located on the long arm of chromosome 7 (7q34) that encodes a protein called B-Raf. B-Raf is a serine / threonine kinase located in the cytoplasm of the cell. B-Raf is an effector molecule within the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) signaling pathway, which is known to regulate various cellular processes including but not limited to growth, proliferation, differentiation, and apoptosis.

[0029] Briefly, and as will be understood by those skilled in the art, in the MAPK / ERK signaling pathway, certain external stimuli such as growth factors activate receptors located on the cell membrane, including receptor tyrosine kinases (RTKs). These receptors in turn activate RAS, causing GDP to be exchanged for GTP, thereby generating RAS-GTP. RAS-GTP then activates mitogen-activated protein kinase kinase kinase (MAPKKK or MAP3K). The activated MAPKKK then activates MAP kinase kinase (MAPKK). The activated MAPKK then activates MAP kinase (MAPK). The activated MAPK then activates downstream effectors including transcription factors, leading to changes in gene expression, thereby regulating the various cellular processes described above, including but not limited to cell growth, proliferation, differentiation, and apoptosis.

[0030] Examples of MAPKKK include members of the rapidly accelerated fibrosarcoma (Raf) family, including Raf-1 (also known as C-Raf), B-Raf, and A-Raf.

[0031] Raf proteins, including B-raf, have three conserved domains, designated conserved region 1 (CR1), conserved region 2 (CR2), and conserved region 3 (CR3). CR1 is an autoinhibitory domain that inhibits the kinase domain (CR3) of the Raf protein. CR1 includes a binding site for the effector domain of RAS-GTP. When CR1 binds to the effector domain of RAS-GTP, CR1 releases CR3, thereby relieving the autoinhibition of the kinase domain. CR2 is a flexible linker that serves as a hinge connecting CR1 and CR3. CR3 is the enzyme kinase domain.

[0032] B-Raf forms a dimer in its active form and functions as a serine / threonine-specific protein kinase. Under activating conditions, the regulatory protein 14-3-3 translocates from CR2 of B-Raf, allowing de-clamping of CR1 and CR2. Additionally, RAS-GTP binds to CR1 of B-Raf, causing CR1 to release CR3. The overall effect is relief of the autoinhibition of the kinase domain of B-Raf. Subsequently, B-Raf is phosphorylated at T599 and S602, which causes the kinase domain to switch to the active conformation. Dimerization can then occur, which further stabilizes the active form of B-Raf.

[0033] Mutations in the BRAF gene have been implicated in a variety of different cancers, including but not limited to melanoma, non-Hodgkin's lymphoma, colorectal cancer, papillary thyroid cancer, non-small cell lung cancer (NSCLC), and glioblastoma. As of 2019, approximately 200 BRAF mutant alleles have been identified in human tumors, and at least 30 different mutations have been functionally characterized. Based on the effect of the mutation on B-Raf activity, BRAF mutations are generally classified into one of three classes.

[0034] Class I (or type 1) mutations are mutations that result in the expression of mutant B-Raf that can become active in monomeric form independent of RAS activity. That is, class I mutations in BRAF result in the expression of B-Raf protein as a RAS-independent active monomer. These RAS-independent active monomers typically exhibit elevated levels of kinase activity.

[0035] Class II (or type 2) mutations are mutations that result in the expression of mutant B-Raf that can form active dimers independent of RAS. That is, class II mutations in BRAF result in the expression of B-Raf protein as a RAS-independent active dimer. These RAS-independent active dimers also show moderate to high levels of kinase activity, but their activity levels are generally lower than those of the RAS-independent active monomers produced by class I BRAF mutations.

[0036] Class III (or type 3) mutations are mutations that result in the expression of mutant B-Raf that is RAS-dependent (i.e., must be activated by RAS-GTP) and can form heterodimers with other MAPK proteins such as C-Raf. Class III mutations in BRAF generally result in B-Raf with low or impaired kinase activity.

[0037] As those skilled in the art will appreciate, since class I BRAF mutations and class II BRAF mutations are RAS-independent, mutant B-Raf proteins carrying class I or class II mutations are not coupled to any upstream signals, resulting in constitutive activation, which can lead to uncontrolled cell growth and ultimately to carcinogenic proliferation.

[0038] Methods and uses of the present disclosure

[0039] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of the present disclosure (e.g., in a therapeutically effective amount).

[0040] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a compound of the present disclosure (e.g., in a therapeutically effective amount).

[0041] In some aspects, the present disclosure provides a compound of the present disclosure for treating or preventing cancer in a subject.

[0042] In some aspects, the present disclosure provides a compound of the present disclosure for treating cancer in a subject.

[0043] In some aspects, the present disclosure provides the use of a compound of the present disclosure for preparing a medicament for treating or preventing cancer in a subject.

[0044] In some aspects, the present disclosure provides the use of a compound of the present disclosure for preparing a medicament for treating cancer in a subject.

[0045] In some embodiments, one or more inhibitors of one or more components of the MAPK pathway are further administered to the subject.

[0046] Suitable Subjects and Diseases

[0047] In some embodiments, the subject is a mammal.

[0048] In some embodiments, the subject is a human.

[0049] In some embodiments, the subject is a mouse.

[0050] In some embodiments, the subject is a rat.

[0051] In some embodiments, the subject is a dog.

[0052] In some embodiments, the subject is a monkey.

[0053] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the BRAF gene.

[0054] It should be understood that cancers characterized by at least one oncogenic mutation in the BRAF gene are cancers that are generally associated with at least one oncogenic mutation in the BRAF gene, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic mutation in the BRAF gene.

[0055] In some embodiments, the cancer is characterized by at least one oncogenic variant of B-Raf.

[0056] It should be understood that cancers characterized by at least one oncogenic variant of B-Raf are cancers that are generally associated with at least one oncogenic variant of B-Raf, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic variant of B-Raf.

[0057] It should be understood that the oncogenic variant of B-Raf is a B-Raf protein that contains at least one oncogenic mutation and is produced as a result of expressing a BRAF gene containing at least one oncogenic mutation.

[0058] In some embodiments, the subject has at least one oncogenic mutation in the BRAF gene.

[0059] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf.

[0060] As those skilled in the art will understand, in the context of a gene (e.g., BRAF), oncogenic mutations can include, but are not limited to, mutations that cause one amino acid to replace another at a specific position within B-Raf, mutations that cause one or more amino acids to replace one or more amino acids between two specific positions within B-Raf, mutations that cause the insertion of one or more amino acids between two positions within B-Raf, mutations that cause the deletion of one or more amino acids between two positions within B-Raf, and mutations that cause the fusion of B-Raf or a portion thereof with another protein or a portion thereof, or any combination thereof. As those skilled in the art will understand, in the context of a gene, oncogenic mutations can include, but are not limited to, missense mutations, non-synonymous mutations, insertions of one or more nucleotides, deletions of one or more nucleotides, inversions, and deletion-insertions. As those skilled in the art will understand, in the context of a gene (e.g., BRAF), the gene can have one or more of the above types of oncogenic mutations, including combinations of different types of oncogenic mutations.

[0061] As those skilled in the art will understand, in the context of a gene (e.g., B-Raf), oncogenic mutations can include, but are not limited to, one amino acid replacing another at a specific position within B-Raf, one or more amino acids replacing one or more amino acids between two specific positions within B-Raf, the insertion of one or more amino acids between two positions within B-Raf, the deletion of one or more amino acids between two positions within B-Raf, and the fusion of B-Raf or a portion thereof with another protein or a portion thereof, or any combination thereof. As those skilled in the art will understand, in the context of a protein (e.g., B-Raf), the protein can have one or more of the above types of oncogenic mutations, including combinations of different types of oncogenic mutations.

[0062] In some embodiments, the oncogenic mutation of B-Raf can be any one of the B-Raf mutations presented in Table 1a. The oncogenic variant of B-Raf can contain one or more than one of the oncogenic mutations presented in Table 1a in any combination. In a non-limiting example, the oncogenic variant of B-Raf can contain the oncogenic mutations K601E and S363F.

[0063] Table 1a: B-Raf Mutations (numbers correspond to SEQ ID NO:1)

[0064]

[0065] As will be understood by those skilled in the art, L485-P490>Y and L485-P490Y refer to the substitution of residues L485 to P490 of B-Raf (SEQ ID NO:1) with a tyrosine (Y) residue.

[0066] In some embodiments, the oncogenic mutations of B-Raf can include deletions of any combination of one or more amino acids between L485 and P490 of B-Raf (SEQ ID NO:1). In some embodiments, the oncogenic mutations of B-Raf can include deletions of any combination of one or more amino acids between L485 and Q494 of B-Raf (SEQ ID NO:1). In some embodiments, the oncogenic mutations of B-Raf can include deletions of any combination of one or more amino acids between A481 and Q494 of B-Raf (SEQ ID NO:1). In some embodiments, the oncogenic mutations of B-Raf can include deletions of any combination of one or more amino acids between K475 and N500 of B-Raf (SEQ ID NO:1). In some embodiments, any of the foregoing deletions can further include any combination of one or more substitutions and / or insertions within the indicated residue ranges.

[0067] In some embodiments, the oncogenic mutation "deletion around 487-493" refers to the deletion of one or more amino acids between residues 487±3 and 498±3 (e.g., the deletion between residues 489 and 497).

[0068] The wild-type B-Raf sequence of the present disclosure can comprise the following amino acid sequence, consist essentially of the following amino acid sequence, or consist of the following amino acid sequence:

[0069]

[0070] In some embodiments, the oncogenic mutation is a class I mutation. Thus, in some embodiments, the oncogenic variant of B-Raf comprises a class I mutation.

[0071] In some embodiments, the oncogenic mutation is a class II mutation. Thus, in some embodiments, the oncogenic variant of B-Raf comprises a class II mutation.

[0072] In some embodiments, the oncogenic mutation is a class III mutation. Thus, in some embodiments, the oncogenic variant of B-Raf comprises a class III mutation.

[0073] In some embodiments, the oncogenic variant of B-Raf can be any one of the B-Raf variants presented in Table 1b. Any one of the variants presented in Table 1b can be combined with any one of the other variants presented in Table 1b. Thus, in a non-limiting example, the oncogenic variant of B-Raf can be B-Raf-K601E+S363F.

[0074] Table 1b: B-Raf Oncogenic Variants (Numbers Correspond to SEQ ID NO:1)

[0075]

[0076] In some embodiments, the oncogenic variant of B-Raf can comprise a deletion of any combination of one or more amino acids between L485 and P490 of B-Raf (SEQ ID NO:1). In some embodiments, the oncogenic variant of B-Raf can comprise a deletion of any combination of one or more amino acids between L485 and Q494 of B-Raf (SEQ ID NO:1). In some embodiments, the oncogenic variant of B-Raf can comprise a deletion of any combination of one or more amino acids between A481 and Q494 of B-Raf (SEQ ID NO:1). In some embodiments, the oncogenic variant of B-Raf can comprise a deletion of any combination of one or more amino acids between K475 and N500 of B-Raf (SEQ ID NO:1). In some embodiments, any one of the foregoing deletions can further comprise any combination of one or more substitutions and / or insertions within the indicated residue ranges.

[0077] As will be understood by those skilled in the art, B-Raf-ex10-18dup refers to an oncogenic variant of B-Raf that comprises a duplication segment of exons 10 to 18 (see, for example, Kemper et al., Cell Rep. June 28, 2016; 16(1):263–277, which is incorporated herein by reference for all purposes). As will be understood by those skilled in the art, oncogenic B-Raf-ex10-18dup may arise after treatment with BRAF inhibitors and / or MEK inhibitors. Without wishing to be bound by theory, B-Raf-ex10-18dup may mediate resistance to BRAF inhibitors and / or MEK inhibitors.

[0078] In some aspects, the oncogenic variant of B-Raf can include a duplication segment of exons 10 to 18 and a V600E mutation (B-Raf-V600E+ex10-18dup).

[0079] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf and at least one additional protein in the RAF and / or MAPK / ERK signaling pathway that contains at least one mutation. In some embodiments, the at least one additional protein can be selected from N-Ras, K-Ras, neurofibromin 1 (NF1). In some embodiments, at least one mutation in the at least one additional protein can be an oncogenic mutation.

[0080] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf and contains at least one mutated N-Ras protein. In some embodiments, the N-Ras protein containing at least one mutation can be N-Ras-G12D, N-Ras-Q61K, and / or N-Ras-Q61R. In some embodiments, the N-Ras protein containing at least one mutation can be N-Ras-Q61L and / or N-Ras-G13D. In a non-limiting example, the subject can have at least one tumor and / or cancer cell that expresses B-Raf-D594G and N-Ras-G12D.

[0081] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf and contains at least one mutated K-Ras protein. In some embodiments, the K-Ras protein containing at least one mutation can be K-Ras-G12V, K-Ras-G12D, K-Ras-G12A, K-Ras-G12S, K-Ras-G12C, K-Ras-Q61H, K-Ras-Q61L, K-Ras-G13C, and / or K-Ras-G13D.

[0082] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf and contains at least one mutated NF1 protein. Exemplary mutations within the NF1 protein include, but are not limited to, missense mutations, nonsense mutations, frameshift mutations, and splice site mutations, insertions, deletions, and translocations.

[0083] In some embodiments, the cancer is characterized by at least one oncogenic mutation in at least one protein in the RAF and / or MAPK / ERK signaling pathway. In some embodiments, the at least one protein in the RAF and / or MAPK / ERK signaling pathway can be selected from N-Ras, K-Ras, and NF1.

[0084] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the KRAS gene.

[0085] It should be understood that a cancer characterized by at least one oncogenic mutation in the KRAS gene is a cancer that is generally associated with at least one oncogenic mutation in the KRAS gene, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic mutation in the KRAS gene.

[0086] In some embodiments, the oncogenic mutation in the KRAS gene induces the formation of one or more homodimers and / or heterodimers of Raf proteins. In non-limiting examples, the oncogenic mutation in the KRAS gene can induce the formation of A-Raf homodimers. In non-limiting examples, the oncogenic mutation in the KRAS gene can induce the formation of B-Raf homodimers. In non-limiting examples, the oncogenic mutation in the KRAS gene can induce the formation of C-Raf homodimers. In non-limiting examples, the oncogenic mutation in the KRAS gene can induce the formation of B-Raf / C-Raf heterodimers, A-Raf / B-Raf heterodimers, and / or A-Raf / C-Raf heterodimers.

[0087] In some embodiments, the cancer is characterized by at least one oncogenic variant of K-Ras.

[0088] In some embodiments, the oncogenic variant of K-Ras induces the formation of one or more homodimers and / or heterodimers of Raf proteins. In non-limiting examples, at least one oncogenic variant of K-Ras can induce the formation of A-Raf homodimers. In non-limiting examples, at least one oncogenic variant of K-Ras can induce the formation of B-Raf homodimers. In non-limiting examples, at least one oncogenic variant of K-Ras can induce the formation of C-Raf homodimers. In non-limiting examples, at least one oncogenic variant of K-Ras can induce the formation of B-Raf / C-Raf heterodimers, A-Raf / B-Raf heterodimers, and / or A-Raf / C-Raf heterodimers.

[0089] It should be understood that a cancer characterized by at least one oncogenic variant of K-Ras is a cancer that is generally associated with at least one oncogenic variant of K-Ras, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic variant of K-Ras.

[0090] It should be understood that an oncogenic variant of K-Ras is a K-Ras protein that contains at least one oncogenic mutation and is produced as a result of expressing a KRAS gene containing at least one oncogenic mutation.

[0091] In some embodiments, the subject has at least one oncogenic mutation in the KRAS gene.

[0092] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of K-Ras.

[0093] In some embodiments, the oncogenic mutation of K-Ras can be selected from K-Ras-G12V, K-Ras-G12D, K-Ras-G12A, K-Ras-G12S, K-Ras-G12C, K-Ras-Q61H, K-Ras-Q61L, K-Ras-G13C, and K-Ras-G13D. In some embodiments, the oncogenic mutation of K-Ras can be a mutation that induces constitutive activation of RAF dimers. In some embodiments, the oncogenic mutation of K-Ras is not a K-Ras-G12C mutation. In some embodiments, the oncogenic mutation of K-Ras can be K-Ras-G12D. In some embodiments, the oncogenic mutation of K-Ras can be K-Ras-G12V.

[0094] In some embodiments, the subject has at least one oncogenic mutation in the KRAS gene, wherein at least one oncogenic mutation in the KRAS gene induces the formation of one or more homodimers and / or heterodimers of Raf proteins. In non-limiting examples, at least one oncogenic mutation in the KRAS gene can induce the formation of A-Raf homodimers. In non-limiting examples, at least one oncogenic mutation in the KRAS gene can induce the formation of B-Raf homodimers. In non-limiting examples, at least one oncogenic mutation in the KRAS gene can induce the formation of C-Raf homodimers. In non-limiting examples, at least one oncogenic mutation in the KRAS gene can induce the formation of B-Raf / C-Raf heterodimers, A-Raf / B-Raf heterodimers, and / or A-Raf / C-Raf heterodimers.

[0095] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of K-Ras, wherein the oncogenic variant of K-Ras induces the formation of one or more homodimers and / or heterodimers of Raf proteins. In non-limiting examples, the oncogenic variant of K-Ras can induce the formation of A-Raf homodimers. In non-limiting examples, the oncogenic variant of K-Ras can induce the formation of B-Raf homodimers. In non-limiting examples, the oncogenic variant of K-Ras can induce the formation of C-Raf homodimers. In non-limiting examples, the oncogenic variant of K-Ras can induce the formation of B-Raf / C-Raf heterodimers, A-Raf / B-Raf heterodimers, and / or A-Raf / C-Raf heterodimers.

[0096] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the NRAS gene.

[0097] It should be understood that a cancer characterized by at least one oncogenic mutation in the NRAS gene is a cancer that is generally associated with at least one oncogenic mutation in the NRAS gene, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic mutation in the NRAS gene.

[0098] In some embodiments, the cancer is characterized by at least one oncogenic variant of N-Ras.

[0099] It should be understood that a cancer characterized by at least one oncogenic variant of N-Ras is a cancer that is generally associated with at least one oncogenic variant of N-Ras, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic variant of N-Ras.

[0100] It should be understood that an oncogenic variant of N-Ras is an N-Ras protein that contains at least one oncogenic mutation and is produced as a result of expressing an NRAS gene containing at least one oncogenic mutation.

[0101] In some embodiments, the subject has at least one oncogenic mutation in the NRAS gene.

[0102] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of N-Ras.

[0103] In some embodiments, the oncogenic mutations of N-Ras can be selected from N-Ras-G12D, N-Ras-Q61K, N-Ras-Q61R, N-Ras-Q61L, and N-Ras-G13D. In some embodiments, the oncogenic mutation of N-Ras can be a mutation that induces constitutive RAF dimer activation.

[0104] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the NF1 gene. In some embodiments, the oncogenic mutation in the NF1 gene can be a loss-of-function mutation.

[0105] It should be understood that a cancer characterized by at least one oncogenic mutation in the NF1 gene is a cancer that is generally associated with at least one oncogenic mutation in the NF1 gene, including but not limited to cancers whose primary oncogenic activity is considered to be driven by at least one oncogenic mutation in the NF1 gene.

[0106] In some embodiments, the cancer is characterized by at least one oncogenic variant of NF1.

[0107] It should be understood that a cancer characterized by at least one oncogenic variant of NF1 is a cancer commonly associated with at least one oncogenic variant of NF1, including but not limited to cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of N-Ras.

[0108] It should be understood that an oncogenic variant of NF1 is an NF1 protein that contains at least one oncogenic mutation and is produced as a result of expressing an NF1 gene containing at least one oncogenic mutation. In some aspects, the oncogenic mutation in the NF1 protein can be a loss-of-function mutation in the NF1 protein.

[0109] In some embodiments, the subject has at least one oncogenic mutation in the NF1 gene.

[0110] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of NF1.

[0111] In some embodiments, the cancer is characterized by any combination of: at least one oncogenic mutation in the NRAS gene, at least one oncogenic mutation in the KRAS gene, and at least one oncogenic mutation in the NF1 gene. The oncogenic mutation can be any of the oncogenic mutations described herein.

[0112] Thus, in some embodiments, the cancer is characterized by any combination of: at least one oncogenic variant of K-Ras, at least one oncogenic variant of N-Ras, and at least one oncogenic variant of NF1.

[0113] In some embodiments, the cancer is characterized by at least one oncogenic mutation in a gene encoding a RAS GTPase.

[0114] It should be understood that a cancer characterized by at least one oncogenic mutation in a gene encoding a RAS GTPase is a cancer commonly associated with at least one oncogenic mutation in a gene encoding a RAS GTPase, including but not limited to cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in a gene encoding a RAS GTPase.

[0115] In some embodiments, the cancer is characterized by at least one oncogenic variant of a RAS GTPase.

[0116] It should be understood that a cancer characterized by at least one oncogenic variant of a RAS GTPase is a cancer commonly associated with at least one oncogenic variant of a RAS GTPase, including but not limited to cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of a RAS GTPase.

[0117] It should be understood that an oncogenic variant of a RAS GTPase is a RAS GTPase protein that contains at least one oncogenic mutation and is produced as a result of expressing a gene encoding a RAS GTPase that contains at least one oncogenic mutation.

[0118] In some embodiments, the subject has at least one oncogenic mutation in the gene encoding a RAS GTPase.

[0119] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of a RAS GTPase.

[0120] In some embodiments, the RAS GTPase can be NRAS, KRAS, or HRAS.

[0121] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the HRAS gene.

[0122] It should be understood that a cancer characterized by at least one oncogenic mutation in the HRAS gene is a cancer that is generally associated with at least one oncogenic mutation in the HRAS gene, including but not limited to cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the HRAS gene.

[0123] In some embodiments, the cancer is characterized by at least one oncogenic variant of H-Ras.

[0124] It should be understood that a cancer characterized by at least one oncogenic variant of H-Ras is a cancer that is generally associated with at least one oncogenic variant of H-Ras, including but not limited to cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of H-Ras.

[0125] It should be understood that an oncogenic variant of H-Ras is an H-Ras protein that contains at least one oncogenic mutation and is produced as a result of expressing an HRAS gene that contains at least one oncogenic mutation.

[0126] In some embodiments, the subject has at least one oncogenic mutation in the HRAS gene.

[0127] In some embodiments, the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of H-Ras.

[0128] In some embodiments, the oncogenic mutation of H-Ras can be H-Ras-G13D.

[0129] In some embodiments, the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer, kidney cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer or colorectal cancer.

[0130] In some embodiments, the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, or gastric cancer. Additional examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, cholangiocarcinoma, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumor, anal cancer, cholangiocarcinoma, bladder cancer, bone cancer, bowel cancer, brain tumor, breast cancer, cancer of unknown primary (CUP), cancer that has spread to bone, cancer that has spread to the brain, cancer that has spread to the liver, cancer that has spread to the lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, gastric cancer, gastroesophageal junction cancer, germ cell tumor, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, linitis plastica, liver cancer, lung cancer, lymphoma, malignant peripheral nerve sheath tumor, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor, non-Hodgkin lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland adenocarcinoma, secondary cancer, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T-cell childhood non-Hodgkin lymphoma (NHL), testicular cancer, thymoma, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumor, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and gynecologic cancer.

[0131] Examples of cancers also include, but are not limited to: hematological malignancies, lymphomas, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia, myelodysplastic syndromes, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0132] In some embodiments, the cancer is a hematological cancer.

[0133] In some embodiments, the cancer is a solid cancer (also known as a solid malignancy or solid tumor).

[0134] In some embodiments, the cancer is melanoma, breast cancer, head and neck cancer, esophagogastric cancer, gastric and small intestine cancer, lung cancer, mesothelioma, hepatobiliary cancer, pancreatic cancer, renal cancer, colorectal cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, soft tissue sarcoma, CNS and brain cancer, or thyroid cancer.

[0135] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, thyroid cancer, histiocytosis, small intestine cancer, gastroenteropancreatic neuroendocrine cancer, cancer of unknown primary origin, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid cancer, or glioblastoma.

[0136] In some embodiments, the cancer is NSCLC. In some embodiments, the NSCLC has not undergone small cell lung cancer transformation. In some embodiments, the cancer is non-small cell lung cancer.

[0137] In some embodiments, the cancer is a histiocytic tumor. In some embodiments, the histiocytic tumor is Langerhans cell histiocytosis (LCH). In some embodiments, the histiocytic tumor is Erdheim-Chester disease (ECD). In some embodiments, the cancer is a histiocytic and dendritic cell tumor.

[0138] In some embodiments, the cancer is melanoma.

[0139] In some embodiments, the cancer is thyroid cancer.

[0140] In some embodiments, the cancer is thyroid cancer.

[0141] In some embodiments, the cancer is colorectal cancer.

[0142] In some embodiments, the cancer is colorectal cancer.

[0143] In some embodiments, the cancer is glioma.

[0144] In some embodiments, the cancer is astrocytoma, brainstem glioma, ependymoma, oligoastrocytoma, oligodendroglioma, or optic pathway glioma.

[0145] In some embodiments, the cancer is low-grade glioma (e.g., glioma caused by astrocytes and / or oligodendrocytes).

[0146] In some embodiments, the cancer is glioma (e.g., low-grade glioma) in a subject 18 years of age or older.

[0147] In some embodiments, the cancer is glioma (e.g., low-grade glioma) in a subject less than 18 years of age.

[0148] In some embodiments, the cancer is glioblastoma.

[0149] In some embodiments, the cancer is recurrent cancer.

[0150] In some embodiments, the cancer is advanced cancer.

[0151] In some embodiments, the cancer is metastatic cancer.

[0152] In some embodiments, the tumor is a recurrent tumor.

[0153] In some embodiments, the tumor is an advanced tumor.

[0154] In some embodiments, the tumor is a metastatic tumor.

[0155] In some embodiments, the cancer is brain cancer.

[0156] In some embodiments, the cancer is recurrent brain cancer.

[0157] In some embodiments, the cancer is advanced brain cancer.

[0158] In some embodiments, the cancer is metastatic brain cancer.

[0159] In some embodiments, the cancer is lung cancer.

[0160] In some embodiments, the cancer is recurrent lung cancer.

[0161] In some embodiments, the cancer is advanced lung cancer.

[0162] In some embodiments, the cancer is metastatic lung cancer.

[0163] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0164] In some embodiments, the cancer is recurrent non-small cell lung cancer (NSCLC).

[0165] In some embodiments, the cancer is advanced non-small cell lung cancer (NSCLC).

[0166] In some embodiments, the cancer is metastatic non-small cell lung cancer (NSCLC).

[0167] In some embodiments, the cancer is NSCLC, and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class I mutation. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class II mutation. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class III mutation. In some embodiments, the oncogenic variant is B-Raf-V600E. In some embodiments, the NSCLC can be recurrent, advanced, metastatic, or any combination thereof.

[0168] In some embodiments, the cancer is NSCLC, and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of K-Ras. In some embodiments, the oncogenic variant of K-Ras is a K-Ras protein that comprises an oncogenic mutation that is not K-Ras-G12C. In some embodiments, the NSCLC can be recurrent, advanced, metastatic, or any combination thereof.

[0169] In some embodiments, the cancer is a histiocytic tumor, and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class I mutation, at least one class II mutation, at least one class III mutation, or any combination thereof. In some embodiments, the cancer is a histiocytic tumor, and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of N-Ras. In some embodiments, the histiocytic tumor can be recurrent.

[0170] In some embodiments, the cancer is melanoma and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class I mutation, at least one class II mutation, at least one class III mutation, or any combination thereof. In some embodiments, the oncogenic variant is B-Raf-V600E. In some embodiments, the melanoma can be recurrent, advanced, metastatic, or any combination thereof.

[0171] In some embodiments, the cancer is melanoma and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of N-Ras. In some embodiments, the melanoma can be recurrent, advanced, metastatic, or any combination thereof.

[0172] In some embodiments, the cancer is thyroid cancer and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class I mutation, at least one class II mutation, at least one class III mutation, or any combination thereof.

[0173] In some embodiments, the cancer is colorectal cancer and the subject has at least one tumor and / or cancer cell that expresses an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that comprises at least one class II mutation, at least one class III mutation, or any combination thereof.

[0174] In some embodiments, administration of the compounds of the present disclosure does not induce paradoxical activation of wild-type B-Raf.

[0175] In some embodiments, administration of the compounds of the present disclosure does not substantially increase the amount of p-ERK in the subject.

[0176] In some embodiments, compared to comparable subjects administered vemurafenib or encorafenib, administration of the compounds of the present disclosure results in at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% lower amount of p-ERK in the subject.

[0177] In some embodiments, administration of a compound of the present disclosure results in at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% lower amount of p-ERK in a subject compared to a comparable subject not receiving the administration.

[0178] In some embodiments, administration of a compound of the present disclosure reduces the tumor volume in a subject by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.

[0179] In some embodiments, the cancer is insensitive or resistant to treatment with one or more inhibitors of the MAPK pathway.

[0180] In some embodiments, the cancer is insensitive or resistant to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0181] In some embodiments, the cancer is insensitive or resistant to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0182] In some embodiments, the cancer is insensitive to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0183] In some embodiments, the cancer is resistant to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0184] In some embodiments, the subject has an adverse reaction to treatment with one or more inhibitors of the MAPK pathway.

[0185] In some embodiments, the subject has an adverse reaction to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0186] In some embodiments, the subject has an adverse reaction to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0187] In some embodiments, the adverse reaction is a new cancer (e.g., skin cancer), bleeding, gastrointestinal effects, effects on the kidney and / or liver, eye problems, lung problems, fever, or any combination thereof.

[0188] In some embodiments, the subject has previously been administered one or more inhibitors of the MAPK pathway and, despite the previous administration, the subject has experienced disease progression.

[0189] In some embodiments, the subject has previously been administered a BRAF inhibitor, a MEK inhibitor, or a combination thereof, and, despite the previous administration, the subject has experienced disease progression.

[0190] In some embodiments, the subject has previously been administered a combination comprising a BRAF inhibitor and a MEK inhibitor, and, despite the previous administration, the subject has experienced disease progression.

[0191] In some embodiments, the subject has at least one central nervous system metastasis. In some embodiments, the at least one central nervous system metastasis is stable.

[0192] In some embodiments, the subject does not have a central nervous system metastasis.

[0193] In some embodiments, the subject has at least one brain metastasis. In some embodiments, the at least one brain metastasis is stable.

[0194] In some embodiments, the subject does not have a brain metastasis.

[0195] In some embodiments, the subject has histiocytosis.

[0196] Inhibitors of the MAPK pathway

[0197] In some embodiments, one or more inhibitors of the MAPK pathway comprise a BRAF inhibitor, a MEK inhibitor, or any combination thereof.

[0198] In some embodiments, one or more inhibitors of the MAPK pathway comprise a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0199] In some embodiments, the BRAF inhibitor is vemurafenib, dabrafenib, or encorafenib.

[0200] In some embodiments, the BRAF inhibitor is vemurafenib.

[0201] In some embodiments, the BRAF inhibitor is dabrafenib.

[0202] In some embodiments, the BRAF inhibitor is encorafenib.

[0203] In some embodiments, the MEK inhibitor is trametinib, cobimetinib, or binimetinib.

[0204] In some embodiments, the MEK inhibitor is trametinib.

[0205] In some embodiments, the MEK inhibitor is cobimetinib.

[0206] In some embodiments, the MEK inhibitor is binimetinib.

[0207] Administration of the compound

[0208] In some embodiments, the compound is administered to the subject by oral administration or parenteral administration.

[0209] In some embodiments, the compound is administered to the subject by oral administration.

[0210] In some embodiments, a pharmaceutical composition comprising the compound is administered to the subject.

[0211] In some embodiments, the pharmaceutical composition is an oral formulation.

[0212] In some embodiments, the pharmaceutical composition is a tablet or a capsule.

[0213] In some embodiments, the pharmaceutical composition comprises a unit dose of the compound.

[0214] In some embodiments, the pharmaceutical composition comprises about 3 ± 1 mg, about 3 ± 0.9 mg, about 3 ± 0.8 mg, about 3 ± 0.7 mg, about 3 ± 0.6 mg, about 3 ± 0.5 mg, about 3 ± 0.4 mg, about 3 ± 0.3 mg, about 3 ± 0.2 mg, or about 3 ± 0.1 mg (e.g., about 3 mg) of the compound.

[0215] In some embodiments, the pharmaceutical composition comprises about 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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) of the compound.

[0216] In some embodiments, the compound is administered at the following doses (e.g., daily dose):

[0217] About 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg or about 6 ± 0.1 mg (e.g., about 6 mg);

[0218] About 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg or about 12 ± 0.1 mg (e.g., about 12 mg);

[0219] About 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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);

[0220] About 50 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg or about 50 ± 1 mg (e.g., about 50 mg);

[0221] About 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg or about 100 ± 1 mg (e.g., about 100 mg);

[0222] About 150 ± 70 mg, about 150 ± 60 mg, about 150 ± 50 mg, about 150 ± 40 mg, about 150 ± 30 mg, about 150 ± 20 mg, about 150 ± 10 mg, about 150 ± 5 mg, about 150 ± 4 mg or about 150 ± 3 mg (e.g., about 150 mg); about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg or about 200 ± 10 mg (e.g., about 200 mg);

[0223] about 300 ± 150 mg, about 300 ± 120 mg, about 300 ± 100 mg, about 300 ± 80 mg, about 300 ± 60 mg, about 300 ± 50 mg, about 300 ± 40 mg, about 300 ± 30 mg, about 300 ± 20 mg or about 300 ± 10 mg (e.g., about 300 mg); about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg or about 400 ± 10 mg (e.g., about 400 mg);

[0224] about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg or about 600 ± 10 mg (e.g., about 600 mg);

[0225] about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg or about 800 ± 10 mg (e.g., about 800 mg);

[0226] about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg or about 1000 ± 10 mg (e.g., about 1000 mg); or

[0227] about 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 80 mg, about 1200 ± 70 mg, about 1200 ± 60 mg, about 1200 ± 50 mg, about 1200 ± 40 mg, about 1200 ± 30 mg, about 1200 ± 20 mg or about 1200 ± 10 mg (e.g., about 1200 mg).

[0228] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg, or about 6 ± 0.1 mg (e.g., about 6 mg).

[0229] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg, or about 12 ± 0.1 mg (e.g., about 12 mg).

[0230] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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).

[0231] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 50 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg, or about 50 ± 1 mg (e.g., about 50 mg).

[0232] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg, or about 100 ± 1 mg (e.g., about 100 mg).

[0233] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 150 ± 70 mg, about 150 ± 60 mg, about 150 ± 50 mg, about 150 ± 40 mg, about 150 ± 30 mg, about 150 ± 20 mg, about 150 ± 10 mg, about 150 ± 5 mg, about 150 ± 4 mg, or about 150 ± 3 mg (e.g., about 150 mg).

[0234] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg, or about 200 ± 10 mg (e.g., about 200 mg).

[0235] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 300 ± 150 mg, about 300 ± 120 mg, about 300 ± 100 mg, about 300 ± 80 mg, about 300 ± 60 mg, about 300 ± 50 mg, about 300 ± 40 mg, about 300 ± 30 mg, about 300 ± 20 mg, or about 300 ± 10 mg (e.g., about 300 mg).

[0236] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg, or about 400 ± 10 mg (e.g., about 400 mg).

[0237] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg, or about 600 ± 10 mg (e.g., about 600 mg).

[0238] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg, or about 800 ± 10 mg (e.g., about 800 mg).

[0239] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg, or about 1000 ± 10 mg (e.g., about 1000 mg).

[0240] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 80 mg, about 1200 ± 70 mg, about 1200 ± 60 mg, about 1200 ± 50 mg, about 1200 ± 40 mg, about 1200 ± 30 mg, about 1200 ± 20 mg, or about 1200 ± 10 mg (e.g., about 1200 mg).

[0241] In some embodiments, the compound is administered at the following doses (e.g., daily doses):

[0242] about 3 ± 1 mg / kg, about 3 ± 0.9 mg / kg, about 3 ± 0.8 mg / kg, about 3 ± 0.7 mg / kg, about 3 ± 0.6 mg / kg, about 3 ± 0.5 mg / kg, about 3 ± 0.4 mg / kg, about 3 ± 0.3 mg / kg, about 3 ± 0.2 mg / kg, or about 3 ± 0.1 mg / kg (e.g., about 3 mg / kg);

[0243] About 5 ± 2 mg / kg, about 5 ± 1 mg / kg, about 5 ± 0.9 mg / kg, about 5 ± 0.8 mg / kg, about 5 ± 0.7 mg / kg, about 5 ± 0.6 mg / kg, about 5 ± 0.5 mg / kg, about 5 ± 0.4 mg / kg, about 5 ± 0.3 mg / kg, about 5 ± 0.2 mg / kg, or about 5 ± 0.1 mg / kg (e.g., about 5 mg / kg); or

[0244] About 10 ± 5 mg / kg, about 10 ± 4 mg / kg, about 10 ± 3 mg / kg, about 10 ± 2 mg / kg, about 10 ± 1 mg / kg, about 10 ± 0.9 mg / kg, about 10 ± 0.8 mg / kg, about 10 ± 0.7 mg / kg, about 10 ± 0.6 mg / kg, about 10 ± 0.5 mg / kg, about 10 ± 0.4 mg / kg, about 10 ± 0.3 mg / kg, about 10 ± 0.2 mg / kg, or about 10 ± 0.1 mg / kg (e.g., about 10 mg / kg).

[0245] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 3 ± 1 mg / kg, about 3 ± 0.9 mg / kg, about 3 ± 0.8 mg / kg, about 3 ± 0.7 mg / kg, about 3 ± 0.6 mg / kg, about 3 ± 0.5 mg / kg, about 3 ± 0.4 mg / kg, about 3 ± 0.3 mg / kg, about 3 ± 0.2 mg / kg, or about 3 ± 0.1 mg / kg (e.g., about 3 mg / kg).

[0246] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 5 ± 2 mg / kg, about 5 ± 1 mg / kg, about 5 ± 0.9 mg / kg, about 5 ± 0.8 mg / kg, about 5 ± 0.7 mg / kg, about 5 ± 0.6 mg / kg, about 5 ± 0.5 mg / kg, about 5 ± 0.4 mg / kg, about 5 ± 0.3 mg / kg, about 5 ± 0.2 mg / kg, or about 5 ± 0.1 mg / kg (e.g., about 5 mg / kg).

[0247] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 10 ± 5 mg / kg, about 10 ± 4 mg / kg, about 10 ± 3 mg / kg, about 10 ± 2 mg / kg, about 10 ± 1 mg / kg, about 10 ± 0.9 mg / kg, about 10 ± 0.8 mg / kg, about 10 ± 0.7 mg / kg, about 10 ± 0.6 mg / kg, about 10 ± 0.5 mg / kg, about 10 ± 0.4 mg / kg, about 10 ± 0.3 mg / kg, about 10 ± 0.2 mg / kg, or about 10 ± 0.1 mg / kg (e.g., about 10 mg / kg).

[0248] In some embodiments, the compound is administered at the following doses (e.g., daily doses):

[0249] about 0.2 ± 0.2 mg / kg, about 0.2 ± 0.1 mg / kg, about 0.2 ± 0.09 mg / kg, about 0.2 ± 0.08 mg / kg, about 0.2 ± 0.07 mg / kg, about 0.2 ± 0.06 mg / kg, about 0.2 ± 0.05 mg / kg, about 0.2 ± 0.04 mg / kg, about 0.2 ± 0.03 mg / kg, about 0.2 ± 0.02 mg / kg or about 0.2 ± 0.01 mg / kg (e.g., about 0.2 mg / kg);

[0250] about 0.4 ± 0.2 mg / kg, about 0.4 ± 0.1 mg / kg, about 0.4 ± 0.09 mg / kg, about 0.4 ± 0.08 mg / kg, about 0.4 ± 0.07 mg / kg, about 0.4 ± 0.06 mg / kg, about 0.4 ± 0.05 mg / kg, about 0.4 ± 0.04 mg / kg, about 0.4 ± 0.03 mg / kg, about 0.4 ± 0.02 mg / kg or about 0.4 ± 0.01 mg / kg (e.g., about 0.4 mg / kg); or

[0251] about 0.8 ± 0.5 mg / kg, about 0.8 ± 0.4 mg / kg, about 0.8 ± 0.3 mg / kg, about 0.8 ± 0.2 mg / kg, about 0.8 ± 0.1 mg / kg, about 0.8 ± 0.09 mg / kg, about 0.8 ± 0.08 mg / kg, about 0.8 ± 0.07 mg / kg, about 0.8 ± 0.06 mg / kg, about 0.8 ± 0.05 mg / kg, about 0.8 ± 0.04 mg / kg, about 0.8 ± 0.03 mg / kg, about 0.8 ± 0.02 mg / kg or about 0.8 ± 0.01 mg / kg (e.g., about 0.8 mg / kg).

[0252] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 0.2 ± 0.2 mg / kg, about 0.2 ± 0.1 mg / kg, about 0.2 ± 0.09 mg / kg, about 0.2 ± 0.08 mg / kg, about 0.2 ± 0.07 mg / kg, about 0.2 ± 0.06 mg / kg, about 0.2 ± 0.05 mg / kg, about 0.2 ± 0.04 mg / kg, about 0.2 ± 0.03 mg / kg, about 0.2 ± 0.02 mg / kg or about 0.2 ± 0.01 mg / kg (e.g., about 0.2 mg / kg).

[0253] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 0.4 ± 0.2 mg / kg, about 0.4 ± 0.1 mg / kg, about 0.4 ± 0.09 mg / kg, about 0.4 ± 0.08 mg / kg, about 0.4 ± 0.07 mg / kg, about 0.4 ± 0.06 mg / kg, about 0.4 ± 0.05 mg / kg, about 0.4 ± 0.04 mg / kg, about 0.4 ± 0.03 mg / kg, about 0.4 ± 0.02 mg / kg, or about 0.4 ± 0.01 mg / kg (e.g., about 0.4 mg / kg).

[0254] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 0.8 ± 0.5 mg / kg, about 0.8 ± 0.4 mg / kg, about 0.8 ± 0.3 mg / kg, about 0.8 ± 0.2 mg / kg, about 0.8 ± 0.1 mg / kg, about 0.8 ± 0.09 mg / kg, about 0.8 ± 0.08 mg / kg, about 0.8 ± 0.07 mg / kg, about 0.8 ± 0.06 mg / kg, about 0.8 ± 0.05 mg / kg, about 0.8 ± 0.04 mg / kg, about 0.8 ± 0.03 mg / kg, about 0.8 ± 0.02 mg / kg, or about 0.8 ± 0.01 mg / kg (e.g., about 0.8 mg / kg).

[0255] In some embodiments, the unit dose strength of the pharmaceutical composition is about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg.

[0256] In some embodiments, the compound is administered with one or more drug holidays.

[0257] In some embodiments, the compound is administered without any drug holidays.

[0258] In some embodiments, before administration, the subject is fasted for at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

[0259] In some embodiments, before administration, the subject is fed for about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.

[0260] In some embodiments, the compound is administered once daily (QD).

[0261] In some embodiments, the compound is administered twice daily (BID).

[0262] In some embodiments, the compound is administered for about 21 days, about 42 days, about 63 days, about 84 days, about 105 days, about 126 days, about 147 days, about 168 days, about 189 days, or about 210 days.

[0263] In some embodiments, the compound is administered for greater than 210 days.

[0264] In some embodiments, the compound is administered until cancer progression or adverse effects (e.g., intolerable toxicity) are observed.

[0265] Combination therapy

[0266] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0267] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and one or more additional therapeutic agents (e.g., in a therapeutically effective amount).

[0268] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and an additional therapeutic agent (e.g., in a therapeutically effective amount).

[0269] In some aspects, the present disclosure provides a combination for treating or preventing cancer in a subject, the combination comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0270] In some aspects, the present disclosure provides a combination for treating cancer in a subject, the combination comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0271] In some aspects, the present disclosure provides a compound of the present disclosure for use in combination with one or more additional therapeutic agents for treating cancer in a subject.

[0272] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and one or more additional therapeutic agents for the preparation of a medicament for treating or preventing cancer in a subject.

[0273] In some aspects, the present disclosure provides a combined use, the combination comprising a compound of the present disclosure and one or more additional therapeutic agents, for preparing a medicament for treating or preventing cancer in a subject.

[0274] In some aspects, the present disclosure provides a combined use, the combination comprising a compound of the present disclosure and an additional therapeutic agent, for preparing a medicament for treating cancer in a subject.

[0275] In some embodiments, the one or more additional therapeutic agents comprise one or more SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) inhibitors, one or more SOS1 inhibitors, one or more KRAS (Kirsten rat sarcoma virus) inhibitors, one or more ERK (extracellular signal-regulated kinase) inhibitors, one or more immune checkpoint inhibitors, one or more chemotherapies, one or more EGFR (epidermal growth factor receptor) inhibitors, one or more MET (mesenchymal-epithelial transition) inhibitors, one or more TEAD (transcriptional enhanced associate domain) inhibitors, one or more YAP (yes-associated protein) inhibitors, one or more PI3K (phosphoinositide 3-kinase) inhibitors, one or more mTOR (mammalian target of rapamycin) inhibitors, one or more metabolic inhibitors, or one or more MEK (mitogen-activated protein kinase kinase) inhibitors.

[0276] In some embodiments, the one or more additional therapeutic agents comprise one or more SHP2 inhibitors.

[0277] In some embodiments, the one or more SHP2 inhibitors comprise JAB-3068, JAB-3312, TNO-155, RLY-1971, or RMC-4630.

[0278] In some embodiments, the one or more additional therapeutic agents comprise one or more SOS1 inhibitors.

[0279] In some embodiments, the one or more SOS1 inhibitors comprise BI-1701963, BI-1703880, or MRTX0902.

[0280] In some embodiments, one or more additional therapeutic agents comprise one or more KRAS inhibitors.

[0281] In some embodiments, the one or more KRAS inhibitors include sotorasib, adagrasib, LY3537982, divarasib, JDQ443, BI-1823911, MRTX1133, RMC-9805, or RMC-6236.

[0282] In some embodiments, the one or more additional therapeutic agents include one or more ERK inhibitors.

[0283] In some embodiments, the one or more ERK inhibitors include ulixertinib, MK-8353, LY3214996, ASTX029, ASN007, LTT462, or KO-947.

[0284] In some embodiments, the one or more additional therapeutic agents include one or more immune checkpoint inhibitors.

[0285] In some embodiments, the one or more immune checkpoint inhibitors include pembrolizumab, ipilimumab, nivolumab, or atezolizumab.

[0286] In some embodiments, the one or more additional therapeutic agents include one or more chemotherapies.

[0287] In some embodiments, the one or more chemotherapies include oxaliplatin or irinotecan.

[0288] In some embodiments, the one or more additional therapeutic agents include one or more EGFR inhibitors.

[0289] In some embodiments, the one or more EGFR inhibitors include erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, or vandetanib.

[0290] In some embodiments, the one or more additional therapeutic agents comprise one or more MET inhibitors.

[0291] In some embodiments, the one or more MET inhibitors comprise crizotinib, capmatinib, tepotinib, savolitinib, cabozantinib, glesatinib, foretinib, merestinib, tivantinib, SAR125844, onartuzumab, telisotuzumab, or JNJ-61186372.

[0292] In some embodiments, the one or more additional therapeutic agents comprise one or more TEAD inhibitors.

[0293] In some embodiments, the one or more TEAD inhibitors comprise VT3989, IK-930, or IAG933.

[0294] In some embodiments, the one or more additional therapeutic agents comprise one or more YAP inhibitors.

[0295] In some embodiments, the one or more YAP inhibitors comprise verteporfin.

[0296] In some embodiments, one or more additional therapeutic agents comprise one or more PI3K inhibitors.

[0297] In some embodiments, the one or more PI3K inhibitors comprise idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib.

[0298] In some embodiments, the one or more additional therapeutic agents comprise one or more mTOR inhibitors.

[0299] In some embodiments, the one or more mTOR inhibitors comprise everolimus, sirolimus, temsirolimus, everolimus, sirolimus, sirolimus protein binding, or everolimus.

[0300] In some embodiments, the one or more additional therapeutic agents comprise one or more metabolic inhibitors.

[0301] In some embodiments, the one or more metabolic inhibitors comprise trifluridine, gemcitabine, fluorouracil, pentostatin, clofarabine, azacitidine, cytarabine, mercaptopurine, fludarabine, or capecitabine.

[0302] In some embodiments, the one or more metabolic inhibitors comprise one or more MEK inhibitors.

[0303] In some embodiments, the one or more MEK inhibitors comprise trametinib, cobimetinib, or binimetinib.

[0304] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway.

[0305] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more MEK inhibitors.

[0306] In some aspects, the present disclosure provides a combination comprising:

[0307] a compound of the present disclosure; and

[0308] one or more of trametinib, cobimetinib, or binimetinib.

[0309] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and trametinib.

[0310] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and cobimetinib.

[0311] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and binimetinib.

[0312] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and one or more inhibitors of the MAPK pathway (e.g., in a therapeutically effective amount).

[0313] In some aspects, the present disclosure provides a method for treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising:

[0314] a compound of the present disclosure (e.g., in a therapeutically effective amount); and

[0315] one or more of trametinib, cobimetinib, or binimetinib (e.g., in a therapeutically effective amount).

[0316] In some aspects, the present disclosure provides a method for treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and trametinib (e.g., in a therapeutically effective amount).

[0317] In some aspects, the present disclosure provides a method for treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and cobimetinib (e.g., in a therapeutically effective amount).

[0318] In some aspects, the present disclosure provides a method for treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and binimetinib (e.g., in a therapeutically effective amount).

[0319] In some aspects, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and one or more inhibitors of the MAPK pathway (e.g., in a therapeutically effective amount).

[0320] In some aspects, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject a combination comprising:

[0321] a compound of the present disclosure (e.g., in a therapeutically effective amount); and

[0322] one or more of trametinib, cobimetinib, or binimetinib (e.g., in a therapeutically effective amount).

[0323] In some aspects, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and trametinib (e.g., in a therapeutically effective amount).

[0324] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and cobimetinib (e.g., in a therapeutically effective amount).

[0325] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a combination comprising a compound of the present disclosure (e.g., in a therapeutically effective amount) and binimetinib (e.g., in a therapeutically effective amount).

[0326] In some aspects, the present disclosure provides a combination for treating or preventing cancer in a subject, the combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway.

[0327] In some aspects, the present disclosure provides a combination comprising:

[0328] a compound of the present disclosure, and

[0329] one or more of trametinib, cobimetinib or binimetinib

[0330] , which is for treating or preventing cancer in a subject.

[0331] In some aspects, the present disclosure provides a combination for treating or preventing cancer in a subject, the combination comprising a compound of the present disclosure and trametinib.

[0332] In some aspects, the present disclosure provides a combination for treating or preventing cancer in a subject, the combination comprising a compound of the present disclosure and cobimetinib.

[0333] In some aspects, the present disclosure provides a combination for treating or preventing cancer in a subject, the combination comprising a compound of the present disclosure and binimetinib.

[0334] In some aspects, the present disclosure provides a combination for treating cancer in a subject, the combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway.

[0335] In some aspects, the present disclosure provides a combination comprising:

[0336] a compound of the present disclosure, and

[0337] one or more of trametinib, cobimetinib or binimetinib

[0338] , which is for treating cancer in a subject.

[0339] In some aspects, the present disclosure provides a combination for treating cancer in a subject, the combination comprising a compound of the present disclosure and trametinib.

[0340] In some aspects, the present disclosure provides a combination for treating cancer in a subject, the combination comprising a compound of the present disclosure and cobimetinib.

[0341] In some aspects, the present disclosure provides a combination for treating cancer in a subject, the combination comprising a compound of the present disclosure and binimetinib.

[0342] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway for the preparation of a medicament for treating or preventing cancer in a subject.

[0343] In some aspects, the present disclosure provides the use of a combination comprising:

[0344] a compound of the present disclosure, and

[0345] one or more of trametinib, cobimetinib or binimetinib

[0346] for the preparation of a medicament for treating or preventing cancer in a subject.

[0347] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and trametinib for the preparation of a medicament for treating or preventing cancer in a subject.

[0348] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and cobimetinib for the preparation of a medicament for treating or preventing cancer in a subject.

[0349] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and binimetinib for the preparation of a medicament for treating or preventing cancer in a subject.

[0350] In some aspects, the present disclosure provides the use of a combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway for the preparation of a medicament for treating cancer in a subject.

[0351] In some aspects, the present disclosure provides the use of a combination comprising:

[0352] a compound of the present disclosure, and

[0353] one or more of trametinib, cobimetinib or binimetinib,

[0354] It is used for preparing a drug for treating cancer in a subject.

[0355] In some aspects, the present disclosure provides a use of a combination, the combination comprising a compound of the present disclosure and trametinib, for preparing a drug for treating cancer in a subject.

[0356] In some aspects, the present disclosure provides a use of a combination, the combination comprising a compound of the present disclosure and cobimetinib, for preparing a drug for treating cancer in a subject.

[0357] In some aspects, the present disclosure provides a use of a combination, the combination comprising a compound of the present disclosure and binimetinib, for preparing a drug for treating cancer in a subject.

[0358] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered simultaneously.

[0359] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered as a co-formulation.

[0360] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered as separate formulations.

[0361] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered sequentially or alternately.

[0362] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered sequentially.

[0363] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered in close temporal proximity.

[0364] In some embodiments, the compound is administered before one or more inhibitors of the MAPK pathway.

[0365] In some embodiments, the compound is administered in close temporal proximity before one or more inhibitors of the MAPK pathway.

[0366] In some embodiments, the compound is administered about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours or about 12 hours before one or more inhibitors of the MAPK pathway.

[0367] In some embodiments, one or more inhibitors of the MAPK pathway are administered before the compound is administered.

[0368] In some embodiments, one or more inhibitors of the MAPK pathway are administered in temporal proximity before the compound is administered.

[0369] In some embodiments, one or more inhibitors of the MAPK pathway are administered about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours before the compound is administered.

[0370] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered alternately.

[0371] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered by the same route of administration.

[0372] In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered by different routes of administration.

[0373] In some embodiments, at least two inhibitors of the MAPK pathway are administered.

[0374] In some embodiments, binimetinib is administered once daily.

[0375] In some embodiments, binimetinib is administered twice daily.

[0376] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg, or about 6 ± 0.1 mg (e.g., about 6 mg); about 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg, or about 12 ± 0.1 mg (e.g., about 12 mg); about 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg, or about 50 ± 1 mg (e.g., about 50 mg); about 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg, or about 100 ± 1 mg (e.g., about 100 mg); about 150 ± 70 mg, about 150 ± 60 mg, about 150 ± 50 mg, about 150 ± 40 mg, about 150 ± 30 mg, about 150 ± 20 mg, about 150 ± 10 mg, about 150 ± 5 mg, about 150 ± 4 mg, or about 150 ± 3 mg (e.g., about 150 mg); about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg, or about 200 ± 10 mg (e.g., about 200 mg); about 300 ± 150 mg, about 300 ± 120 mg, about 300 ± 100 mg, about 300 ± 80 mg, about 300 ± 60 mg, about 300 ± 50 mg, about 300 ± 40 mg, about 300 ± 30 mg, about 300 ± 20 mg, or about 300 ± 10 mg (e.g., about 300 mg);about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg, or about 400 ± 10 mg (e.g., about 400 mg); about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg, or about 600 ± 10 mg (e.g., about 600 mg); about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg, or about 800 ± 10 mg (e.g., about 800 mg); about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg, or about 1000 ± 10 mg (e.g., about 1000 mg); or about 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 80 mg, about 1200 ± 70 mg, about 1200 ± 60 mg, about 1200 ± 50 mg, about 1200 ± 40 mg, about 1200 ± 30 mg, about 1200 ± 20 mg, or about 1200 ± 10 mg (e.g., about 1200 mg); and;

[0377] Binimetinib is administered at the following doses (e.g., daily dose): about 15 ± 6 mg, about 15 ± 5 mg, about 15 ± 4 mg, about 15 ± 3 mg, about 15 ± 2 mg, about 15 ± 1 mg, about 15 ± 0.9 mg, about 15 ± 0.8 mg, about 15 ± 0.7 mg, about 15 ± 0.6 mg, about 15 ± 0.5 mg, about 15 ± 0.4 mg, about 15 ± 0.3 mg, about 15 ± 0.2 mg, or about 15 ± 0.1 mg (e.g., about 15 mg); about 30 ± 10 mg, about 30 ± 9 mg, about 30 ± 8 mg, about 30 ± 7 mg, about 30 ± 6 mg, about 30 ± 5 mg, about 30 ± 4 mg, about 30 ± 3 mg, about 30 ± 2 mg, or about 30 ± 1 mg (e.g., about 30 mg); about 45 ± 20 mg, about 45 ± 10 mg, about 45 ± 9 mg, about 45 ± 8 mg, about 45 ± 7 mg, about 45 ± 6 mg, about 45 ± 5 mg, about 45 ± 4 mg, about 45 ± 3 mg, about 45 ± 2 mg, or about 45 ± 1 mg (e.g., about 45 mg); about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); about 75 ± 40 mg, about 75 ± 30 mg, about 75 ± 20 mg, about 75 ± 10 mg, about 75 ± 9 mg, about 75 ± 8 mg, about 75 ± 7 mg, about 75 ± 6 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); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0378] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg, or about 6 ± 0.1 mg (e.g., about 6 mg); about 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg, or about 12 ± 0.1 mg (e.g., about 12 mg); about 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg, or about 50 ± 1 mg (e.g., about 50 mg); about 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg, or about 100 ± 1 mg (e.g., about 100 mg); about 150 ± 70 mg, about 150 ± 60 mg, about 150 ± 50 mg, about 150 ± 40 mg, about 150 ± 30 mg, about 150 ± 20 mg, about 150 ± 10 mg, about 150 ± 5 mg, about 150 ± 4 mg, or about 150 ± 3 mg (e.g., about 150 mg); about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg, or about 200 ± 10 mg (e.g., about 200 mg); about 300 ± 150 mg, about 300 ± 120 mg, about 300 ± 100 mg, about 300 ± 80 mg, about 300 ± 60 mg, about 300 ± 50 mg, about 300 ± 40 mg, about 300 ± 30 mg, about 300 ± 20 mg, or about 300 ± 10 mg (e.g., about 300 mg);about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg or about 400 ± 10 mg (e.g., about 400 mg); about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg or about 600 ± 10 mg (e.g., about 600 mg); about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg or about 800 ± 10 mg (e.g., about 800 mg); about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg or about 1000 ± 10 mg (e.g., about 1000 mg); or about 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 80 mg, about 1200 ± 70 mg, about 1200 ± 60 mg, about 1200 ± 50 mg, about 1200 ± 40 mg, about 1200 ± 30 mg, about 1200 ± 20 mg or about 1200 ± 10 mg (e.g., about 1200 mg); and;

[0379] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0380] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg, or about 6 ± 0.1 mg (e.g., about 6 mg); and

[0381] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0382] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg, or about 12 ± 0.1 mg (e.g., about 12 mg); and

[0383] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0384] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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); and

[0385] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0386] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 50 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg, or about 50 ± 1 mg (e.g., about 50 mg); and

[0387] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0388] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg, or about 100 ± 1 mg (e.g., about 100 mg); and

[0389] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0390] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 150 ± 70 mg, about 150 ± 60 mg, about 150 ± 50 mg, about 150 ± 40 mg, about 150 ± 30 mg, about 150 ± 20 mg, about 150 ± 10 mg, about 150 ± 5 mg, about 150 ± 4 mg, or about 150 ± 3 mg (e.g., about 150 mg); and

[0391] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0392] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg, or about 200 ± 10 mg (e.g., about 200 mg); and

[0393] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0394] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 300 ± 150 mg, about 300 ± 120 mg, about 300 ± 100 mg, about 300 ± 80 mg, about 300 ± 60 mg, about 300 ± 50 mg, about 300 ± 40 mg, about 300 ± 30 mg, about 300 ± 20 mg, or about 300 ± 10 mg (e.g., about 300 mg); and

[0395] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0396] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg, or about 400 ± 10 mg (e.g., about 400 mg); and

[0397] Binimetinib is administered at the following doses (e.g., daily dose): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0398] In some embodiments, the compound is administered at the following doses (e.g., daily dose): about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg, or about 600 ± 10 mg (e.g., about 600 mg); and

[0399] Binimetinib is administered at the following doses (e.g., daily doses): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0400] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg, or about 800 ± 10 mg (e.g., about 800 mg); and

[0401] Binimetinib is administered at the following doses (e.g., daily doses): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0402] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg, or about 1000 ± 10 mg (e.g., about 1000 mg); and

[0403] Binimetinib is administered at the following doses (e.g., daily doses): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0404] In some embodiments, the compound is administered at the following doses (e.g., daily doses): about 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 80 mg, about 1200 ± 70 mg, about 1200 ± 60 mg, about 1200 ± 50 mg, about 1200 ± 40 mg, about 1200 ± 30 mg, about 1200 ± 20 mg, or about 1200 ± 10 mg (e.g., about 1200 mg); and

[0405] Binimetinib is administered at the following doses (e.g., daily doses): about 60 ± 30 mg, about 60 ± 20 mg, about 60 ± 10 mg, about 60 ± 9 mg, about 60 ± 8 mg, about 60 ± 7 mg, about 60 ± 6 mg, about 60 ± 5 mg, about 60 ± 4 mg, about 60 ± 3 mg, about 60 ± 2 mg, or about 60 ± 1 mg (e.g., about 60 mg); or about 90 ± 50 mg, about 90 ± 40 mg, about 90 ± 30 mg, about 90 ± 20 mg, about 90 ± 10 mg, about 90 ± 9 mg, about 90 ± 8 mg, about 90 ± 7 mg, about 90 ± 6 mg, about 90 ± 5 mg, about 90 ± 4 mg, about 90 ± 3 mg, about 90 ± 2 mg, or about 90 ± 1 mg (e.g., about 90 mg).

[0406] Other additional therapeutic agents

[0407] In some embodiments, the one or more additional therapeutic agents comprise agents known to modulate other pathways or other components of the same pathway or even overlapping sets of target enzymes.

[0408] In some embodiments, the one or more additional therapeutic agents comprise chemotherapeutic agents, therapeutic antibodies, and radiation treatment.

[0409] Many chemotherapeutic agents are currently known in the art. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as (Imatinib Mesylate), (carfilzomib), (bortezomib), Casodex (bicalutamide), (gefitinib) and Adriamycin, and hosts of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM TM);alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and hexamethylmelamine; nitrogen mustards such as chlorambucil, clofazimine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenyl mustard hydrochloride, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex TM, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, drostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenal such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate;Defofamine; Demecolcine; Diaziquone; Elfomithine; Elliptinium acetate; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2”-Trichloroethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Dibromomannitol; Pipobroman; Gacytosine; Cytarabine (“Ara-C”); Cyclophosphamide; Thiotepa; Taxanes, such as paclitaxel and docetaxel; Retinoic acid; Esperamicin; Capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.;

[0410] Also included as suitable chemotherapeutic cell conditioning agents are antihormonal agents which are used to modulate or inhibit the action of hormones on tumors, such as antiestrogens, including, for example, tamoxifen, (tamoxifen Tn) raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO).

[0411] In some embodiments, the one or more additional therapeutic agents comprise commonly prescribed anti-cancer drugs such as ABVD, AVICINE, Abagovomab, acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carbaldehyde thiosemicarbazone, Amonafide, anthraquinone, anti-CD22 immunotoxin, antineoplastic agent, antineoplastic herb, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, buthionine sulfoximine, CBV (chemotherapy), Calyculin, cell cycle non-specific antineoplastic agent, dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen,IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-Uracil, Temodar, Tesetaxel, Tris(platinum(IV)) nitrate, Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.,

[0412] In some embodiments, the one or more additional therapeutic agents include radiation therapy for inhibiting abnormal cell growth in a mammal or treating a hyperproliferative disorder. Techniques for administering radiation therapy are known in the art.

[0413] Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by spatially confined radioactive material inserted into the body at or near the site of a tumor or other hyperplastic tissue disease. The term is intended to include but not be limited to exposure to radioactive isotopes (e.g., radioactive isotopes of At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radiation sources for use as cell modulators in the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of one or more radionuclides (e.g., a solution of I-125 or I-131), or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide such as Au-198, Y-90. In addition, one or more radionuclides can be embodied in a gel or radioactive microspheres.

[0414] In some embodiments, the one or more additional therapeutic agents comprise one or more substances selected from: anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[0415] Angiogenesis inhibitors, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. Angiogenesis inhibitors include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172, WO 96 / 27583, European Patent Publication EP0818442, European Patent Publication EP1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, European Patent Publication 606046, European Patent Publication 931788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO1999007675, European Patent Publication EP1786785, European Patent Publication No. EP1181017, US Publication No. US20090012085, US Patent No. 5,863,949, US Patent No. 5,861,510, and European Patent Publication EP0780386, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are inhibitors that have little or no inhibitory activity against MMP-1. More preferably, they are inhibitors that selectively inhibit MMP-2 and / or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO 32-3555, and RS13-0830.

[0416] In some embodiments, the one or more additional therapeutic agents include anti-tumor agents such as acetyl mannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, anceslim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac,Interferon α, daunorubicin, doxorubicin, retinoic acid, edelfosine, edrecolomab, eflomithine, emitefur, epirubicin, β-epoetin, etoposide phosphate, exemestane, eptazocine, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod, interferon α, interferon α, natural interferon α-2, interferon α-2a, interferon α-2b, interferon α-N1, interferon α-n3, interferon αcon-1, interferon α, natural interferon β, interferon β-1a,Interferon β-1b, Interferon γ, Natural Interferon γ-1a, Interferon γ-1b, Interleukin-1β, Iobenguane, Irinotecan, Irsogladine, Lanreotide, LC 9018 (Yakult), Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Leukocyte α-Interferon, Leuprorelin, Levamisole + Fluorouracil, Liarozole, Lobaplatin, Lonidamine, Lovastatin, Masoprocol, Melarsoprol, Metoclopramide, Mifepristone, Miltefosine, Mirimostim, Mismatched Double-Stranded RNA, Mitoguazone, Dibromodulcitol, Mitoxantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoiesis-Stimulating Protein, NSC 631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Pegylated Interferon α-2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit Anti-Thymocyte Polyclonal Antibody, Pegylated Interferon α-2a,Porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecane, thalidomide, thymalfasin, thyrotropin alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural bestatin, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexamethasone, diaziquone, EL 532 (Elan),EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technologies), idiotypic CEA MAb (Trilex),LYM-1-Iodine 131 MAb (Techniclone), polymorphic epithelial mucin-Yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurine, tirapazamine, cancer vaccine (Bemira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolytic agent vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital) or valspodar.,

[0417] In some embodiments, the one or more additional therapeutic agents comprise VEGFR inhibitors, including compounds described in the following patents and patent applications: U.S. Patent No. 6,258,812, US2003 / 0105091, WO / 2001 / 037820, U.S. Patent No. 6,235,764, WO / 2001 / 032651, U.S. Patent No. 6,630,500, No. 6,515,004, No. 6,713,485, No. 5,521,184, No. 5,770,599, and No. 5,747,498, WO / 2002 / 068406, WO / 2002 / 066470, WO / 2002 / 055501, WO / 2004 / 005279, WO / 2004 / 007481, WO / 2004 / 007458, WO / 2004 / 09784, WO / 2002 / 059110, WO / 1999 / 045009, WO / 2000 / 059509, WO / 1999 / 061422, U.S. Patent No. 5,990,141, WO / 2000 / 012089, and WO / 2000 / 002871.

[0418] In some embodiments, the one or more additional therapeutic agents comprise at least one anti-angiogenic agent. The agents include, but are not limited to, chemically synthesized compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. The agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or prevent cell growth.

[0419] Exemplary anti-angiogenic agents include ERBITUX TM (IMC-C 225 )、KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF, or soluble VEGF receptors or their ligand-binding regions), such as AVASTIN TM or VEGF-TRAP TM and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto), such as Vectibix (panitumumab), IRESSA TM (gefitinib), TARCEVA TMErlotinib, anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind thereto or specifically bind to their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical compositions of the invention may further include one or more agents that specifically bind and inhibit growth factor activity (e.g., antibodies, antigen-binding regions or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor "c-met".

[0420] Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2003 / 0162712; US Patent No. 6,413,932), anti-TWEAK agents (e.g., antibodies or antigen-binding regions or soluble TWEAK receptor antagonists that specifically bind; see Wiley, US Patent No. 6,727,225), ADAM disintegrin domains to antagonize the binding of integrin to its ligand (Fanslow et al., US Publication No. 2002 / 0042368), antibodies or antigen-binding regions that specifically bind to anti-eph receptors and / or anti-ephrin (US Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of their patent families) and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind) and antibodies or antigen-binding regions that specifically bind to the PDGF-BB ligand and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto).

[0421] Additional anti-angiogenic / anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, U.S., U.S. Patent No. 5,712,291); ilomastat (Arriva, USA, U.S. Patent No. 5,892,112); emaxanib (Pfizer, USA, U.S. Patent No. 5,792,783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC: anti-angiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 970070); ARGENT technology (Ariad, USA); YIGSR-stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA);ABT-567 (Abbott, USA); Metastatin (Incyte, USA); angiogenesis inhibitor (Tripep, Sweden); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Science, USA); ER-68203-00 (IVAX, USA); Benefin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, α5β3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); gene therapy, retinopathy (Oxford BioMedica, UK); enzastaurin hydrochloride (USAN) (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor (Alchemia, Australia); VEGF antagonist (Regeneron, USA); rBPI 21 and BPI-derived anti-angiogenic (XOMA, USA); PI 88 (Progen, Australia); cilengitide (pINN) (Merck, Germany);Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA; Cetuximab (INN) (Aventis, France); AVE 8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Childrens Hospital, USA); ATN 161 (Attenuon, USA); Angiostatin (Boston Childrens Hospital, USA); 2-Methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); Vandetanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue Factor Pathway Inhibitor (Inventys Therapeutics, Inc., USA); Pegaptanib (Pinn) (Gilead Sciences, Inc., USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based vaccine VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California at San Diego, USA); PX 478 (ProlX, USA); Metastatin (Inventys Therapeutics, Inc., USA); Troponin I (Harvard University, USA); SU 6668 (SUGEN, Inc., USA); OXI 4503 (OXiGENE, USA);o-guanidines (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atimolol (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (EntreMed, Canada); vaccines, angiogenesis (Endocyte, USA); urokinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-lα inhibitor (Xenova, UK); CEP 5214 (Falcon, USA); BAY RES2622 (Bayer, Germany); angiotensin (Endorecherche, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); drug delivery systems, intraocular, 2-methoxyestradiol (Endocyte, USA); anginex (Maastricht University, Netherlands and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA);Tumor necrosis factor-α inhibitor (National Institute on Aging, USA); SU 11248 (Pfizer Inc., USA and SUGEN Inc., USA); ABT 518 (Abbott Laboratories, USA); YH16 (Yantai Rongchang, China); S-3APG (Children's Hospital Boston, USA and Inventis BioSciences, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (University of South Florida, USA and Yale University, USA); CS 706 (Sankyo, Japan); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer AG, Germany); AGM 1470 (Harvard University, USA, Takeda Pharmaceutical Company Limited, Japan and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South Korea); MAb, vascular endothelial growth factor (Nova Ltd., UK); Irsogladine (INN) (Nippon Shinyaku Co., Ltd., Japan); RG 13577 (Annette SA, France); WX 360 (Wilex AG, Germany); Squalamine (pINN) (Genaera Corporation, USA); RPI 4610 (Sirna, USA); Cancer therapy (Marinova Pty Ltd., Australia); Heparanase inhibitor (InSight Biotechnology Ltd., Israel); KL 3106 (Kolon Industries, South Korea);Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angi, (Schering AG, Germany); ZK 229561 (Novartis AG, Switzerland and Schering AG, Germany); XMP 300 (XOMA Corporation, USA); VGA 1102 (Taisho, Japan); VEGF receptor modulator (Pharmacopeia, USA); VE-cadherin-2 antagonist (ImClone Systems Incorporated, USA); Angiostatin (National Institutes of Health, USA); vaccine, Flk-1 (ImClone Systems Incorporated, USA); TZ 93 (Tsumura & Co., Japan); Tumstatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron Pharmaceuticals, Inc., USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).;

[0422] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM ), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit protein phosphatase type 2A or type 1, analogs of cAMP, and drugs that elevate cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA that inhibits the expression of a protein may be used, including, but not limited to, ATG5 (which is involved in autophagy).

[0423] In some embodiments, the one or more additional therapeutic agents comprise epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ansermin; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; AMG 706 or a pharmaceutically acceptable salt thereof.

[0424] In some embodiments, the one or more additional therapeutic agents include chemotherapeutic agents. Suitable chemotherapeutic agents can include: natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxin (e.g., etoposide and teniposide), antibiotics (e.g., actinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and deprives cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, anti-proliferative / anti-mitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyleneimine and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), temozolomide (DTIC), anti-proliferative / anti-mitotic antimetabolites such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidin, suberoylanilide hydroxamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., array 520), DNA binders (e.g., Zalypsis), PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130), multi-kinase inhibitors (e.g., TG02 and sorafenib),Hormones (e.g., estrogen) and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprorelin, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab)), HSP90 inhibitors (e.g., 17AAG and KOS 953), PI3K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zamestra, TM ), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists. Other chemotherapeutic agents can include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analogs or derivative variants of the foregoing.

[0425] In some embodiments, one or more additional therapeutic agents comprise radiotherapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0426] In some embodiments, the one or more additional therapeutic agents comprise steroids. Suitable steroids can include, but are not limited to: 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednoletabonate), mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25 - diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone benetonide, hexatriamcinolone and salts and / or derivatives thereof. In certain embodiments, the compounds of the invention may also be used in combination with additional pharmaceutically active agents for treating nausea. Examples of agents useful for treating nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0427] In some embodiments, the one or more additional therapeutic agents comprise a compound that disrupts or inhibits the RAS - RAF - ERK or PI3K - AKT - TOR signaling pathway. In other such combinations, the additional pharmaceutically active compound is a PD - 1 and PD - L1 antagonist. The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more substances selected from: EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl - 1 inhibitors, BCL - 2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies, the immunotherapies including monoclonal antibodies, immunomodulatory imides (IMiDs), anti - PD - 1, anti - PDL - 1, anti - CTLA4, anti - LAG1 and anti - OX40 agents, GITR agonists, CAR - T cells, and BiTE.

[0428] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors or specific antisense nucleotides or siRNAs. Available antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva) and more recently lapatinib (TykerB). See, for example, Yan L et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005; 39(4):565-8 and Paez JG et al., EGFR Mutations In Lung Cancer: Correlation With Clinical Response To Gefitinib Therapy, Science 2004; 304(5676):1497-500.

[0429] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications and all pharmaceutically acceptable salts of said EGFR inhibitors: European Patent Publication EP 520722 published on December 30, 1992; European Patent Publication EP 566226 published on October 20, 1993; PCT International Publication WO 96 / 33980 published on October 31, 1996; U.S. Patent No. 5,747,498 issued on May 5, 1998; PCT International Publication WO 96 / 30347 published on October 3, 1996; European Patent Publication EP787772 published on August 6, 1997; PCT International Publication WO 97 / 30034 published on August 21, 1997; PCT International Publication WO 97 / 30044 published on August 21, 1997; PCT International Publication WO 97 / 38994 published on October 23, 1997; PCT International Publication WO 97 / 49688 published on December 31, 1997; European Patent Publication EP 837063 published on April 22, 1998; PCT International Publication WO 98 / 02434 published on January 22, 1998; PCT International Publication WO97 / 38983 published on October 23, 1997; PCT International Publication WO 95 / 19774 published on July 27, 1995; PCT International Publication WO 95 / 19970 published on July 27, 1995; PCT International Publication WO 97 / 13771 published on April 17, 1997; PCT International Publication WO 98 / 02437 published on January 22, 1998; PCT International Publication WO 98 / 02438 published on January 22, 1998; PCT International Publication WO 97 / 32881 published on September 12, 1997; German Application DE19629652 published on January 29, 1998; PCT International Publication WO 98 / 33798 published on August 6, 1998; PCT International Publication WO 97 / 32880 published on September 12, 1997; PCT International Publication WO 97 / 32880 published on September 12, 1997; European Patent Publication EP 682027 published on November 15, 1995; PCT International Publication WO 97 / 02266 published on January 23, 1997; PCT International Publication WO 97 / 27199 published on July 31, 1997; PCT International Publication WO98 / 07726 published on February 26, 1998; PCT International Publication WO 97 / 34895 published on September 25, 1997;PCT International Publication WO 96 / 31510, published on October 10, 1996; PCT International Publication WO 98 / 14449, published on April 9, 1998; PCT International Publication WO 98 / 14450, published on April 9, 1998; PCT International Publication WO 98 / 14451, published on April 9, 1998; PCT International Publication WO 95 / 09847, published on April 13, 1995; PCT International Publication WO 97 / 19065, published on May 29, 1997; PCT International Publication WO 98 / 17662, published on April 30, 1998; U.S. Patent No. 5,789,427, issued on August 4, 1997; U.S. Patent No. 5,650,415, issued on July 22, 1997; U.S. Patent No. 5,656,643, issued on August 12, 1997; PCT International Publication WO 99 / 35146, published on July 15, 1999; PCT International Publication WO 99 / 35132, published on July 15, 1999; PCT International Publication WO 99 / 07701, published on February 18, 1999; and PCT International Publication WO 92 / 20642, published on November 26, 1992. Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following: Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.;

[0430] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include the inhibitors described in the following: Modjtahedi, H. et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T. et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, S.M. et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X. et al., 1999, Cancer Res. 59:1236-1243. Thus, an EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or an antibody or antibody fragment having binding specificity thereto.

[0431] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0432] PI3K inhibitors include, but are not limited to: wortmannin, 17-hydroxy wortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT publications WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propanenitrile (also known as BEZ 235 or NVP-BEZ 235 and described in PCT publication WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in PCT publication WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, which is available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinopyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, which is available from Axon Medchem), PIK 75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfonyl-hydrazine hydrochloride, which is available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide, which is available from Axon Medchem), GDC-0941 dimethanesulfonate (2-(1H-indazol-4-yl)-6-(4-methylsulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine dimethanesulfonate, which is available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]methyl-(Z)-methylene]-thiazolidine-2,4-dione, which is available from Axon Medchem), and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one, which is available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0433] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al., (2005) Biochem. J. 385 (Pt 2), 399-408); Akt-1-1,2 (inhibits Akt1 and 2) (Barnett et al., (2005) Biochem. J. 385 (Pt 2), 399-408); API-59CJ-Ome (e.g., Jin et al., (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-methanol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J. Nutr. 134 (12 Suppl), 3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. (2004) Clin. Cancer Res. 10 (15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Clin. Res. 64, 4394-9).

[0434] TOR inhibitors include, but are not limited to, inhibitors including AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors, which include PI-103, PP242, PP30, and Torin 1. Other TOR inhibitors in FKBP12 enhancers; rapamycin and its derivatives, including: CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010), and AP23573; rapamycin analogs, for example, as disclosed in WO 98 / 02441 and WO 01 / 14387, for example, AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy( hydroxymethyl)methyl propionate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxyrapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin; and other derivatives disclosed in WO 05005434; derivatives disclosed in U.S. Patent No. 5,258,389, WO 94 / 090101, WO 92 / 05179, U.S. Patent Nos. 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807, and U.S. Patent No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Application No. 60 / 528,340).

[0435] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely related to tumor progression and resistance, not only related to traditional chemotherapy, but also related to targeted therapeutic drugs including BCL-2 inhibitors such as ABT-263.

[0436] SHP inhibitors include, but are not limited to, SHP099.

[0437] Proteasome inhibitors include, but are not limited to (carfilzomib), (Bortezomib) and oprozomib.

[0438] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0439] Monoclonal antibodies include, but are not limited to (daratumumab, (trastuzumab), (bevacizumab), (rituximab), and (ranibizumab).

[0440] Fusion proteins include, but are not limited to (aflibercept).

[0441] Immunomodulatory drugs (IMiDs) are a class of immunomodulatory drugs containing imide groups (drugs that modulate the immune response). The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0442] Exemplary anti-PD-1 antibodies and methods of use thereof are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clinical Cancer Research 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (Publication No. WO 2006 / 121168A1), each of which is expressly incorporated herein by reference, including: Yervoy TMIpilimumab or tremelimumab (against CTLA-4), galiximab (against B7.1), BMS-936558 (against PD-1), MK-3475 (against PD-1), AMP224 (against B7DC), BMS-936559 (against B7-H1), MPDL3280A (against B7-H1), MEDI-570 (against ICOS), AMG557 (against B7H2), MGA271 (against B7H3), IMP321 (against LAG-3), BMS-663513 (against CD137), PF-05082566 (against CD137), CDX-1127 (against CD27), anti-OX40 (Providence Health Services), huMAbOX40L (against OX40L), atacicept (against TACI), CP-870893 (against CD40), lucatumumab (against CD40), dacetuzumab (against CD40), muromonab-CD3 (against CD3), ipilimumab (against CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE).

[0443] In some embodiments, the one or more additional therapeutic agents comprise an anti-PD-1 antibody.

[0444] In some embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises 1, 2, 3, 4, 5 or all 6 complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 2-7 (represented in that order as HC CDR1, HC CDR2, HCCDR3, LC CDR1, LC CDR2 and LC CDR3). In a specific embodiment, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises all 6 CDR amino acid sequences of SEQ ID NOs: 2-7.

[0445] In some embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises (a) the heavy chain variable region (VH) amino acid sequence of SEQ ID NO:8 or a variant sequence thereof that differs therefrom by only one or two amino acids or has at least or about 70% sequence identity, or (b) the light chain variable region (VL) amino acid sequence of SEQ ID NO:9 or a variant sequence thereof that differs therefrom by only one or two amino acids or has at least or about 70% sequence identity. In some embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises the heavy chain variable region amino acid sequence of SEQ ID NO:8 and the light chain variable region amino acid sequence of SEQ ID NO:9.

[0446] In some embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises (a) the heavy chain (HC) amino acid sequence of SEQ ID NO:10 or a variant sequence thereof that differs therefrom by only one or two amino acids or has at least or about 70% sequence identity, or (b) the light chain (LC) amino acid sequence of SEQ ID NO:11 or a variant sequence thereof that differs therefrom by only one or two amino acids or has at least or about 70% sequence identity. In some embodiments, the anti-PD-1 antibody comprises the heavy chain amino acid sequence of SEQ ID NO:10 and the light chain amino acid sequence of SEQ ID NO:11.

[0447] In some embodiments, the antibody comprises 1, 2, 3, 4, 5, or all 6 CDRs (designated as HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 in that order) encoded by one or more nucleic acids of SEQ ID NOs:12 - 17. In some embodiments, the antibody comprises all 6 CDRs encoded by the nucleic acids of SEQ ID NOs:12 - 17.

[0448] In some embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises (a) a heavy chain variable region encoded by SEQ ID NO:18 or a variant sequence thereof that differs therefrom by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity, or (b) a light chain variable region encoded by SEQ ID NO:19 or a variant sequence thereof that differs therefrom by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity. In some embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises the heavy chain variable region encoded by SEQ ID NO:18 and the light chain variable region encoded by SEQ ID NO:19.

[0449] In some embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises (a) a heavy chain encoded by SEQ ID NO:20 or a variant sequence thereof that differs therefrom by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity or (b) a light chain encoded by SEQ ID NO:21 or a variant sequence thereof that differs therefrom by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity. In some embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises a heavy chain encoded by SEQ ID NO:20 and a light chain encoded by SEQ ID NO:21.

[0450] The sequences of exemplary anti-PD-1 antibodies are provided in Table 2.

[0451] Table 2: Sequences of exemplary anti-PD-1 antibodies.

[0452]

[0453]

[0454]

[0455] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent No. 6,111,090, box c, European Patent No.: 090505B1, U.S. Patent No. 8,586,023, PCT Publication No.: WO 2010 / 003118 and 2011 / 090754, or the anti-GITR antibodies described in, for example, U.S. Patent No. 7,025,962, European Patent No.: 1947183B1, U.S. Patent No. 7,812,135, No. 8,388,967, No. 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011 / 028683, PCT Publication No.: WO 2013 / 039954, PCT Publication No.: WO2005 / 007190, PCT Publication No.: WO 2007 / 133822, PCT Publication No.: WO2005 / 055808, PCT Publication No.: WO 99 / 40196, PCT Publication No.: WO 2001 / 03720, PCT Publication No.: WO99 / 20758, PCT Publication No.: WO2006 / 083289, PCT Publication No.: WO 2005 / 115451, U.S. Patent No. 7,618,632 and PCT Publication No.: WO 2011 / 051726.

[0456] The compounds of the present disclosure

[0457] In some aspects, the present disclosure provides a compound of formula (0):

[0458]

[0459] its isomers, or pharmaceutically acceptable salts thereof, wherein:

[0460] X is CR X or N;

[0461] R X is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl or the C1-C6 alkoxy is optionally substituted by one or more halogens, cyano, oxo or OH;

[0462] W 1 is N or CR W1 ;

[0463] R W1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0464] W 2 is N or CR W2 ;

[0465] R W2 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally substituted by one or more halogens;

[0466] W 3 is N or CR W3 ;

[0467] R W3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0468] W 4 is N or CR W4 ;

[0469] R W4 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or S(C1-C6 alkyl);

[0470] R 1is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heteroalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heteroalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R 1a substituents;

[0471] Each R 1a is independently halogen, cyano, oxo, OH, NH2, NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heteroalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl;

[0472] R 2 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy;

[0473] R 3 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy; or

[0474] R 1 and R 3 together with the intervening atom form a 4- to 12-membered heteroalkyl optionally substituted with one or more oxo;

[0475] X 1 is -NR X1 -*, -C(=O)NR X1 -*, -NR X1 C(=O)-*, -NR X1 C(=O)O-*, -NR X1 N=C-*, -NR X1 C(=NR X1 )-*, -NR X1 C(=NH)NR X1 -*, -NR X1 C(=O)NR X1 -*, -S(=O)2NR X1 -* or -NR X1S(=O)2-*, where * indicates connection to A;

[0476] R X1 is independently H, S(=O)2R X1a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R X1a substituents;

[0477] Each R X1a is independently halogen, C1-C6 alkyl or 3- to 12-membered heterocycloalkyl, where the C1-C6 alkyl or the 3- to 12-membered heterocycloalkyl is optionally substituted by one or more halogens;

[0478] A is C1-C6 alkyl, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl) or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), where the C1-C6 alkyl, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl, the 5- to 10-membered heteroaryl, the -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), the -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), the -(C1-C6 alkyl)-(C6-C 10 aryl) or the -(C1-C6 alkyl)-(5- to 10-membered heteroaryl is optionally substituted by one or more R A substituents;

[0479] Each R A is independently halogen, cyano, oxo, OH, OR A1 , NH2, NHR A1 , N(R A1 )2, (=N)R A1, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A1 substituents;

[0480] Each R A1 is independently halogen, cyano, oxo, OH, OR A2 , NH2, NHR A2 , N(R A2 )2, C(=O)R A2 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A2 substituents; and

[0481] Each R A2 is independently halogen, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl,

[0482] wherein R A3 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl.

[0483] In some aspects, the present disclosure provides a compound of formula (I'):

[0484]

[0485] its isomers, or a pharmaceutically acceptable salt thereof.

[0486] In some aspects, the present disclosure provides a compound of formula (I):

[0487]

[0488] its isomers, or pharmaceutically acceptable salts thereof.

[0489] In some aspects, the present disclosure provides a compound of formula (II'):

[0490]

[0491] its isomers, or pharmaceutically acceptable salts thereof.

[0492] It should be understood that for the compounds of the present disclosure, the variables X, R X , W 1 , R W1 , W 2 , R W2 , W 3 , R W3 , W 4 , R W4 , R 1 , R 1a , R 2 , R 3 , X 1 , R X1 , R X1a , A, R A , R A1 , R A2 , R A3 can each independently be selected from the groups described herein, and any of the groups described herein for any one of the variables X, R X , W 1 , R W1 , W 2 , R W2 , W 3 , R W3 , W 4 , R W4 , R 1 , R 1a , R 2 , R 3 , X 1 , R X1 , R X1a , A, R A , R A1 , R A2 , R A3 can, in applicable cases, be combined with any of the groups described herein for use in the variables X, R X , W 1 , R W1 , W 2 , R W2 , W 3 , R W3 , W4 , R W4 , R 1 , R 1a , R 2 , R 3 , X 1 , R X1 , R X1a , A, R A , R A1 , R A2 , R A3 one or more of the remaining parts in

[0493] The variables X and R X

[0494] In some embodiments, X is CR X or N. In some embodiments, X is N. In some embodiments, X is CR X . In some embodiments, X is CH. In some embodiments, X is C(CN). In some embodiments, X is CF.

[0495] In some embodiments, R X is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl or the C1-C6 alkoxy is optionally substituted by one or more halogens, cyano, oxo or OH. In some embodiments, R X is H, halogen, cyano, oxo or OH. In some embodiments, R X is H. In some embodiments, R X is halogen. In some embodiments, R X is fluorine. In some embodiments, R X is chlorine. In some embodiments, R X is bromine. In some embodiments, R X is iodine. In some embodiments, R X is cyano. In some embodiments, R X is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl or the C1-C6 alkoxy is optionally substituted by one or more halogens, cyano, oxo or OH. In some embodiments, R X is C1-C6 alkoxy optionally substituted by one or more OH. In some embodiments, R X is C1 alkoxy optionally substituted by one or more OH. In some embodiments, R X ​is a C2 alkoxy optionally substituted by one or more OH. In some embodiments, R X is a C3 alkoxy optionally substituted by one or more OH. In some embodiments, R X is a C4 alkoxy optionally substituted by one or more OH. In some embodiments, R X is a C5 alkoxy optionally substituted by one or more OH. In some embodiments, R X is a C6 alkoxy optionally substituted by one or more OH.

[0496] Variant W 1 , R W1 , W 2 , R W2 , W 3 , R W3 , W 4 , R W4

[0497] In some embodiments, W 1 is N or CR W1 . In some embodiments, W 1 is N. In some embodiments, W 1 is CR W1 . In some embodiments, W 1 is CH.

[0498] In some embodiments, R W1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In some embodiments, R W1 is H or halogen. In some embodiments, R W1 is H. In some embodiments, R W1 is halogen. In some embodiments, R W1 is fluorine. In some embodiments, R W1 is chlorine. In some embodiments, R W1 is bromine. In some embodiments, R W1 is iodine. In some embodiments, R W1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In some embodiments, R W1 is C1-C6 alkyl. In some embodiments, R W1 is C1 alkyl. In some embodiments, R W1 is C2 alkyl. In some embodiments, R W1 is C3 alkyl. In some embodiments, R W1 is C4 alkyl. In some embodiments, R W1 is C5 alkyl. In some embodiments, R W1is a C6 alkyl group. In some embodiments, R W1 is CH3.

[0499] In some embodiments, W 2 is N or CR W2 . In some embodiments, W 2 is N. In some embodiments, W 2 is CR W2 . In some embodiments, W 2 is CH. In some embodiments, W 2 is C(CH3).

[0500] In some embodiments, R W2 is H, a halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group or the C2-C6 alkynyl group is optionally substituted with one or more halogens.

[0501] In some embodiments, R W2 is H or a halogen. In some embodiments, R W2 is H. In some embodiments, R W2 is a halogen. In some embodiments, R W2 is fluorine. In some embodiments, R W2 is chlorine. In some embodiments, R W2 is bromine. In some embodiments, R W2 is iodine. In some embodiments, R W2 is a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group or the C2-C6 alkynyl group is optionally substituted with one or more halogens. In some embodiments, R W2 is a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group. In some embodiments, R W2 is a C1-C6 alkyl group. In some embodiments, R W2 is a C1 alkyl group. In some embodiments, R W2 is a C2 alkyl group. In some embodiments, R W2 is a C3 alkyl group. In some embodiments, R W2 is a C4 alkyl group. In some embodiments, R W2 is a C5 alkyl group. In some embodiments, R W2 is a C6 alkyl group. In some embodiments, R W2 is CH3.

[0502] In some embodiments, W 3 is N or CR W3 . In some embodiments, W 3is N. In some embodiments, W 3 is CR W3 In some embodiments, W 3 is CH.

[0503] In some embodiments, R W3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In some embodiments, R W3 is H or halogen. In some embodiments, R W3 is H. In some embodiments, R W3 is halogen. In some embodiments, R W3 is fluorine. In some embodiments, R W3 is chlorine. In some embodiments, R W3 is bromine. In some embodiments, R W3 is iodine. In some embodiments, R W3 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In some embodiments, R W3 is C1-C6 alkyl. In some embodiments, R W3 is C1 alkyl. In some embodiments, R W3 is C2 alkyl. In some embodiments, R W3 is C3 alkyl. In some embodiments, R W3 is C4 alkyl. In some embodiments, R W3 is C5 alkyl. In some embodiments, R W3 is C6 alkyl.

[0504] In some embodiments, W 4 is N or CR W4 In some embodiments, W 4 is N. In some embodiments, W 4 is CR W4 In some embodiments, W 4 is CH.

[0505] In some embodiments, R W4 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or S(C1-C6 alkyl). In some embodiments, R W4 is H or halogen. In some embodiments, R W4 is H. In some embodiments, R W4 is halogen. In some embodiments, R W4 is fluorine. In some embodiments, R W4 is chlorine. In some embodiments, R W4 is bromine. In some embodiments, R W4 is iodine.

[0506] In some embodiments, R W4 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or S(C1-C6 alkyl).

[0507] In some embodiments, R W4 is a C1-C6 alkyl group. In some embodiments, R W4 is a C1 alkyl group. In some embodiments, R W4 is a C2 alkyl group. In some embodiments, R W4 is a C3 alkyl group. In some embodiments, R W4 is a C4 alkyl group. In some embodiments, R W4 is a C5 alkyl group. In some embodiments, R W4 is a C6 alkyl group. In some embodiments, W 1 is CR W1 , W 2 is CR W2 , W 3 is CR W3 , and W 4 is CR W4 .

[0508] In some embodiments, W 1 is CH, W 2 is CH, W 3 is CH and W 4 is CH. In some embodiments, W 1 is CH, W 2 is C(CH3), W 3 is CH and W 4 is CH. In some embodiments, W 1 is CR W1 , W 2 is CR W2 , W 3 is N and W 4 is CR W4 . In some embodiments, W 1 is CH, W 2 is C(CH3), W 3 is N and W 4 is CH. In some embodiments, W 1 is CR W1 , W 2 is N, W 3 is N and W 4 is CR W4 . In some embodiments, W 1 is CR W1 , W 2 is CRW2 is W 3 is N and W 4 is N.

[0509] The variable R 1 , R 1a , R 2 , R 3

[0510] In some embodiments, R 1 is H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a C6-C 10 aryl group or a 5- to 10-membered heteroaryl group, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the C6-C 10 aryl group or the 5- to 10-membered heteroaryl group is optionally substituted by one or more R 1a . In some embodiments, R 1 is H. In some embodiments, R 1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more R 1a . In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 is a C1 alkyl group. In some embodiments, R 1 is a C2 alkyl group. In some embodiments, R 1 is a C3 alkyl group. In some embodiments, R 1 is a C4 alkyl group. In some embodiments, R 1 is a C5 alkyl group. In some embodiments, R 1 is a C6 alkyl group. In some embodiments, R 1 is CH3. In some embodiments, R 1 is CH2CH3.

[0511] In some embodiments, R 1a is a halogen, a cyano group, an oxo group, OH, NH2, NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a C6-C 10 aryl group or a 5- to 10-membered heteroaryl group. In some embodiments, R 1a is a halogen, a cyano group, an oxo group, OH or NH2. In some embodiments, R 1a is a cyano group. In some embodiments, R 1ais NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0512] In some embodiments, R 2 is H, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy. In some embodiments, R 2 is H, cyano, oxo or OH. In some embodiments, R 2 is H. In some embodiments, R 2 is cyano. In some embodiments, R 2 is OH. In some embodiments, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy. In some embodiments, R 2 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy.

[0513] In some embodiments, R 3 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy.

[0514] In some embodiments, R 1 and R 3 together with the intervening atom form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo groups.

[0515] The variable X 1 、R X1 、R X1a 、A、R A 、R A1 、R A2 、R A3

[0516] In some embodiments, X 1 is -NR X1 -*, -C(=O)NR X1 -*, -NR X1 C(=O)-*, -NR X1 C(=O)O-*, -NR X1 N=C-*, -NR X1 C(=NH)-*, -NR X1 C(=NH)NR X1 -*, -NRX1 C(=O)NR X1 -*, -S(=O)2NR X1 -* or -NR X1 S(=O)2-*, where * indicates connection to A. In some embodiments, X 1 is -NR X1 -*, -C(=O)NR X1 -*, -NR X1 C(=O)-*, -NR X1 C(=O)O-*, -NR X1 N=C-*, -NR X1 C(=NR X1 )-*, -NR X1 C(=NH)NR X1 -*, -NR X1 C(=O)NR X1 -*, -S(=O)2NR X1 -* or -NR X1 S(=O)2-*, where * indicates connection to A. In some embodiments, it is -NR X1 -*, where * indicates connection to A. In some embodiments, -NH-*, where * indicates connection to A. In some embodiments, X 1 is -C(=O)NR X1 -* or -NR X1 C(=O)-*, where * indicates connection to A. In some embodiments, X 1 is -C(=O)NR X1 -*, where * indicates connection to A. In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A. In some embodiments, X 1 is -NR X1 C(=O)-*, where * indicates connection to A. In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A. In some embodiments, X 1 is -NR X1 C(=NH)-*, where * indicates connection to A. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A.

[0517] In some embodiments, R X1 is H, S(=O)2R X1a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3 to 8-membered heterocycloalkyl, C6-C 10An aryl or a 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C8 cycloalkyl, the 3- to 8-membered heterocycloalkyl, the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R X1a . In some embodiments, R X1 is H. In some embodiments, R X1 is S(=O)2R X1a . In some embodiments, R X1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C8 cycloalkyl, the 3- to 8-membered heterocycloalkyl, the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R X1a . In some embodiments, R X1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl. In some embodiments, R X1 is C1-C6 alkyl. In some embodiments, R X1 is CH3.

[0518] In some embodiments, R X1a is a halogen, C1-C6 alkyl or 3- to 8-membered heterocycloalkyl, wherein the C1-C6 alkyl or the 3- to 8-membered heterocycloalkyl is optionally substituted by one or more halogens. In some embodiments, R X1a is a halogen. In some embodiments, R X1a is C1-C6 alkyl optionally substituted by one or more halogens. In some embodiments, R X1a is 3- to 8-membered heterocycloalkyl optionally substituted by one or more halogens.

[0519] In some embodiments, A is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 An aryl, a 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10(aryl) or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein said C1-C6 alkyl, said C3-C8 cycloalkyl, said 3- to 8-membered heterocycloalkyl, said C6-C 10 aryl, said 5- to 10-membered heteroaryl, said -(C1-C6 alkyl)-(C3-C8 cycloalkyl), said -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl), said -(C1-C6 alkyl)-(C6-C 10 aryl) or said -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R A substituents. In some embodiments, A is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein said C1-C6 alkyl, said C3-C8 cycloalkyl, said 3- to 8-membered heterocycloalkyl, said C6-C 10 aryl or said 5- to 10-membered heteroaryl is optionally substituted with one or more R A substituents. In some embodiments, A is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein said C3-C8 cycloalkyl, said 3- to 8-membered heterocycloalkyl, said C6-C 10 aryl or said 5- to 10-membered heteroaryl is optionally substituted with one or more R A substituents. In some embodiments, A is C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein said C3-C8 cycloalkyl or said 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R A substituents. In some embodiments, A is 3- to 8-membered heterocycloalkyl. In some embodiments, A is tetrahydropyranyl. In some embodiments, A is piperidinyl. In some embodiments, A is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R A substituents. In some embodiments, A is tetrahydropyranyl optionally substituted with one or more R A substituents. In some embodiments, A is piperidinyl optionally substituted with one or more R A substituents. In some embodiments, A is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein said C6-C 10 aryl or said 5- to 10-membered heteroaryl is optionally substituted with one or more R A substituents. In some embodiments, A is C6-C A aryl optionally substituted with one or more R 10 substituents. In some embodiments, A is C6-C 10 aryl. In some embodiments, A is phenyl. In some embodiments, A is optionally substituted with one or more RA Substituted phenyl. In some embodiments, A is optionally substituted with one or more R A Substituted 5- to 10-membered heteroaryl. In some embodiments, A is a 5- to 10-membered heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is triazolyl. In some embodiments, A is pyrazolyl. In some embodiments, A is imidazolyl. In some embodiments, A is oxazolyl. In some embodiments, A is imidazo[1,5-a]pyridinyl. In some embodiments, A is 2,3-dihydrofuro[2,3-c]pyridinyl. In some embodiments, A is 2,3-dihydrofuro[3,2-b]pyridinyl. In some embodiments, A is 3,4-dihydro-1H-pyrano[3,4-c]pyridinyl. In some embodiments, A is 4,5,6,7-tetrahydrobenzo[d]isoxazolyl. In some embodiments, A is optionally substituted with one or more R A Substituted pyridyl. In some embodiments, A is optionally substituted with one or more R A Substituted triazolyl. In some embodiments, A is optionally substituted with one or more R A Substituted pyrazolyl. In some embodiments, A is optionally substituted with one or more R A Substituted imidazolyl. In some embodiments, A is optionally substituted with one or more R A Substituted oxazolyl. In some embodiments, A is optionally substituted with one or more R A Substituted imidazo[1,5-a]pyridinyl. In some embodiments, A is optionally substituted with one or more R A Substituted 2,3-dihydrofuro[2,3-c]pyridinyl. In some embodiments, A is optionally substituted with one or more R A Substituted 2,3-dihydrofuro[3,2-b]pyridinyl. In some embodiments, A is optionally substituted with one or more R A Substituted 3,4-dihydro-1H-pyrano[3,4-c]pyridinyl. In some embodiments, A is optionally substituted with one or more R A Substituted 4,5,6,7-tetrahydrobenzo[d]isoxazolyl. In some embodiments, A is -(C1-C6 alkyl)-(C3-C8 cycloalkyl), -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl) or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein the -(C1-C6 alkyl)-(C3-C8 cycloalkyl), the -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl), the -(C1-C6 alkyl)-(C6-C 10(aryl) or said -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R A In some embodiments, A is -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl) or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein said -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl) or said -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R A In some embodiments, A is optionally substituted with one or more R A substituted -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl). In some embodiments, A is -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl). In some embodiments, A is -(C1 alkyl)-(tetrahydropyranyl). In some embodiments, A is -(C1 alkyl)-(piperidinyl). In some embodiments, A is optionally substituted with one or more R A substituted -(C1 alkyl)-(tetrahydropyranyl). In some embodiments, A is optionally substituted with one or more R A substituted -(C1 alkyl)-(piperidinyl). In some embodiments, A is optionally substituted with one or more R A substituted -(C1-C6 alkyl)-(5- to 10-membered heteroaryl). In some embodiments, A is -(C1-C6 alkyl)-(5- to 10-membered heteroaryl). In some embodiments, A is -(C1 alkyl)-(triazolyl). In some embodiments, A is -(C2 alkyl)-(triazolyl). In some embodiments, A is optionally substituted with one or more R A substituted -(C1 alkyl)-(triazolyl). In some embodiments, A is optionally substituted with one or more R A substituted -(C2 alkyl)-(triazolyl).

[0520] In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is optionally substituted with one or more R A substituted phenyl. In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is optionally substituted with one or more R A substituted phenyl. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is optionally substituted with one or more R A substituted phenyl. In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is optionally substituted with one or more R AA substituted pyridyl group. In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is an optionally substituted pyridyl group by one or more R A A substituted pyridyl group. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is an optionally substituted pyridyl group by one or more R A A substituted pyridyl group. In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is an optionally substituted triazolyl group by one or more R A A substituted triazolyl group. In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is an optionally substituted triazolyl group by one or more R A A substituted triazolyl group. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is an optionally substituted triazolyl group by one or more R A A substituted triazolyl group. In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is an optionally substituted tetrahydropyranyl group by one or more R A A substituted tetrahydropyranyl group. In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is an optionally substituted tetrahydropyranyl group by one or more R A A substituted tetrahydropyranyl group. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is an optionally substituted tetrahydropyranyl group by one or more R A A substituted tetrahydropyranyl group. In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is an optionally substituted piperidyl group by one or more R A A substituted piperidyl group. In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is an optionally substituted piperidyl group by one or more R A A substituted piperidyl group. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is an optionally substituted piperidyl group by one or more R A A substituted piperidyl group. In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is an optionally substituted -(C1 alkyl)-(tetrahydropyranyl) group by one or more R A A substituted -(C1 alkyl)-(tetrahydropyranyl) group. In some embodiments, X 1is -NHC(=O)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(tetrahydropyranyl). In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(tetrahydropyranyl). In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(piperidinyl). In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(piperidinyl). In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(piperidinyl). In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(triazolyl). In some embodiments, X 1 is -C(=O)NH-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C2 alkyl)-(triazolyl). In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(triazolyl). In some embodiments, X 1 is -NHC(=O)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C2 alkyl)-(triazolyl). In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C1 alkyl)-(triazolyl). In some embodiments, X 1 is -NHC(=NH)-*, where * indicates connection to A, and A is optionally substituted by one or more R A substituted -(C2 alkyl)-(triazolyl).

[0521] In some embodiments, R Ais halogen, cyano, oxo, OH, OR A1 , NH2, NHR A1 , N(R A1 )2, (=N)R A1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C8 cycloalkyl, the 3- to 8-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R A1 . In some embodiments, R A is halogen, cyano, oxo, OH, OR A1 , NH2, NHR A1 , N(R A1 )2 or (=N)R A1 . In some embodiments, R A is halogen. In some embodiments, R A is fluorine. In some embodiments, R A is chlorine. In some embodiments, R A is bromine. In some embodiments, R A is iodine. In some embodiments, R A is cyano. In some embodiments, R A is OH. In some embodiments, R A is OR A1 . In some embodiments, R A is O(C1-C6 alkyl) optionally substituted by one or more R A2 . In some embodiments, R A is NHR A1 . In some embodiments, R A is N(R A1 )2. In some embodiments, R A is N(CH3)2. In some embodiments, R A is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C8 cycloalkyl, the 3- to 8-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more RA1 is substituted. In some embodiments, R A is a C1-C6 alkyl group. In some embodiments, R A is a C1 alkyl group. In some embodiments, R A is a C2 alkyl group. In some embodiments, R A is a C3 alkyl group. In some embodiments, R A is a C4 alkyl group. In some embodiments, R A is a C5 alkyl group. In some embodiments, R A is a C6 alkyl group. In some embodiments, R A is a C1-C6 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C1 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C2 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C3 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C4 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C5 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C6 alkyl group optionally substituted by one or more R A1 groups. In some embodiments, R A is a C1-C6 alkyl group optionally substituted by one or more halogens. In some embodiments, R A is a C1 alkyl group optionally substituted by one or more halogens. In some embodiments, R A is a C3 alkyl group optionally substituted by one or more halogens. In some embodiments, R A is CH3. In some embodiments, R A is CF3.

[0522] In some embodiments, R A is C(CH3)2CN. In some embodiments, R A is a C1-C6 alkoxy group. In some embodiments, R A is a C1 alkoxy group. In some embodiments, R A is a C2 alkoxy group. In some embodiments, R A is a C3 alkoxy group. In some embodiments, R A is a C4 alkoxy group. In some embodiments, RA is a C5 alkoxy group. In some embodiments, R A is a C6 alkoxy group. In some embodiments, R A is a C1-C6 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C1 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C2 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C3 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C4 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C5 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C6 alkoxy group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C3-C8 cycloalkyl group. In some embodiments, R A is a C3 cycloalkyl group. In some embodiments, R A is a C4 cycloalkyl group. In some embodiments, R A is a C5 cycloalkyl group. In some embodiments, R A is a C6 cycloalkyl group. In some embodiments, R A is a C7 cycloalkyl group. In some embodiments, R A is a C8 cycloalkyl group.

[0523] In some embodiments, R A is a C3-C8 cycloalkyl group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C3 cycloalkyl group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C4 cycloalkyl group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C5 cycloalkyl group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C6 cycloalkyl group optionally substituted with one or more R A1 groups. In some embodiments, R A is a C7 cycloalkyl group optionally substituted with one or more R A1Substituted C7 cycloalkyl. In some embodiments, R A is optionally a C8 cycloalkyl substituted with one or more R A1 .

[0524] In some embodiments, R A1 is halogen, cyano, oxo, OH, OR A2 , NH2, NHR A2 , N(R A2 )2, C(=O)R A2 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C8 cycloalkyl, the 3- to 8-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A2 . In some embodiments, R A1 is halogen, cyano, oxo, OH, OR A2 , NH2, NHR A2 , N(R A2 )2 or C(=O)R A2 . In some embodiments, R A1 is halogen. In some embodiments, R A1 is fluorine. In some embodiments, R A1 is chlorine. In some embodiments, R A1 is bromine. In some embodiments, R A1 is iodine. In some embodiments, R A1 is cyano. In some embodiments, R A1 is oxo. In some embodiments, R A1 is OH. In some embodiments, R A1 is OR A2 . In some embodiments, R A1 is NH2. In some embodiments, R A1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C8 cycloalkyl, the 3- to 8-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more RA2 is substituted. In some embodiments, R A1 is a C1-C6 alkyl group. In some embodiments, R A1 is a C1 alkyl group. In some embodiments, R A1 is a C2 alkyl group. In some embodiments, R A1 is a C3 alkyl group. In some embodiments, R A1 is a C4 alkyl group. In some embodiments, R A1 is a C5 alkyl group. In some embodiments, R A1 is a C6 alkyl group. In some embodiments, R A1 is a C1-C6 alkyl group optionally substituted with one or more R A2 groups. In some embodiments, R A1 is a C1 alkyl group optionally substituted with one or more R A2 groups. In some embodiments, R A1 is a C2 alkyl group optionally substituted with one or more R A2 groups. In some embodiments, R A1 is a C3 alkyl group optionally substituted with one or more R A2 groups. In some embodiments, R A1 is a C4 alkyl group optionally substituted with one or more R A2 groups. In some embodiments, R A1 is a C5 alkyl group optionally substituted with one or more R A2 groups. In some embodiments, R A1 is a C6 alkyl group optionally substituted with one or more R A2 groups.

[0525] In some embodiments, R A is a C1-C6 alkyl group and R A1 is a halogen. In some embodiments, R A is a C1 alkyl group and R A1 is fluorine. In some embodiments, R A is a C1-C6 alkyl group and R A1 is a cyano group. In some embodiments, R A is a C1 alkyl group and R A1 is a cyano group.

[0526] In some embodiments, R A2 is a halogen, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In some embodiments, R A2 is a halogen, cyano, OH, NH2, N(R A3)2 or C(=O)R A3 . In some embodiments, R A2 is a halogen. In some embodiments, R A2 is fluorine. In some embodiments, R A2 is chlorine. In some embodiments, R A2 is bromine. In some embodiments, R A2 is iodine. In some embodiments, R A2 is OH. In some embodiments, R A2 is a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group. In some embodiments, R A2 is a C1-C6 alkyl group. In some embodiments, R A2 is a C1 alkyl group. In some embodiments, R A2 is a C2 alkyl group. In some embodiments, R A2 is a C3 alkyl group. In some embodiments, R A2 is a C4 alkyl group. In some embodiments, R A2 is a C5 alkyl group. In some embodiments, R A2 is a C6 alkyl group.

[0527] In some embodiments, R A3 is a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group.

[0528] In some embodiments, the compound is a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e) or (I-f):

[0529]

[0530]

[0531] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0532] In some embodiments, the compound is a compound of formula (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s) or (I-t):

[0533]

[0534]

[0535]

[0536] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0537] In some embodiments, the compound is a compound of formula (I-u), (I-v), (I-w), or (I-x):

[0538]

[0539] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0540] In some embodiments, the compound is a compound of formula (I-a-i), (I-b-i), (I-c-i), (I-d-i), (I-e-i), or (I-f-i):

[0541]

[0542]

[0543] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0544] In some embodiments, the compound is a compound of formula (I-g-i), (I-h-i), (I-i-i), (I-j-i), (I-k-i), (I-l-i), (I-m-i), (I-n-i), (I-o-i), (I-p-i), (I-q-i), (I-r-i), (I-s-i), or (I-t-i):

[0545]

[0546]

[0547]

[0548] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0549] In some embodiments, the compound is a compound of formula (I-u-i), (I-v-i), (I-w-i), or (I-x-i):

[0550]

[0551]

[0552] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0553] In some embodiments, the compound is a compound of formula (I-a-ii), (I-b-ii), (I-c-ii), (I-d-ii), (I-e-ii), (I-f-ii), (I-g-ii), (I-h-ii), (I-i-ii), (I-j-ii), (I-k-ii), (I-l-ii), (I-m-ii), (I-n-ii), (I-o-ii) or (I-p-ii):

[0554]

[0555]

[0556]

[0557]

[0558] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0559] In some embodiments, the compound is a compound of formula (I-q-ii), (I-r-ii), (I-s-ii), (I-t-ii), (I-u-ii), (I-v-ii), (I-w-ii), (I-x-ii), (I-y-ii), (I-z-ii), (I-a-ii), (I-bb-ii), (I-cc-ii) or (I-dd-ii):

[0560]

[0561]

[0562]

[0563] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0564] In some embodiments, the compound is a compound of formula (I-ee-i), (I-ff-i), (I-gg-i) or (I-hh-i):

[0565]

[0566]

[0567] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0568] In some embodiments, the compound is selected from the compounds described in Table I and pharmaceutically acceptable salts and stereoisomers thereof.

[0569] In some embodiments, the compound is selected from the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0570] In some embodiments, the compound is selected from the compounds described in Table I.

[0571] Table I

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] In some embodiments, the compound is selected from Compound No. 1, No. 2, No. 3, No. 4, No. 5, No. 6, No. 7, No. 8, No. 9, No. 10, No. 11, No. 12, No. 14, No. 15, No. 16, No. 17, No. 18, No. 19, No. 20, No. 21, No. 22, No. 23, No. 24, No. 25, No. 26, No. 27, No. 29, No. 30, No. 31, No. 32, No. 33, No. 34, No. 35, No. 37, No. 38, No. 39, No. 40, No. 41, No. 42, No. 43, No. 44, No. 49, No. 52, No. 53, No. 55, No. 56, No. 57, No. 58, No. 59, No. 60, No. 62, No. 63, No. 65, No. 66, No. 68, No. 71, No. 75, No. 77, No. 78, No. 79, No. 153, No. 154, No. 173, No. 174, No. 175, No. 176, No. 191, No. 193, No. 194, No. 200, No. 201, No. 202, No. 203, No. 204, No. 206, No. 214, No. 215, No. 217, No. 218, No. 220, No. 221, No. 222, No. 223, No. 225, No. 226, No. 227, No. 229, No. 230, No. 231, No. 233, No. 234, No. 235, No. 236, No. 237, No. 238, No. 242, No. 243, No. 245, No. 247, No. 248, No. 249, No. 252, No. 253, No. 255, No. 256, No. 257, No. 258, No. 259, No. 260, No. 261, No. 262, No. 263, No. 264, No. 265, No. 266, No. 267, No. 271, No. 272, No. 274, No. 275 and No. 276, and pharmaceutically acceptable salts and stereoisomers thereof.

[0649] In some embodiments, the compound is selected from Compound No. 1, No. 2, No. 3, No. 4, No. 5, No. 6, No. 7, No. 8, No. 9, No. 10, No. 11, No. 12, No. 14, No. 15, No. 16, No. 17, No. 18, No. 19, No. 20, No. 21, No. 22, No. 23, No. 24, No. 25, No. 26, No. 27, No. 29, No. 30, No. 31, No. 32, No. 33, No. 34, No. 35, No. 37, No. 38, No. 39, No. 40, No. 41, No. 42, No. 43, No. 44, No. 49, No. 52, No. 53, No. 55, No. 56, No. 57, No. 58, No. 59, No. 60, No. 62, No. 63, No. 65, No. 66, No. 68, No. 71, No. 75, No. 77, No. 78, No. 79, No. 153, No. 154, No. 173, No. 174, No. 175, No. 176, No. 191, No. 193, No. 194, No. 200, No. 201, No. 202, No. 203, No. 204, No. 206, No. 214, No. 215, No. 217, No. 218, No. 220, No. 221, No. 222, No. 223, No. 225, No. 226, No. 227, No. 229, No. 230, No. 231, No. 233, No. 234, No. 235, No. 236, No. 237, No. 238, No. 242, No. 243, No. 245, No. 247, No. 248, No. 249, No. 252, No. 253, No. 255, No. 256, No. 257, No. 258, No. 259, No. 260, No. 261, No. 262, No. 263, No. 264, No. 265, No. 266, No. 267, No. 271, No. 272, No. 274, No. 275 and No. 276, and pharmaceutically acceptable salts thereof.

[0650] In some embodiments, the compound is selected from Compound No. 1, No. 2, No. 3, No. 4, No. 5, No. 6, No. 7, No. 8, No. 9, No. 10, No. 11, No. 12, No. 14, No. 15, No. 16, No. 17, No. 18, No. 19, No. 20, No. 21, No. 22, No. 23, No. 24, No. 25, No. 26, No. 27, No. 29, No. 30, No. 31, No. 32, No. 33, No. 34, No. 35, No. 37, No. 38, No. 39, No. 40, No. 41, No. 42, No. 43, No. 44, No. 49, No. 52, No. 53, No. 55, No. 56, No. 57, No. 58, No. 59, No. 60, No. 62, No. 63, No. 65, No. 66, No. 68, No. 71, No. 75, No. 77, No. 78, No. 79, No. 153, No. 154, No. 173, No. 174, No. 175, No. 176, No. 191, No. 193, No. 194, No. 200, No. 201, No. 202, No. 203, No. 204, No. 206, No. 214, No. 215, No. 217, No. 218, No. 220, No. 221, No. 222, No. 223, No. 225, No. 226, No. 227, No. 229, No. 230, No. 231, No. 233, No. 234, No. 235, No. 236, No. 237, No. 238, No. 242, No. 243, No. 245, No. 247, No. 248, No. 249, No. 252, No. 253, No. 255, No. 256, No. 257, No. 258, No. 259, No. 260, No. 261, No. 262, No. 263, No. 264, No. 265, No. 266, No. 267, No. 271, No. 272, No. 274, No. 275 and No. 276.

[0651] In some embodiments, the compound is selected from Compound No. 1, No. 3, No. 4, No. 6, No. 7, No. 9, No. 10, No. 14, No. 16, No. 17, No. 18, No. 19, No. 20, No. 24, No. 27, No. 29, No. 32, No. 33, No. 49, No. 52, No. 55, No. 57, No. 60, No. 79, No. 154, No. 193, No. 200, No. 203, No. 204, No. 261, No. 263, No. 265, No. 267, No. 274 and No. 276, and pharmaceutically acceptable salts and stereoisomers thereof.

[0652] In some embodiments, the compound is selected from Compound No. 1, No. 3, No. 4, No. 6, No. 7, No. 9, No. 10, No. 14, No. 16, No. 17, No. 18, No. 19, No. 20, No. 24, No. 27, No. 29, No. 32, No. 33, No. 49, No. 52, No. 55, No. 57, No. 60, No. 79, No. 154, No. 193, No. 200, No. 203, No. 204, No. 261, No. 263, No. 265, No. 267, No. 274 and No. 276, and pharmaceutically acceptable salts thereof.

[0653] In some embodiments, the compound is selected from Compound No. 1, No. 3, No. 4, No. 6, No. 7, No. 9, No. 10, No. 14, No. 16, No. 17, No. 18, No. 19, No. 20, No. 24, No. 27, No. 29, No. 32, No. 33, No. 49, No. 52, No. 55, No. 57, No. 60, No. 79, No. 154, No. 193, No. 200, No. 203, No. 204, No. 261, No. 263, No. 265, No. 267, No. 274 and No. 276.

[0654] In some embodiments, the compound is Compound No. 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0655] In some embodiments, the compound is Compound No. 1 or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments, the compound is Compound No. 1.

[0657] In some embodiments, the compound is Compound No. 2 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0658] In some embodiments, the compound is Compound No. 2 or a pharmaceutically acceptable salt thereof.

[0659] In some embodiments, the compound is Compound No. 2.

[0660] In some embodiments, the compound is Compound No. 3 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0661] In some embodiments, the compound is Compound No. 3 or a pharmaceutically acceptable salt thereof.

[0662] In some embodiments, the compound is Compound No. 3.

[0663] In some embodiments, the compound is Compound No. 4 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0664] In some embodiments, the compound is Compound No. 4 or a pharmaceutically acceptable salt thereof.

[0665] In some embodiments, the compound is Compound No. 4.

[0666] In some embodiments, the compound is Compound No. 5 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0667] In some embodiments, the compound is Compound No. 5 or a pharmaceutically acceptable salt thereof.

[0668] In some embodiments, the compound is Compound No. 5.

[0669] In some embodiments, the compound is Compound No. 6 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0670] In some embodiments, the compound is Compound No. 6 or a pharmaceutically acceptable salt thereof.

[0671] In some embodiments, the compound is Compound No. 6.

[0672] In some embodiments, the compound is Compound No. 7 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0673] In some embodiments, the compound is Compound No. 7 or a pharmaceutically acceptable salt thereof.

[0674] In some embodiments, the compound is Compound No. 7.

[0675] In some embodiments, the compound is Compound No. 8 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0676] In some embodiments, the compound is Compound No. 8 or a pharmaceutically acceptable salt thereof.

[0677] In some embodiments, the compound is Compound No. 8.

[0678] In some embodiments, the compound is Compound No. 9 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0679] In some embodiments, the compound is Compound No. 9 or a pharmaceutically acceptable salt thereof.

[0680] In some embodiments, the compound is Compound No. 9.

[0681] In some embodiments, the compound is Compound No. 10 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0682] In some embodiments, the compound is Compound No. 10 or a pharmaceutically acceptable salt thereof.

[0683] In some embodiments, the compound is Compound No. 10.

[0684] In some embodiments, the compound is Compound No. 11 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0685] In some embodiments, the compound is Compound No. 11 or a pharmaceutically acceptable salt thereof.

[0686] In some embodiments, the compound is Compound No. 11.

[0687] In some embodiments, the compound is Compound No. 12 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0688] In some embodiments, the compound is Compound No. 12 or a pharmaceutically acceptable salt thereof.

[0689] In some embodiments, the compound is Compound No. 12.

[0690] In some embodiments, the compound is Compound No. 14 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0691] In some embodiments, the compound is Compound No. 14 or a pharmaceutically acceptable salt thereof.

[0692] In some embodiments, the compound is Compound No. 14.

[0693] In some embodiments, the compound is Compound No. 15 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0694] In some embodiments, the compound is Compound No. 15 or a pharmaceutically acceptable salt thereof.

[0695] In some embodiments, the compound is Compound No. 15.

[0696] In some embodiments, the compound is Compound No. 16 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0697] In some embodiments, the compound is Compound No. 16 or a pharmaceutically acceptable salt thereof.

[0698] In some embodiments, the compound is Compound No. 16.

[0699] In some embodiments, the compound is Compound No. 17 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0700] In some embodiments, the compound is Compound No. 17 or a pharmaceutically acceptable salt thereof.

[0701] In some embodiments, the compound is Compound No. 17.

[0702] In some embodiments, the compound is Compound No. 18 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0703] In some embodiments, the compound is Compound No. 18 or a pharmaceutically acceptable salt thereof.

[0704] In some embodiments, the compound is Compound No. 18.

[0705] In some embodiments, the compound is Compound No. 19 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0706] In some embodiments, the compound is Compound No. 19 or a pharmaceutically acceptable salt thereof.

[0707] In some embodiments, the compound is Compound No. 19.

[0708] In some embodiments, the compound is Compound No. 20 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0709] In some embodiments, the compound is Compound No. 20 or a pharmaceutically acceptable salt thereof.

[0710] In some embodiments, the compound is Compound No. 20.

[0711] In some embodiments, the compound is Compound No. 21 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0712] In some embodiments, the compound is Compound No. 21 or a pharmaceutically acceptable salt thereof.

[0713] In some embodiments, the compound is Compound No. 21.

[0714] In some embodiments, the compound is Compound No. 22 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0715] In some embodiments, the compound is Compound No. 22 or a pharmaceutically acceptable salt thereof.

[0716] In some embodiments, the compound is Compound No. 22.

[0717] In some embodiments, the compound is Compound No. 23 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0718] In some embodiments, the compound is Compound No. 23 or a pharmaceutically acceptable salt thereof.

[0719] In some embodiments, the compound is Compound No. 23.

[0720] In some embodiments, the compound is Compound No. 24 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0721] In some embodiments, the compound is Compound No. 24 or a pharmaceutically acceptable salt thereof.

[0722] In some embodiments, the compound is Compound No. 24.

[0723] In some embodiments, the compound is Compound No. 25 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0724] In some embodiments, the compound is Compound No. 25 or a pharmaceutically acceptable salt thereof.

[0725] In some embodiments, the compound is Compound No. 25.

[0726] In some embodiments, the compound is Compound No. 26 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0727] In some embodiments, the compound is Compound No. 26 or a pharmaceutically acceptable salt thereof.

[0728] In some embodiments, the compound is Compound No. 26.

[0729] In some embodiments, the compound is Compound No. 27 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0730] In some embodiments, the compound is Compound No. 27 or a pharmaceutically acceptable salt thereof.

[0731] In some embodiments, the compound is Compound No. 27.

[0732] In some embodiments, the compound is Compound No. 29 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0733] In some embodiments, the compound is Compound No. 29 or a pharmaceutically acceptable salt thereof.

[0734] In some embodiments, the compound is Compound No. 29.

[0735] In some embodiments, the compound is Compound No. 30 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0736] In some embodiments, the compound is Compound No. 30 or a pharmaceutically acceptable salt thereof.

[0737] In some embodiments, the compound is Compound No. 30.

[0738] In some embodiments, the compound is Compound No. 31 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0739] In some embodiments, the compound is Compound No. 31 or a pharmaceutically acceptable salt thereof.

[0740] In some embodiments, the compound is Compound No. 31.

[0741] In some embodiments, the compound is Compound No. 32 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0742] In some embodiments, the compound is Compound No. 32 or a pharmaceutically acceptable salt thereof.

[0743] In some embodiments, the compound is Compound No. 32.

[0744] In some embodiments, the compound is Compound No. 33 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0745] In some embodiments, the compound is Compound No. 33 or a pharmaceutically acceptable salt thereof.

[0746] In some embodiments, the compound is Compound No. 33.

[0747] In some embodiments, the compound is Compound No. 34 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0748] In some embodiments, the compound is Compound No. 34 or a pharmaceutically acceptable salt thereof.

[0749] In some embodiments, the compound is Compound No. 34.

[0750] In some embodiments, the compound is Compound No. 35 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0751] In some embodiments, the compound is Compound No. 35 or a pharmaceutically acceptable salt thereof.

[0752] In some embodiments, the compound is Compound No. 35.

[0753] In some embodiments, the compound is Compound No. 37 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0754] In some embodiments, the compound is Compound No. 37 or a pharmaceutically acceptable salt thereof.

[0755] In some embodiments, the compound is Compound No. 37.

[0756] In some embodiments, the compound is Compound No. 38 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0757] In some embodiments, the compound is Compound No. 38 or a pharmaceutically acceptable salt thereof.

[0758] In some embodiments, the compound is Compound No. 38.

[0759] In some embodiments, the compound is Compound No. 39 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0760] In some embodiments, the compound is Compound No. 39 or a pharmaceutically acceptable salt thereof.

[0761] In some embodiments, the compound is Compound No. 39.

[0762] In some embodiments, the compound is Compound No. 40 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0763] In some embodiments, the compound is Compound No. 40 or a pharmaceutically acceptable salt thereof.

[0764] In some embodiments, the compound is Compound No. 40.

[0765] In some embodiments, the compound is Compound No. 41 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0766] In some embodiments, the compound is Compound No. 41 or a pharmaceutically acceptable salt thereof.

[0767] In some embodiments, the compound is Compound No. 41.

[0768] In some embodiments, the compound is Compound No. 42 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0769] In some embodiments, the compound is Compound No. 42 or a pharmaceutically acceptable salt thereof.

[0770] In some embodiments, the compound is Compound No. 42.

[0771] In some embodiments, the compound is Compound No. 43 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0772] In some embodiments, the compound is Compound No. 43 or a pharmaceutically acceptable salt thereof.

[0773] In some embodiments, the compound is Compound No. 43.

[0774] In some embodiments, the compound is Compound No. 44 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0775] In some embodiments, the compound is Compound No. 44 or a pharmaceutically acceptable salt thereof.

[0776] In some embodiments, the compound is Compound No. 44.

[0777] In some embodiments, the compound is Compound No. 49 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0778] In some embodiments, the compound is Compound No. 49 or a pharmaceutically acceptable salt thereof.

[0779] In some embodiments, the compound is Compound No. 49.

[0780] In some embodiments, the compound is Compound No. 52 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0781] In some embodiments, the compound is Compound No. 52 or a pharmaceutically acceptable salt thereof.

[0782] In some embodiments, the compound is Compound No. 52.

[0783] In some embodiments, the compound is Compound No. 53 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0784] In some embodiments, the compound is Compound No. 53 or a pharmaceutically acceptable salt thereof.

[0785] In some embodiments, the compound is Compound No. 53.

[0786] In some embodiments, the compound is Compound No. 55 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0787] In some embodiments, the compound is Compound No. 55 or a pharmaceutically acceptable salt thereof.

[0788] In some embodiments, the compound is Compound No. 55.

[0789] In some embodiments, the compound is Compound No. 56 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0790] In some embodiments, the compound is Compound No. 56 or a pharmaceutically acceptable salt thereof.

[0791] In some embodiments, the compound is Compound No. 56.

[0792] In some embodiments, the compound is Compound No. 57 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0793] In some embodiments, the compound is Compound No. 57 or a pharmaceutically acceptable salt thereof.

[0794] In some embodiments, the compound is Compound No. 57.

[0795] In some embodiments, the compound is Compound No. 58 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0796] In some embodiments, the compound is Compound No. 58 or a pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the compound is Compound No. 58.

[0798] In some embodiments, the compound is Compound No. 59 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0799] In some embodiments, the compound is Compound No. 59 or a pharmaceutically acceptable salt thereof.

[0800] In some embodiments, the compound is Compound No. 59.

[0801] In some embodiments, the compound is Compound No. 60 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0802] In some embodiments, the compound is Compound No. 60 or a pharmaceutically acceptable salt thereof.

[0803] In some embodiments, the compound is Compound No. 60.

[0804] In some embodiments, the compound is Compound No. 62 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0805] In some embodiments, the compound is Compound No. 62 or a pharmaceutically acceptable salt thereof.

[0806] In some embodiments, the compound is Compound No. 62.

[0807] In some embodiments, the compound is Compound No. 63 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0808] In some embodiments, the compound is Compound No. 63 or a pharmaceutically acceptable salt thereof.

[0809] In some embodiments, the compound is Compound No. 63.

[0810] In some embodiments, the compound is Compound No. 65 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0811] In some embodiments, the compound is Compound No. 65 or a pharmaceutically acceptable salt thereof.

[0812] In some embodiments, the compound is Compound No. 65.

[0813] In some embodiments, the compound is Compound No. 66 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0814] In some embodiments, the compound is Compound No. 66 or a pharmaceutically acceptable salt thereof.

[0815] In some embodiments, the compound is Compound No. 66.

[0816] In some embodiments, the compound is Compound No. 68 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0817] In some embodiments, the compound is Compound No. 68 or a pharmaceutically acceptable salt thereof.

[0818] In some embodiments, the compound is Compound No. 68.

[0819] In some embodiments, the compound is Compound No. 71 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0820] In some embodiments, the compound is Compound No. 71 or a pharmaceutically acceptable salt thereof.

[0821] In some embodiments, the compound is Compound No. 71.

[0822] In some embodiments, the compound is Compound No. 75 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0823] In some embodiments, the compound is Compound No. 75 or a pharmaceutically acceptable salt thereof.

[0824] In some embodiments, the compound is Compound No. 75.

[0825] In some embodiments, the compound is Compound No. 77 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0826] In some embodiments, the compound is Compound No. 77 or a pharmaceutically acceptable salt thereof.

[0827] In some embodiments, the compound is Compound No. 77.

[0828] In some embodiments, the compound is Compound No. 78 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0829] In some embodiments, the compound is Compound No. 78 or a pharmaceutically acceptable salt thereof.

[0830] In some embodiments, the compound is Compound No. 78.

[0831] In some embodiments, the compound is Compound No. 79 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0832] In some embodiments, the compound is Compound No. 79 or a pharmaceutically acceptable salt thereof.

[0833] In some embodiments, the compound is Compound No. 79.

[0834] In some embodiments, the compound is Compound No. 153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0835] In some embodiments, the compound is Compound No. 153 or a pharmaceutically acceptable salt thereof.

[0836] In some embodiments, the compound is Compound No. 153.

[0837] In some embodiments, the compound is Compound No. 154 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0838] In some embodiments, the compound is Compound No. 154 or a pharmaceutically acceptable salt thereof.

[0839] In some embodiments, the compound is Compound No. 154.

[0840] In some embodiments, the compound is Compound No. 173 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0841] In some embodiments, the compound is Compound No. 173 or a pharmaceutically acceptable salt thereof.

[0842] In some embodiments, the compound is Compound No. 173.

[0843] In some embodiments, the compound is Compound No. 174 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0844] In some embodiments, the compound is Compound No. 174 or a pharmaceutically acceptable salt thereof.

[0845] In some embodiments, the compound is Compound No. 174.

[0846] In some embodiments, the compound is Compound No. 175 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0847] In some embodiments, the compound is Compound No. 175 or a pharmaceutically acceptable salt thereof.

[0848] In some embodiments, the compound is Compound No. 175.

[0849] In some embodiments, the compound is Compound No. 176 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0850] In some embodiments, the compound is Compound No. 176 or a pharmaceutically acceptable salt thereof.

[0851] In some embodiments, the compound is Compound No. 176.

[0852] In some embodiments, the compound is Compound No. 191 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0853] In some embodiments, the compound is Compound No. 191 or a pharmaceutically acceptable salt thereof.

[0854] In some embodiments, the compound is Compound No. 191.

[0855] In some embodiments, the compound is Compound No. 193 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0856] In some embodiments, the compound is Compound No. 193 or a pharmaceutically acceptable salt thereof.

[0857] In some embodiments, the compound is Compound No. 193.

[0858] In some embodiments, the compound is Compound No. 194 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0859] In some embodiments, the compound is Compound No. 194 or a pharmaceutically acceptable salt thereof.

[0860] In some embodiments, the compound is Compound No. 194.

[0861] In some embodiments, the compound is Compound No. 200 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0862] In some embodiments, the compound is Compound No. 200 or a pharmaceutically acceptable salt thereof.

[0863] In some embodiments, the compound is Compound No. 200.

[0864] In some embodiments, the compound is Compound No. 201 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0865] In some embodiments, the compound is Compound No. 201 or a pharmaceutically acceptable salt thereof.

[0866] In some embodiments, the compound is Compound No. 201.

[0867] In some embodiments, the compound is Compound No. 202 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0868] In some embodiments, the compound is Compound No. 202 or a pharmaceutically acceptable salt thereof.

[0869] In some embodiments, the compound is Compound No. 202.

[0870] In some embodiments, the compound is Compound No. 203 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0871] In some embodiments, the compound is Compound No. 203 or a pharmaceutically acceptable salt thereof.

[0872] In some embodiments, the compound is Compound No. 203.

[0873] In some embodiments, the compound is Compound No. 204 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0874] In some embodiments, the compound is Compound No. 204 or a pharmaceutically acceptable salt thereof.

[0875] In some embodiments, the compound is Compound No. 204.

[0876] In some embodiments, the compound is Compound No. 206 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0877] In some embodiments, the compound is Compound No. 206 or a pharmaceutically acceptable salt thereof.

[0878] In some embodiments, the compound is Compound No. 206.

[0879] In some embodiments, the compound is Compound No. 214 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0880] In some embodiments, the compound is Compound No. 214 or a pharmaceutically acceptable salt thereof.

[0881] In some embodiments, the compound is Compound No. 214.

[0882] In some embodiments, the compound is Compound No. 215 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0883] In some embodiments, the compound is Compound No. 215 or a pharmaceutically acceptable salt thereof.

[0884] In some embodiments, the compound is Compound No. 215.

[0885] In some embodiments, the compound is Compound No. 217 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0886] In some embodiments, the compound is Compound No. 217 or a pharmaceutically acceptable salt thereof.

[0887] In some embodiments, the compound is Compound No. 217.

[0888] In some embodiments, the compound is Compound No. 218 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0889] In some embodiments, the compound is Compound No. 218 or a pharmaceutically acceptable salt thereof.

[0890] In some embodiments, the compound is Compound No. 218.

[0891] In some embodiments, the compound is Compound No. 220 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0892] In some embodiments, the compound is Compound No. 220 or a pharmaceutically acceptable salt thereof.

[0893] In some embodiments, the compound is Compound No. 220.

[0894] In some embodiments, the compound is Compound No. 221 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0895] In some embodiments, the compound is Compound No. 221 or a pharmaceutically acceptable salt thereof.

[0896] In some embodiments, the compound is Compound No. 221.

[0897] In some embodiments, the compound is Compound No. 222 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0898] In some embodiments, the compound is Compound No. 222 or a pharmaceutically acceptable salt thereof.

[0899] In some embodiments, the compound is Compound No. 222.

[0900] In some embodiments, the compound is Compound No. 223 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0901] In some embodiments, the compound is Compound No. 223 or a pharmaceutically acceptable salt thereof.

[0902] In some embodiments, the compound is Compound No. 223.

[0903] In some embodiments, the compound is Compound No. 225 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0904] In some embodiments, the compound is Compound No. 225 or a pharmaceutically acceptable salt thereof.

[0905] In some embodiments, the compound is Compound No. 225.

[0906] In some embodiments, the compound is Compound No. 226 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0907] In some embodiments, the compound is Compound No. 226 or a pharmaceutically acceptable salt thereof.

[0908] In some embodiments, the compound is Compound No. 226.

[0909] In some embodiments, the compound is Compound No. 227 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0910] In some embodiments, the compound is Compound No. 227 or a pharmaceutically acceptable salt thereof.

[0911] In some embodiments, the compound is Compound No. 227.

[0912] In some embodiments, the compound is Compound No. 229 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0913] In some embodiments, the compound is Compound No. 229 or a pharmaceutically acceptable salt thereof.

[0914] In some embodiments, the compound is Compound No. 229.

[0915] In some embodiments, the compound is Compound No. 230 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0916] In some embodiments, the compound is Compound No. 230 or a pharmaceutically acceptable salt thereof.

[0917] In some embodiments, the compound is Compound No. 230.

[0918] In some embodiments, the compound is Compound No. 231 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0919] In some embodiments, the compound is Compound No. 231 or a pharmaceutically acceptable salt thereof.

[0920] In some embodiments, the compound is Compound No. 231.

[0921] In some embodiments, the compound is Compound No. 233 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0922] In some embodiments, the compound is Compound No. 233 or a pharmaceutically acceptable salt thereof.

[0923] In some embodiments, the compound is Compound No. 233.

[0924] In some embodiments, the compound is Compound No. 234 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0925] In some embodiments, the compound is Compound No. 234 or a pharmaceutically acceptable salt thereof.

[0926] In some embodiments, the compound is Compound No. 234.

[0927] In some embodiments, the compound is Compound No. 235 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0928] In some embodiments, the compound is Compound No. 235 or a pharmaceutically acceptable salt thereof.

[0929] In some embodiments, the compound is Compound No. 235.

[0930] In some embodiments, the compound is Compound No. 236 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0931] In some embodiments, the compound is Compound No. 236 or a pharmaceutically acceptable salt thereof.

[0932] In some embodiments, the compound is Compound No. 236.

[0933] In some embodiments, the compound is Compound No. 237 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0934] In some embodiments, the compound is Compound No. 237 or a pharmaceutically acceptable salt thereof.

[0935] In some embodiments, the compound is Compound No. 237.

[0936] In some embodiments, the compound is Compound No. 238 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0937] In some embodiments, the compound is Compound No. 238 or a pharmaceutically acceptable salt thereof.

[0938] In some embodiments, the compound is Compound No. 238.

[0939] In some embodiments, the compound is Compound No. 242 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0940] In some embodiments, the compound is Compound No. 242 or a pharmaceutically acceptable salt thereof.

[0941] In some embodiments, the compound is Compound No. 242.

[0942] In some embodiments, the compound is Compound No. 243 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0943] In some embodiments, the compound is Compound No. 243 or a pharmaceutically acceptable salt thereof.

[0944] In some embodiments, the compound is Compound No. 243.

[0945] In some embodiments, the compound is Compound No. 245 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0946] In some embodiments, the compound is Compound No. 245 or a pharmaceutically acceptable salt thereof.

[0947] In some embodiments, the compound is Compound No. 245.

[0948] In some embodiments, the compound is Compound No. 247 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0949] In some embodiments, the compound is Compound No. 247 or a pharmaceutically acceptable salt thereof.

[0950] In some embodiments, the compound is Compound No. 247.

[0951] In some embodiments, the compound is Compound No. 248 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0952] In some embodiments, the compound is Compound No. 248 or a pharmaceutically acceptable salt thereof.

[0953] In some embodiments, the compound is Compound No. 248.

[0954] In some embodiments, the compound is Compound No. 249 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0955] In some embodiments, the compound is Compound No. 249 or a pharmaceutically acceptable salt thereof.

[0956] In some embodiments, the compound is Compound No. 249.

[0957] In some embodiments, the compound is Compound No. 252 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0958] In some embodiments, the compound is Compound No. 252 or a pharmaceutically acceptable salt thereof.

[0959] In some embodiments, the compound is Compound No. 252.

[0960] In some embodiments, the compound is Compound No. 253 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0961] In some embodiments, the compound is Compound No. 253 or a pharmaceutically acceptable salt thereof.

[0962] In some embodiments, the compound is Compound No. 253.

[0963] In some embodiments, the compound is Compound No. 255 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0964] In some embodiments, the compound is Compound No. 255 or a pharmaceutically acceptable salt thereof.

[0965] In some embodiments, the compound is Compound No. 255.

[0966] In some embodiments, the compound is Compound No. 256 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0967] In some embodiments, the compound is Compound No. 256 or a pharmaceutically acceptable salt thereof.

[0968] In some embodiments, the compound is Compound No. 256.

[0969] In some embodiments, the compound is Compound No. 257 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0970] In some embodiments, the compound is Compound No. 257 or a pharmaceutically acceptable salt thereof.

[0971] In some embodiments, the compound is Compound No. 257.

[0972] In some embodiments, the compound is Compound No. 258 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0973] In some embodiments, the compound is Compound No. 258 or a pharmaceutically acceptable salt thereof.

[0974] In some embodiments, the compound is Compound No. 258.

[0975] In some embodiments, the compound is Compound No. 259 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0976] In some embodiments, the compound is Compound No. 259 or a pharmaceutically acceptable salt thereof.

[0977] In some embodiments, the compound is Compound No. 259.

[0978] In some embodiments, the compound is Compound No. 260 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0979] In some embodiments, the compound is Compound No. 260 or a pharmaceutically acceptable salt thereof.

[0980] In some embodiments, the compound is Compound No. 260.

[0981] In some embodiments, the compound is Compound No. 261 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0982] In some embodiments, the compound is Compound No. 261 or a pharmaceutically acceptable salt thereof.

[0983] In some embodiments, the compound is Compound No. 261.

[0984] In some embodiments, the compound is Compound No. 262 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0985] In some embodiments, the compound is Compound No. 262 or a pharmaceutically acceptable salt thereof.

[0986] In some embodiments, the compound is Compound No. 262.

[0987] In some embodiments, the compound is Compound No. 263 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0988] In some embodiments, the compound is Compound No. 263 or a pharmaceutically acceptable salt thereof.

[0989] In some embodiments, the compound is Compound No. 263.

[0990] In some embodiments, the compound is Compound No. 264 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0991] In some embodiments, the compound is Compound No. 264 or a pharmaceutically acceptable salt thereof.

[0992] In some embodiments, the compound is Compound No. 264.

[0993] In some embodiments, the compound is Compound No. 265 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0994] In some embodiments, the compound is Compound No. 265 or a pharmaceutically acceptable salt thereof.

[0995] In some embodiments, the compound is Compound No. 265.

[0996] In some embodiments, the compound is Compound No. 266 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0997] In some embodiments, the compound is Compound No. 266 or a pharmaceutically acceptable salt thereof.

[0998] In some embodiments, the compound is Compound No. 266.

[0999] In some embodiments, the compound is Compound No. 267 or a pharmaceutically acceptable salt or stereoisomer thereof.

[1000] In some embodiments, the compound is Compound No. 267 or a pharmaceutically acceptable salt thereof.

[1001] In some embodiments, the compound is Compound No. 267.

[1002] In some embodiments, the compound is Compound No. 271 or a pharmaceutically acceptable salt or stereoisomer thereof.

[1003] In some embodiments, the compound is Compound No. 271 or a pharmaceutically acceptable salt thereof.

[1004] In some embodiments, the compound is Compound No. 271.

[1005] In some embodiments, the compound is Compound No. 272 or a pharmaceutically acceptable salt or stereoisomer thereof.

[1006] In some embodiments, the compound is Compound No. 272 or a pharmaceutically acceptable salt thereof.

[1007] In some embodiments, the compound is Compound No. 272.

[1008] In some embodiments, the compound is Compound No. 274 or a pharmaceutically acceptable salt or stereoisomer thereof.

[1009] In some embodiments, the compound is Compound No. 274 or a pharmaceutically acceptable salt thereof.

[1010] In some embodiments, the compound is Compound No. 274.

[1011] In some embodiments, the compound is Compound No. 275 or a pharmaceutically acceptable salt or stereoisomer thereof.

[1012] In some embodiments, the compound is Compound No. 275 or a pharmaceutically acceptable salt thereof.

[1013] In some embodiments, the compound is Compound No. 275.

[1014] In some embodiments, the compound is Compound No. 276 or a pharmaceutically acceptable salt or stereoisomer thereof.

[1015] In some embodiments, the compound is Compound No. 276 or a pharmaceutically acceptable salt thereof.

[1016] In some embodiments, the compound is Compound No. 276.

[1017] Compounds of the present disclosure containing one or more of the above deuterium atoms or pharmaceutically acceptable salts thereof are within the scope of the present disclosure. Further, substitution with deuterium (i.e., 2 H) can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[1018] To avoid doubt, it should be understood that in this specification, if a group is defined by "described herein", the group encompasses the earliest and broadest definition as well as each and all specific definitions of the group.

[1019] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure having sufficient basicity, such as, for example, acid addition salts with inorganic acids or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonate of citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present disclosure having sufficient acidity are: alkali metal salts, such as sodium salts or potassium salts; alkaline earth metal salts, such as calcium salts or magnesium salts, ammonium salts or salts with organic bases providing pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[1020] It should be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof include stereoisomers of the compounds, mixtures of stereoisomers, and polymorphs of all isomeric forms.

[1021] As used herein, the term "isomer" means a compound having the same molecular formula but different orders of bonding of its atoms or different spatial arrangements of its atoms. Isomers having different spatial arrangements of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes "optical isomers". A mixture containing equal amounts of the individual enantiomeric forms having opposite chirality is called a "racemic mixture".

[1022] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[1023] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers (referred to as a "mixture of diastereomers"). When there is one chiral center, the stereoisomers can be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the "Sequence Rule" of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Erratum 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).

[1024] As used herein, the term "geometric isomer" means a diastereomer that exists due to restricted rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[1025] It should be understood that the compounds of the present disclosure may be described as different chiral or geometric isomers. It should also be understood that when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form. It should be understood that not all isomers may have the same level of activity.

[1026] It should be understood that the structures and other compounds discussed in the present disclosure include all of their atropisomers. It should also be understood that not all atropisomers may have the same level of activity.

[1027] As used herein, the term "atropisomer" is a class of stereoisomers in which the atoms of two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by the hindered rotation of large groups around a central bond. Such atropisomers usually exist as a mixture. However, due to recent advances in chromatographic techniques, it has become possible to separate mixtures of two atropisomers in selected cases.

[1028] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the conversion of an adjacent conjugated double bond. Tautomers exist as a mixture of a tautomeric group in solution. In a solution where tautomerization can occur, the tautomers will reach chemical equilibrium. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that interconvert by tautomerization is called tautomerism. Among the various possible types of tautomerism, two types of tautomerism are usually observed. In keto-enol tautomerism, simultaneous transfer of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs because the aldehyde group (-CHO) in a sugar chain molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic (ring-shaped) form as exhibited by glucose.

[1029] It should be understood that the compounds of the present disclosure may be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It can be understood that the activity level of some tautomers may be higher than that of other tautomers.

[1030] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R and S sequence rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., designated as the (+) isomer or the (-) isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[1031] The compounds of the present disclosure can have one or more asymmetric centers; thus, such compounds can be produced as individual (R) stereoisomers or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th Edition, J. March, John Wiley and Sons, New York, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of the racemic form. Some of the compounds of the present disclosure can have geometric isomeric centers (E isomers and Z isomers). It should be understood that the present disclosure encompasses all optically diastereoisomers and geometric isomers having antitumor activity and mixtures thereof.

[1032] The present disclosure also encompasses compounds of the present disclosure containing one or more isotope substitutions as defined herein.

[1033] It should be understood that, where applicable, compounds having any of the formulas described herein include the compounds themselves, as well as their salts and solvates. For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[1034] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include salts containing a tetravalent nitrogen atom.

[1035] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[1036] As used herein, the term "solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by combining one or more water molecules with one molecule of a substance in which water retains its molecular state as H2O.

[1037] As used herein, the term "analogue" refers to a compound that is structurally similar to another compound but slightly different in composition (such as an atom being replaced by an atom with a different element, or the presence of a specific functional group, or one functional group being replaced by another functional group). Thus, an analogue is a compound that is similar or equivalent to a reference compound in function and appearance, but different from the reference compound in structure or origin.

[1038] As used herein, the term "derivative" refers to a compound having a common core structure and substituted with various groups as described herein.

[1039] As used herein, the term "bioisostere" refers to a compound produced by the exchange of an atom or group of atoms with another, generally similar atom or group of atoms. The purpose of bioisosteric replacement is to produce a new compound with biological properties similar to those of the parent compound. Bioisosteric replacements can be physicochemical or topological. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev., 96, 3147-3176, 1996.

[1040] It should also be understood that certain compounds of the present disclosure may exist in solvated forms as well as unsolvated forms (such as hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It is understood that the present disclosure encompasses all such solvated forms having anti-tumor activity.

[1041] It should also be understood that certain compounds of the present disclosure may exhibit polymorphism, and the present disclosure encompasses all such forms having anti-tumor activity or mixtures thereof. It is well known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[1042] The compounds of the present disclosure can exist in many different tautomeric forms, and reference to a compound of the present disclosure includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one tautomeric form is specifically described or shown, all other tautomeric forms are still included by the disclosed formula. Examples of tautomeric forms include keto forms, enol forms, and enolate forms, such as in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidoxime, nitroso / oxime, thione / enethiol, and nitro / aci-nitro.

[1043]

[1044] The compounds of the present disclosure containing an amine functional group can also form N-oxides. As used herein, the compounds containing an amine functional group disclosed herein also include N-oxides. In the case where a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of the nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., performic acid), see, for example, Jerry March's "Advanced Organic Chemistry", 4th Edition, Wiley Interscience, page. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with meta-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[1045] The compounds of the present disclosure can be administered in the form of prodrugs, which decompose in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain a suitable group or substituent to which a characteristic modifying group can be attached. Examples of prodrugs include derivatives containing an in vivo cleavable alkyl or acyl substituent at the sulfonylurea group in the compounds of any of the formulas disclosed herein.

[1046] Accordingly, when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of its prodrug, the present disclosure includes those compounds of the present disclosure as defined above. Thus, the present disclosure includes those compounds of the present disclosure produced by organic synthesis means and also encompasses such compounds produced in the human or animal body by metabolism of a precursor compound, that is, the compounds of the present disclosure can be synthetically produced compounds or metabolically produced compounds.

[1047] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure are prodrugs that are suitable for administration to a human or animal body based on reasonable medical judgment, without undesirable pharmacological activity and without excessive toxicity. Various forms of prodrugs have been described, for example, in the following documents: a) "Methods in Enzymology", Volume 42, pages 309 - 396 (Academic Press, 1985), edited by K. Widder et al.; b) "Design of Pro-drugs" (Elsevier, 1985), edited by H. Bundgaard; c) "A Textbook of Drug Design and Development", Chapter 5, "Design and Application of Pro-drugs" by H. Bundgaard, pages 113 - 191 (1991), edited by Krogsgaard-Larsen and H. Bundgaard; d) H. Bundgaard, "Advanced Drug Delivery Reviews", 8, 1 - 38 (1992); e) H. Bundgaard et al., "Journal of Pharmaceutical Sciences", 77, 285 (1988); f) N. Kakeya et al., "Chem. Pharm. Bull.", 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design" (Pergamon Press, 1987).

[1048] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a hydroxyl group are, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of the compounds of the present disclosure containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in a human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including cyclic amino phosphate esters). Other suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include: C1 - C 10Alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; C1-C 10 Alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[1049] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a carboxyl group are, for example, amides cleavable in vivo, for example with amines such as: ammonia; C 1-4 Alkylamines such as methylamine; (C1-C4 alkyl)2 amines such as dimethylamine; N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines such as benzylamine; and amino acids such as glycine or amides formed from their esters.

[1050] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having an amino group are, for example, amide derivatives cleavable in vivo. Suitable pharmaceutically acceptable amides from the amino group include, for example, amides formed with C1-C 10 Alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[1051] The in vivo effects of the compounds of the present disclosure can be exerted in part by one or more metabolites formed in a human or animal body after administration of the compounds of the present disclosure. As described above, the in vivo effects of the compounds of the present disclosure can also be exerted through the metabolism of precursor compounds (prodrugs).

[1052] Synthetic methods

[1053] In some aspects, the present disclosure provides a method for preparing the compounds disclosed herein.

[1054] In some aspects, the present disclosure provides a method for preparing a compound, the method comprising one or more steps as described herein.

[1055] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by the method for preparing the compounds described herein.

[1056] In some aspects, the present disclosure provides an intermediate suitable for a method of preparing the compounds described herein.

[1057] The compounds of the present disclosure can be prepared by any suitable techniques known in the art. The specific processes for preparing these compounds are further described in the appended examples.

[1058] In the description of the synthetic methods described herein and any reference synthetic methods for preparing starting materials, it should be understood that all proposed reaction conditions can be selected by those skilled in the art, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and handling procedures.

[1059] Those skilled in the art of organic synthesis should understand that the functional groups present on the various parts of the molecule must be compatible with the reagents and reaction conditions used.

[1060] It should be understood that during the synthesis of the compounds of the present disclosure in the methods defined herein or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent their unwanted reactions. Skilled chemists will know when such protection is needed and how such protecting groups can be placed in place and subsequently removed. For examples of protecting groups, see one of the many general textbooks on the subject, e.g., ‘Protective Groups in Organic Synthesis’ by Theodora Green (Publisher: John Wiley & Sons). The protecting groups can be removed as needed by any convenient method described in the literature or known to the skilled chemist for removing the protecting groups under discussion, selecting such methods to effect removal of the protecting group with minimal interference to groups elsewhere in the molecule. Thus, for example, if the reactants include groups such as amino, carboxyl, or hydroxyl groups, then it may be necessary to protect such groups in some of the reactions mentioned herein.

[1061] As an example, suitable protecting groups for amino or alkylamino are, for example, acyl groups; for example, alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups must vary with the choice of the protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl or aroyl can be removed by hydrolysis, for example, with a suitable base such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl can be removed by hydrogenation, for example, over a catalyst such as palladium / carbon or by treatment with a Lewis acid such as borane tris(trifluoroacetate). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or with hydrazine.

[1062] Suitable protecting groups for hydroxy are, for example, acyl groups, such as alkanoyl groups like acetyl; aroyl groups, such as benzoyl; or arylmethyl groups, such as benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of the protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl can be removed by hydrolysis, for example, with a suitable base such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or ammonia. Alternatively, arylmethyl groups such as benzyl can be removed by hydrogenation, for example, over a catalyst such as palladium / carbon.

[1063] Suitable protecting groups for carboxy are, for example, esterifying groups, such as methyl or ethyl, which can be removed by hydrolysis, for example, with a base such as sodium hydroxide; or, for example, tert-butyl, which can be removed by treatment with an acid such as an organic acid like trifluoroacetic acid; or, for example, benzyl, which can be removed by hydrogenation, for example, over a catalyst such as palladium / carbon.

[1064] Once a compound of the present disclosure has been synthesized by any of the methods defined herein, the method can further comprise the following additional steps: (i) removing any existing protecting groups; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming its pharmaceutically acceptable salts, hydrates or solvates; and / or (iv) forming its prodrugs.

[1065] The resulting compounds of the present disclosure can be isolated and purified using techniques well known in the art.

[1066] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the corresponding reaction conditions. Examples of suitable solvents include, but are not limited to: hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; ethylene glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or methyl ethyl ketone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate; or mixtures of the solvents or mixtures with water.

[1067] Depending on the reaction step and the conditions used, the reaction temperature is suitably between about -100 °C and 300 °C.

[1068] The reaction time generally ranges from fractions of a minute to several days, depending on the reactivity of the corresponding compounds and the corresponding reaction conditions. The appropriate reaction time can be readily determined by methods known in the art (such as reaction monitoring). Based on the reaction temperature given above, the appropriate reaction time generally ranges between 10 minutes and 48 hours.

[1069] In addition, by using the procedures described herein, in combination with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and procedures of the following preparation procedures can be used to prepare these compounds.

[1070] As those skilled in the art of organic synthesis will understand, the compounds of the present disclosure can be readily obtained by various synthetic routes, some of which are shown in the accompanying examples. Those skilled in the art will readily recognize what types of reagents and reaction conditions should be used and, when necessary or applicable, how to apply and adapt them in any specific instance to obtain the compounds of the present disclosure. In addition, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by converting a specific functional group or its suitable precursor molecule present in the compounds of the present disclosure into another functional group via application of standard synthetic methods such as reduction, oxidation, addition, or substitution reactions; these methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or protective) groups when necessary or applicable; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, “Greene's Protective Groups in Organic Synthesis”, 4th Edition (2006) (John Wiley & Sons).

[1071] General routes for preparing the compounds of the present application are described in Schemes I-X.

[1072] Scheme I

[1073]

[1074] Scheme II

[1075]

[1076] Scheme III

[1077]

[1078] Scheme IV

[1079]

[1080] Scheme V

[1081]

[1082] Scheme VI

[1083]

[1084] Scheme VII

[1085]

[1086] Scheme VIII

[1087]

[1088] Scheme IX

[1089]

[1090] Scheme X

[1091]

[1092] Biological Assay

[1093] Once the compounds designed, selected, and / or optimized by the methods described above are generated, they can be characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether these molecules have predicted activity, binding activity, and / or binding specificity.

[1094] In addition, high-throughput screening can be used to accelerate the analysis using such assays. Thus, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

[1095] Various in vitro or in vivo biological assays can be adapted to detect the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays can include but not limited to enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[1096] In some embodiments, the biological assay can involve retrovirus production.

[1097] In some embodiments, a fusion mutant (e.g., BRAF-KIAA1549) can be subcloned into a retroviral expression vector (e.g., pMX-IRES-Blasticidin), wherein the retrovirus can be produced by transfecting cells (e.g., HEK 293T) with a retroviral plasmid (e.g., a retroviral BRAF mutant expression vector).

[1098] In some embodiments, cells (e.g., HEK 293T) can be plated and incubated. In some embodiments, a retroviral plasmid (e.g., BRAF-KIAA fusion mutant) can be added to a transfection reagent and then added to cells (e.g., HEK 293T), where the cells can be harvested.

[1099] In some embodiments, a bioassay can involve generating a fusion-stable cell line (e.g., BRAF-KIAA1549 fusion-stable cell line).

[1100] In some embodiments, cells (e.g., BaF3) can be transduced with a viral supernatant (e.g., BRAF-KIAA1549 fusion viral supernatant), and the cells can be sampled (e.g., by a luminescent cell viability assay such as CellTiterGlo) for viability. In some embodiments, the fusion-stable cell line can undergo cell banking and sequence confirmation (e.g., Sanger sequencing).

[1101] In some embodiments, the bioassay is for cell proliferation.

[1102] In some embodiments, cells (e.g., BaF3 BRAF-KIAA1549 fusion cells) are suspended and distributed in plates. In some embodiments, to determine the effect of the compounds of the present disclosure on cell proliferation, the cells (e.g., BaF3 BRAF-KIAA1549 fusion cells) can be incubated at different concentrations in the presence of a vehicle control (e.g., DMSO) or a compound of the present disclosure, and the inhibition of cell growth can be determined by luminescence quantification (e.g., intracellular ATP content using CellTiterGlo) according to the manufacturer's protocol. In some embodiments, to determine the IC 50 value, vehicle-treated cells are normalized to live cells and analyzed using software (e.g., CDD Vault (Collaborative Drug Discovery, Burlingame, CA)) using an algorithm (e.g., Levenberg-Marquardt algorithm; Levenberg, K., 1994; Marquardt, D., 1963).

[1103] Drug composition

[1104] In some aspects, the present disclosure provides a drug composition comprising a compound of the present disclosure as an active ingredient.

[1105] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table I and Table II. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table I. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table II.

[1106] As used herein, the term "composition" is intended to encompass a product comprising the specified amounts of the specified ingredients, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients.

[1107] The compounds of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes a sustained-release or extended-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all in forms well known to those of ordinary skill in the art of pharmacy.

[1108] The formulations of the present disclosure can be in the form of an aqueous solution containing an aqueous medium. The aqueous medium component can contain water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of solubilizers, chelating agents, preservatives, tonicity agents, viscosity agents / suspending agents, buffers, and pH regulators and mixtures thereof.

[1109] Any suitable solubilizer can be used. Examples of solubilizers include cyclodextrins, such as cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin and mixtures thereof.

[1110] Any suitable chelating agent can be used. Examples of suitable chelating agents include chelating agents selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate and mixtures thereof.

[1111] Any suitable preservative can be used. Examples of preservatives include preservatives selected from the group consisting of: quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methyl paraben, propyl paraben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl paraben, polyaminopropyl biguanide and butyl paraben and sorbic acid and mixtures thereof.

[1112] The aqueous vehicle may also include tonicity agents to adjust the tonicity (osmotic pressure). Tonicity agents may be selected from the group consisting of ethylene glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride and sodium chloride and mixtures thereof.

[1113] The aqueous vehicle may also contain viscosity agents / suspending agents. Suitable viscosity agents / suspending agents include viscosity agents / suspending agents selected from the group consisting of: cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose and cross-linked acrylic polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkylene ethers or divinyl glycol (carbomers - such as carbomer 934, carbomer 934P, carbomer 971, carbomer 974 and carbomer 974P) and mixtures thereof.

[1114] To adjust the formulation to an acceptable pH (usually in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, specifically about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9 or about 7.5 to about 8.0), the formulation may contain a pH regulator. The pH regulator is typically a mineral acid or a metal hydroxide base, the metal hydroxide base being selected from the group consisting of potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably being sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH regulators are added to adjust the formulation to the target acceptable pH range. Thus, it may not be necessary to use both an acid and a base, and depending on the formulation, adding one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[1115] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, buffers are selected from the group consisting of: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate) and ε-aminocaproic acid and mixtures thereof.

[1116] The formulation may further comprise a humectant. Suitable types of humectants include humectants selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyethylene glycol 40 stearate, ethylene glycol fatty acid esters, glycerol fatty acid esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters and mixtures thereof.

[1117] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. It may be encapsulated in a gelatin capsule or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a fluid carrier as a mouthwash, wherein the compound in the fluid carrier is orally administered and then rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, primogel, or corn starch; lubricants such as magnesium stearate or stearotes; glidants such as colloidal silica; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[1118] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[1119] The compositions of the present disclosure may be in forms suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), forms suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), forms suitable for administration by inhalation (e.g., as a finely divided powder or a liquid aerosol), forms suitable for administration by insufflation (e.g., as a finely divided powder), or forms suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular injection, or as a suppository for rectal administration).

[1120] The compositions of the present disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents, and / or preservatives.

[1121] According to well-known medical principles, the dosage size of the compounds of the present disclosure for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal, subject or patient, and the route of administration.

[1122] Exemplary embodiment

[1123] Exemplary embodiment No. 1. A method for treating or preventing cancer in a subject, the method comprising administering to the subject a compound of formula (0):

[1124]

[1125] its isomers, or a pharmaceutically acceptable salt thereof, wherein:

[1126] X is CR X or N;

[1127] R X is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl or the C1-C6 alkoxy is optionally substituted by one or more halogens, cyano, oxo or OH;

[1128] W 1 is N or CR W1 ;

[1129] R W1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[1130] W 2 is N or CR W2 ;

[1131] R W2 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally substituted by one or more halogens;

[1132] W 3 is N or CR W3 ;

[1133] R W3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[1134] W 4 is N or CR W4 ;

[1135] R W4is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or S(C1-C6 alkyl);

[1136] R 1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R 1a substituents;

[1137] Each R 1a is independently halogen, cyano, oxo, OH, NH2, NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl;

[1138] R 2 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy;

[1139] R 3 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy; or

[1140] R 1 and R 3 together with the intervening atom form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo groups;

[1141] X 1 is -NR X1 -*, -C(=O)NR X1 -*, -NR X1 C(=O)-*, -NR X1 C(=O)O-*, -NR X1 N=C-*, -NR X1 C(=NR X1 )-*, -NR X1 C(=NH)NR X1 -*, -NRX1 C(=O)NR X1 -*, -S(=O)2NR X1 -* or -NR X1 S(=O)2-*, where * indicates connection to A;

[1142] R X1 is independently H, S(=O)2R X1a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R X1a substituents;

[1143] Each R X1a is independently halogen, C1-C6 alkyl or 3- to 12-membered heterocycloalkyl, where the C1-C6 alkyl or the 3- to 12-membered heterocycloalkyl is optionally substituted by one or more halogens;

[1144] A is C1-C6 alkyl, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl) or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), where the C1-C6 alkyl, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl, the 5- to 10-membered heteroaryl, the -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), the -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), the -(C1-C6 alkyl)-(C6-C 10 aryl) or the -(C1-C6 alkyl)-(5- to 10-membered heteroaryl is optionally substituted by one or more R A substituents;

[1145] Each R A is independently halogen, cyano, oxo, OH, OR A1, NH2, NHR A1 , N(R A1 )2, (=N)R A1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heteroalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heteroalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A1 substituents;

[1146] Each R A1 independently is halogen, cyano, oxo, OH, OR A2 , NH2, NHR A2 , N(R A2 )2, C(=O)R A2 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heteroalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heteroalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A2 substituents; and

[1147] Each R A2 independently is halogen, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl,

[1148] wherein R A3 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl.

[1149] Exemplary Embodiment No. 2. A compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject.

[1150] Exemplary Embodiment No. 3. Use of a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing cancer in a subject.

[1151] Exemplary Embodiment No. 4. A combination comprising: (i) a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more inhibitors of the MAPK pathway.

[1152] Exemplary Embodiment No. 5. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising: (i) a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more inhibitors of the MAPK pathway.

[1153] Exemplary Embodiment No. 6. A combination for treating or preventing cancer in a subject, the combination comprising: (i) a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more inhibitors of the MAPK pathway.

[1154] Exemplary Embodiment No. 7. Use of a combination comprising: (i) a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more inhibitors of the MAPK pathway for the preparation of a medicament for treating or preventing cancer in a subject.

[1155] Exemplary Embodiment No. 8. The method, compound, combination or use according to any one of the preceding exemplary embodiments, wherein the subject is a human.

[1156] Exemplary Embodiment No. 9. The method, compound, combination or use according to any one of the preceding exemplary embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the BRAF gene.

[1157] Exemplary Embodiment No. 10. The method, compound, combination or use according to any one of the preceding exemplary embodiments, wherein the cancer is characterized by at least one oncogenic variant of B-Raf.

[1158] Exemplary Embodiment No. 11. The method, compound, combination or use according to any one of the preceding exemplary embodiments, wherein the subject has at least one oncogenic mutation in the BRAF gene.

[1159] Exemplary Embodiment No. 12. The method, compound, combination or use according to any one of the preceding exemplary embodiments, wherein the subject has at least one tumor and / or cancer cell expressing an oncogenic variant of B-Raf.

[1160] Exemplary Embodiment No. 13. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the oncogenic mutation of B-Raf is any one of the B-Raf mutations presented in Table 1a.

[1161] Exemplary Embodiment No. 14. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the oncogenic variant of B-Raf can be any one of the B-Raf variants presented in Table 1b.

[1162] Exemplary Embodiment No. 15. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the KRAS gene.

[1163] Exemplary Embodiment No. 16. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is characterized by at least one oncogenic variant of K-Ras.

[1164] Exemplary Embodiment No. 17. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has at least one oncogenic mutation in the KRAS gene.

[1165] Exemplary Embodiment No. 18. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has at least one tumor and / or cancer cell expressing an oncogenic variant of K-Ras.

[1166] Exemplary Embodiment No. 19. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the NRAS gene.

[1167] Exemplary Embodiment No. 20. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is characterized by at least one oncogenic variant of N-Ras.

[1168] Exemplary Embodiment No. 21. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has at least one oncogenic mutation in the NRAS gene.

[1169] Exemplary Embodiment No. 22. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has at least one tumor and / or cancer cell expressing an oncogenic variant of N-Ras.

[1170] Exemplary Embodiment No. 23. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the NF1 gene.

[1171] Exemplary Embodiment No. 24. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is characterized by at least one oncogenic variant of NF1.

[1172] Exemplary Embodiment No. 25. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has at least one oncogenic mutation in the NF1 gene.

[1173] Exemplary Embodiment No. 26. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has at least one tumor and / or cancer cell expressing an oncogenic variant of NF1.

[1174] Exemplary Embodiment No. 27. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer, kidney cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer or colorectal cancer.

[1175] Exemplary embodiment No. 28. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, diffuse large B-cell lymphoma of lymphoid tumors, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, low-grade glioma of the brain, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer or gastric cancer. Further examples of cancer include neuroendocrine carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, cholangiocarcinoma, esophageal cancer, anal cancer, salivary cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, cholangiocarcinoma, bladder cancer, bone cancer, bowel cancer, brain tumors, breast cancer, cancer of unknown primary (CUP), cancer that has spread to the bone, cancer that has spread to the brain, cancer that has spread to the liver, cancer that has spread to the lung, carcinoid, cervical cancer, pediatric cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, gastric cancer (Gastric cancer), gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, linitis plastica, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary adenocarcinoma, secondary cancer, signet ring cell carcinoma, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer (Stomachcancer), T-cell childhood non-Hodgkin lymphoma (NHL), testicular cancer, thymoma, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms tumor, uterine cancer and gynecological cancer.Examples of cancers also include, but are not limited to: hematological malignancies, lymphomas, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndromes, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma or glioblastoma multiforme.

[1176] Exemplary embodiment No. 29. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is a hematological cancer.

[1177] Exemplary embodiment No. 30. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is a solid cancer.

[1178] Exemplary embodiment No. 31. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is melanoma, breast cancer, head and neck cancer, esophagogastric cancer, gastric and small intestine cancer, lung cancer, mesothelioma, hepatobiliary duct cancer, pancreatic cancer, renal cancer, colorectal cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, soft tissue sarcoma, CNS and brain cancer or thyroid cancer.

[1179] Exemplary embodiment No. 32. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, thyroid cancer, histiocytosis, small intestine cancer, gastroenteropancreatic neuroendocrine cancer, cancer of unknown primary origin, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid cancer or glioblastoma.

[1180] Exemplary embodiment No. 33. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is glioma.

[1181] Exemplary embodiment No. 34. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is low-grade glioma.

[1182] Exemplary embodiment No. 35. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is glioblastoma multiforme.

[1183] Exemplary Embodiment No. 36. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is insensitive or resistant to treatment with one or more inhibitors of the MAPK pathway.

[1184] Exemplary Embodiment No. 37. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the cancer is insensitive or resistant to treatment with a BRAF inhibitor, a MEK inhibitor or a combination thereof.

[1185] Exemplary Embodiment No. 38. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has an adverse reaction to treatment with one or more inhibitors of the MAPK pathway.

[1186] Exemplary Embodiment No. 39. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has an adverse reaction to treatment with a BRAF inhibitor, a MEK inhibitor or a combination thereof.

[1187] Exemplary Embodiment No. 40. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has previously been administered one or more inhibitors of the MAPK pathway and, despite the previous administration, the subject has experienced disease progression.

[1188] Exemplary Embodiment No. 41. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the subject has previously been administered a BRAF inhibitor, a MEK inhibitor or a combination thereof and, despite the previous administration, the subject has experienced disease progression.

[1189] Exemplary Embodiment No. 42. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the BRAF inhibitor is vemurafenib, dabrafenib or encorafenib.

[1190] Exemplary Embodiment No. 43. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the MEK inhibitor is trametinib, cobimetinib or binimetinib.

[1191] Exemplary Embodiment No. 44. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the compound is administered to the subject by oral administration or parenteral administration.

[1192] Exemplary Embodiment No. 45. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the pharmaceutical composition comprising the compound is administered to the subject.

[1193] Exemplary Embodiment No. 46. The method, compound, combination or use according to any one of the foregoing exemplary embodiments, wherein the compound is administered at the following doses (e.g., daily dose):

[1194] About 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg or about 6 ± 0.1 mg (e.g., about 6 mg);

[1195] About 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg or about 12 ± 0.1 mg (e.g., about 12 mg);

[1196] About 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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);

[1197] About 50 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg or about 50 ± 1 mg (e.g., about 50 mg);

[1198] About 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg or about 100 ± 1 mg (e.g., about 100 mg);

[1199] about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg or about 200 ± 10 mg (e.g., about 200 mg);

[1200] about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg or about 400 ± 10 mg (e.g., about 400 mg);

[1201] about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg or about 600 ± 10 mg (e.g., about 600 mg);

[1202] about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg or about 800 ± 10 mg (e.g., about 800 mg);

[1203] about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg or about 1000 ± 10 mg (e.g., about 1000 mg); or

[1204] about 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 8...

Claims

1. A method for treating or preventing cancer in a subject, the method comprising administering to the subject a compound of formula (0): its isomers, or a pharmaceutically acceptable salt thereof, wherein: X is CR X or N; R X is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl or the C1-C6 alkoxy is optionally substituted by one or more halogen, cyano, oxo or OH; W 1 is N or CR W1 ; R W1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; W 2 is N or CR W2 ; R W2 is H, a halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group or the C2-C6 alkynyl group is optionally substituted by one or more halogens; W 3 is N or CR W3 ; R W3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; W 4 is N or Cr W4 ; R W4 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or S(C1-C6 alkyl); R 1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R 1a substituents; Each R 1a independently is halogen, cyano, oxo, OH, NH2, NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; R 2 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy; R 3 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy; or R 1 and R 3 together with the intervening atom form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo groups; X 1 is -NR X1 -*, -C(=O)NR X1 -*, -NR X1 C(=O)-*, -NR X1 C(=O)O-*, -NR X1 N=C-*, -NR X1 C(=NR X1 )-*, -NR X1 C(=NH)NR X1 -*, -NR X1 C(=O)NR X1 -*, -S(=O)2NR X1 -* or -NR X1 S(=O)2-*, where * indicates connection to A; R X1 independently H, S(=O)2R X1a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R X1a substituents; Each R X1a is independently a halogen, C1-C6 alkyl or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl or the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more halogens; A is C1-C6 alkyl, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl) or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6 alkyl, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl, the 5- to 10-membered heteroaryl, the -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), the -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), the -(C1-C6 alkyl)-(C6-C 10 aryl) or the -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted by one or more R A substituents; Each R A is independently halogen, cyano, oxo, OH, OR A1 , NH2, NHR A1 , N(R A1 )2, (=N)R A1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A1 ; Each R A1 is independently halogen, cyano, oxo, OH, OR A2 , NH2, NHR A2 , N(R A2 )2, C(=O)R A2 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C1-C6 alkoxy, the C3-C 12 cycloalkyl, the 3- to 12-membered heterocycloalkyl, the C6-C 10 aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R A2 ; and Each R A2 is independently halogen, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein R A3 is a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group.

2. A compound of formula (0), its isomers, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject.

3. Use of a compound of formula (0), its isomers, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing cancer in a subject.

4. A combination comprising: (i) a compound of formula (0), its isomers, or a pharmaceutically acceptable salt thereof, and (ii) one or more additional therapeutic agents.

5. A method for treating or preventing cancer in a subject, the method comprising administering to the subject a combination comprising: (i) a compound of formula (0), its isomers, or a pharmaceutically acceptable salt thereof, and (ii) one or more additional therapeutic agents.

6. A combination for treating or preventing cancer in a subject, the combination comprising: (i) a compound of formula (0), its isomers, or a pharmaceutically acceptable salt thereof, and (ii) one or more additional therapeutic agents.

7. Use of a combination comprising: (i) a compound of formula (0), its isomers, or a pharmaceutically acceptable salt thereof, and (ii) one or more additional therapeutic agents for the preparation of a medicament for treating or preventing cancer in a subject.

8. The method, compound, combination or use according to any one of the preceding claims, wherein the subject is a human.

9. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer (renal cancer), kidney cancer (kidney cancer), gastric cancer (gastric cancer), thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, gastric cancer (stomach cancer), soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer or colorectal cancer.

10. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, cholangiocarcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma of lymphoid tumors, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, low-grade glioma of the brain, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, uterine carcinosarcoma, uveal melanoma; other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer or gastric cancer;Additional examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, bile duct cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenal gland tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, bowel cancer, brain tumors, breast cancer, cancer of unknown primary (CUP), cancer that has spread to the bone, cancer that has spread to the brain, cancer that has spread to the liver, cancer that has spread to the lung, carcinoid tumors, cervical cancer, pediatric cancers, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, gastric cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, linitis plastica, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumors, melanoma skin cancer, male cancers, Merkel cell skin cancer, mesothelioma, molar pregnancy, oropharyngeal cancer, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland adenocarcinoma, secondary cancers, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T-cell childhood non-Hodgkin lymphoma (NHL), testicular cancer, thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal gland tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer and gynecological cancers; examples of cancer also include, but are not limited to: hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndromes, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma or glioblastoma multiforme.; 11. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is a hematological cancer.

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

13. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is melanoma, breast cancer, head and neck cancer, esophagogastric cancer, gastric and small intestine cancer, lung cancer, mesothelioma, hepatobiliary duct cancer, pancreatic cancer, kidney cancer, colorectal cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, soft tissue sarcoma, CNS and brain cancer or thyroid cancer.

14. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, thyroid cancer, histiocytosis, small intestine cancer, gastroenteropancreatic neuroendocrine cancer, cancer of unknown primary origin, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin lymphoma, papillary thyroid cancer or glioblastoma.

15. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is glioma.

16. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is glioblastoma.

17. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is lung cancer.

18. The method, compound, combination or use according to any one of the preceding claims, wherein the cancer is non-small cell lung cancer (NSCLC).

19. The method, compound, combination or use according to any one of the preceding claims, wherein the compound is administered to the subject by oral administration or parenteral administration.

20. The method, compound, combination or use according to any one of the preceding claims, wherein a pharmaceutical composition comprising the compound is administered to the subject.

21. The method, compound, combination or use according to any one of the preceding claims, wherein the compound is administered at the following doses (e.g., daily dose): about 6 ± 3 mg, about 6 ± 2 mg, about 6 ± 1 mg, about 6 ± 0.9 mg, about 6 ± 0.8 mg, about 6 ± 0.7 mg, about 6 ± 0.6 mg, about 6 ± 0.5 mg, about 6 ± 0.4 mg, about 6 ± 0.3 mg, about 6 ± 0.2 mg or about 6 ± 0.1 mg (e.g., about 6 mg); about 12 ± 6 mg, about 12 ± 5 mg, about 12 ± 4 mg, about 12 ± 3 mg, about 12 ± 2 mg, about 12 ± 1 mg, about 12 ± 0.9 mg, about 12 ± 0.8 mg, about 12 ± 0.7 mg, about 12 ± 0.6 mg, about 12 ± 0.5 mg, about 12 ± 0.4 mg, about 12 ± 0.3 mg, about 12 ± 0.2 mg or about 12 ± 0.1 mg (e.g., about 12 mg); about 25 ± 10 mg, about 25 ± 9 mg, about 25 ± 8 mg, about 25 ± 7 mg, about 25 ± 6 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 ± 20 mg, about 50 ± 10 mg, about 50 ± 9 mg, about 50 ± 8 mg, about 50 ± 7 mg, about 50 ± 6 mg, about 50 ± 5 mg, about 50 ± 4 mg, about 50 ± 3 mg, about 50 ± 2 mg or about 50 ± 1 mg (e.g., about 50 mg); about 100 ± 50 mg, about 100 ± 40 mg, about 100 ± 30 mg, about 100 ± 20 mg, about 100 ± 10 mg, about 100 ± 9 mg, about 100 ± 8 mg, about 100 ± 7 mg, about 100 ± 6 mg, about 100 ± 5 mg, about 100 ± 4 mg, about 100 ± 3 mg, about 100 ± 2 mg or about 100 ± 1 mg (e.g., about 100 mg); about 200 ± 100 mg, about 200 ± 90 mg, about 200 ± 80 mg, about 200 ± 70 mg, about 200 ± 60 mg, about 200 ± 50 mg, about 200 ± 40 mg, about 200 ± 30 mg, about 200 ± 20 mg or about 200 ± 10 mg (e.g., about 200 mg); about 400 ± 200 mg, about 400 ± 100 mg, about 400 ± 90 mg, about 400 ± 80 mg, about 400 ± 70 mg, about 400 ± 60 mg, about 400 ± 50 mg, about 400 ± 40 mg, about 400 ± 30 mg, about 400 ± 20 mg or about 400 ± 10 mg (e.g., about 400 mg); about 600 ± 300 mg, about 600 ± 200 mg, about 600 ± 100 mg, about 600 ± 90 mg, about 600 ± 80 mg, about 600 ± 70 mg, about 600 ± 60 mg, about 600 ± 50 mg, about 600 ± 40 mg, about 600 ± 30 mg, about 600 ± 20 mg or about 600 ± 10 mg (e.g., about 600 mg); about 800 ± 400 mg, about 800 ± 300 mg, about 800 ± 200 mg, about 800 ± 100 mg, about 800 ± 90 mg, about 800 ± 80 mg, about 800 ± 70 mg, about 800 ± 60 mg, about 800 ± 50 mg, about 800 ± 40 mg, about 800 ± 30 mg, about 800 ± 20 mg or about 800 ± 10 mg (e.g., about 800 mg); about 1000 ± 500 mg, about 1000 ± 400 mg, about 1000 ± 300 mg, about 1000 ± 200 mg, about 1000 ± 100 mg, about 1000 ± 90 mg, about 1000 ± 80 mg, about 1000 ± 70 mg, about 1000 ± 60 mg, about 1000 ± 50 mg, about 1000 ± 40 mg, about 1000 ± 30 mg, about 1000 ± 20 mg or about 1000 ± 10 mg (e.g., about 1000 mg); or About 1200 ± 600 mg, about 1200 ± 500 mg, about 1200 ± 400 mg, about 1200 ± 300 mg, about 1200 ± 200 mg, about 1200 ± 100 mg, about 1200 ± 90 mg, about 1200 ± 80 mg, about 1200 ± 70 mg, about 1200 ± 60 mg, about 1200 ± 50 mg, about 1200 ± 40 mg, about 1200 ± 30 mg, about 1200 ± 20 mg, or about 1200 ± 10 mg (e.g., about 1200 mg).

22. The method, compound, combination, or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) inhibitors, one or more SOS1 inhibitors, one or more KRAS (Kirsten rat sarcoma virus) inhibitors, one or more ERK (extracellular signal-regulated kinase) inhibitors, one or more immune checkpoint inhibitors, one or more chemotherapies, one or more EGFR (epidermal growth factor receptor) inhibitors, one or more MET (mesenchymal-epithelial transition) inhibitors, one or more TEAD (transcriptional enhanced associate domain) inhibitors, one or more YAP (yes-associated protein) inhibitors, one or more PI3K (phosphoinositide 3-kinase) inhibitors, one or more mTOR (mammalian target of rapamycin) inhibitors, one or more metabolic inhibitors, or one or more MEK (mitogen-activated protein kinase kinase) inhibitors.

23. The method, compound, combination, or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more SHP2 inhibitors; Optionally, the one or more SHP2 inhibitors comprise JAB-3068, JAB-3312, TNO-155, RLY-1971, or RMC-4630.

24. The method, compound, combination, or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more SOS1 inhibitors; Optionally, the one or more SOS1 inhibitors comprise BI-1701963, BI-1703880, or MRTX0902.

25. The method, compound, combination, or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more KRAS inhibitors; Optionally, the one or more KRAS inhibitors comprise sotorasib, adagrasib, LY3537982, divarasib, JDQ443, BI-1823911, MRTX1133, RMC-9805, or RMC-6236.

26. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more ERK inhibitors; Optionally, the one or more ERK inhibitors comprise ulixertinib, MK-8353, LY3214996, ASTX029, ASN007, LTT462 or KO-947.

27. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more immune checkpoint inhibitors; Optionally, the one or more immune checkpoint inhibitors comprise pembrolizumab, ipilimumab, nivolumab or atezolizumab.

28. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more chemotherapies; Optionally, the one or more chemotherapies comprise oxaliplatin or irinotecan.

29. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more EGFR inhibitors; Optionally, the one or more EGFR inhibitors comprise erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib or vandetanib.

30. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more MET inhibitors; Optionally, the one or more MET inhibitors comprise crizotinib, capmatinib, tepotinib, savolitinib, cabozantinib, glesatinib, foretinib, merestinib, tivantinib, SAR125844, onartuzumab, telisotuzumab or JNJ-61186372.

31. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more TEAD inhibitors; Optionally, the one or more TEAD inhibitors comprise VT3989, IK-930 or IAG933.

32. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more YAP inhibitors; Optionally, the one or more YAP inhibitors comprise verteporfin.

33. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more PI3K inhibitors; Optionally, the one or more PI3K inhibitors comprise idelalisib, alpelisib, leniolisib, duvelisib or copanlisib.

34. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more mTOR inhibitors; Optionally, the one or more mTOR inhibitors comprise everolimus, sirolimus, temsirolimus, sirolimus protein-bound or everolimus.

35. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more additional therapeutic agents comprise one or more metabolic inhibitors; Optionally, the one or more metabolic inhibitors comprise trifluridine, gemcitabine, fluorouracil, pentostatin, clofarabine, azacitidine, cytarabine, mercaptopurine, fludarabine or capecitabine.

36. The method, compound, combination or use according to any one of the preceding claims, wherein the one or more metabolic inhibitors comprise one or more MEK inhibitors; Optionally, the one or more MEK inhibitors comprise trametinib, cobimetinib or binimetinib.

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