Methods of Treating Cancer Using Isoquinoline or 6-AZA-Quinoline Derivatives

Abstract

The present disclosure provides a compound of formula (0): The present disclosure also relates to pharmaceutical compositions and kits suitable for the treatment or prevention.

Description

[Background technology]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application Nos. 63 / 416,305, filed October 14, 2022, 63 / 431,997, filed December 12, 2022, 63 / 449,757, filed March 3, 2023, and 63 / 472,037, filed June 9, 2023, which are incorporated by reference herein in their entireties.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (ASET-041_001WO_SeqList_ST26.xml, size 23,649 bytes, and created on October 12, 2023) are incorporated herein by reference in their entirety.

[0003] Specific mutations in BRAF, the human gene encoding the protein B-Raf, are known to induce oncogenic activity in a variety of different cancers. Targeted inactivation of mutant B-Raf proteins by administering protein kinase inhibitors has been used to treat a variety of cancers in many patients. However, some patients treated with these therapies fail to respond, ultimately relapse, or experience secondary lesion / pathway recurrence. More specifically, many existing B-Raf-targeting kinase inhibitors have low specificity for B-Raf, resulting in undesirable off-target effects, or target only a specific subset of BRAF / B-Raf mutations. Therefore, 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 with oncogenic mutations in the BRAF gene and B-Raf protein. Summary of the Invention

[0004] 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).

[0005] 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).

[0006] In some aspects, the disclosure provides a compound of the disclosure for treating or preventing cancer in a subject.

[0007] Some aspects Now, the present disclosure provides a compound of the present disclosure for treating cancer in a subject.

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

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

[0010] In some aspects, the present disclosure provides combinations comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0011] In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the methods 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).

[0012] In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods 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).

[0013] In some aspects, the present disclosure provides combinations comprising a compound of the present disclosure and one or more additional therapeutic agents for treating or preventing cancer in a subject.

[0014] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more additional therapeutic agents for treating cancer in a subject.

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

[0016] In some aspects, the present disclosure provides compounds of the present disclosure for use in combination with one or more additional therapeutic agents in the treatment or prevention of cancer in a subject.

[0017] In some aspects, the present disclosure provides compounds of the present disclosure for use in combination with one or more additional therapeutic agents in the treatment of cancer in a subject.

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

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

[0020] 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. As used herein, the singular also includes the plural unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between a chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0021] Features and advantages of the present disclosure will become apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a graph showing a schematic of an exemplary study of compounds of the present disclosure. [Figure 2] FIG. 2 is a graph depicting the anti-tumor activity of a compound of the disclosure (“Compound”) in combination with binimetinib in a mouse-bearing KRAS G12D NSCLC patient-derived xenograft (PDX) model. [Figure 3] FIG. 3 is a graph depicting the anti-tumor activity of a compound of the present disclosure ("Compound") in combination with binimetinib in mice bearing a melanoma cell line harboring a BRAF V600E mutation. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present disclosure relates to methods of using compounds, and pharmaceutically acceptable salts and stereoisomers thereof, in the treatment or prevention of cancers associated with B-Raf oncogenic activity, as well as compositions and kits suitable for the methods.

[0024] BRAF is a human gene located on the long arm of chromosome 7 (7q34) that encodes a protein known as B-Raf. B-Raf is a serine / threonine kinase present in the cytoplasm of cells. B-Raf is an effector molecule in 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.

[0025] Briefly, as understood by those skilled in the art, in the MAPK / ERK signaling pathway, specific external stimuli, such as growth factors, activate receptors located on the cell membrane, including receptor tyrosine kinases (RTKs). These receptors then activate RAS, which exchanges GDP for GTP, thereby generating RAS-GTP. RAS-GTP then activates mitogen-activated protein kinase kinase kinases (MAPKKKs or MAP3Ks). The activated MAPKKKs then activate MAP kinase kinases (MAPKKs). The activated MAPKKs then activate MAP kinases (MAPKs). The activated MAPKs then activate downstream effectors, including transcription factors, which cause changes in gene expression and regulate various cellular processes, including but not limited to cell growth, proliferation, differentiation, and apoptosis.

[0026] Examples of MAPKKKs include the rapidly accelerated fibrosarcoma (Raf) (Raf) family, which includes Raf-1 (also known as C-Raf), B-Raf, and A-Raf.

[0027] 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 Raf proteins. CR1 contains the binding site for the effector domain of RAS-GTP. When CR1 binds to the effector domain of RAS-GTP, it releases CR3, relieving the autoinhibitory effect of the kinase domain. CR2 is a flexible linker that functions as a hinge for the connection between CR1 and CR3. CR3 is the enzyme kinase domain.

[0028] In its active form, B-Raf forms a dimer and functions as a serine / threonine-specific protein kinase. Under activating conditions, the regulatory protein 14-3-3 displaces B-Raf from CR2, allowing CR1 and CR2 to disengage. RAS-GTP then binds to B-Raf's CR1, causing CR1 to release CR3. The overall effect is that the autoinhibitory properties of the B-Raf kinase domain are relieved. B-Raf is then phosphorylated at T599 and S602, switching the kinase domain to an active conformation. Dimer formation then occurs, further stabilizing the active form of B-Raf.

[0029] Mutations in the BRAF gene are implicated in a variety of 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 distinct mutations have been functionally characterized. BRAF mutations are typically classified into one of three classes based on the effect of the mutation on B-Raf activity.

[0030] Class I (or class 1) mutations are mutations that result in the expression of mutant B-Raf that can be active in the monomeric form independent of RAS activity. That is, class I mutations of BRAF result in the expression of RAS-independent active monomeric B-Raf proteins. These RAS-independent active monomers typically exhibit elevated levels of kinase activity.

[0031] Class II (or class 2) mutations result in the expression of mutant B-Raf proteins that can form active dimers independently of RAS. That is, class II mutations in BRAF result in the expression of B-Raf proteins that are RAS-independent active dimers. These RAS-independent active dimers also exhibit moderate to high levels of kinase activity, but their activity levels are typically lower than the RAS-independent active monomers produced by class I BRAF mutations.

[0032] Class III (or Class 3) mutations result in the expression of mutant B-Raf that is RAS-dependent (i.e., requires activation by RAS-GTP) and can heterodimerize with other MAPK proteins, such as C-Raf. Class III mutations in BRAF typically result in B-Raf with reduced kinase activity or malfunction.

[0033] As will be appreciated by those skilled in the art, because class I and class II BRAF mutations are RAS-independent, mutant B-Raf proteins carrying class I or class II mutations are not bound by any upstream signals, resulting in constitutive activation and the development of unchecked cells, which can ultimately lead to oncogenic proliferation.

[0034] Methods and Uses of the Disclosure 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).

[0035] 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).

[0036] In some aspects, the disclosure provides a compound of the disclosure for treating or preventing cancer in a subject.

[0037] In some aspects, the present disclosure provides a compound of the present disclosure for treating cancer in a subject.

[0038] In some aspects, the disclosure provides the use of a compound of the disclosure in the manufacture of a medicament for treating or preventing cancer in a subject.

[0039] In some aspects, the disclosure provides the use of a compound of the disclosure in the manufacture of a medicament for treating cancer in a subject.

[0040] In some embodiments, one or more inhibitors of one or more components of the MAPK pathway are further administered to the subject.

[0041] Suitable subjects and diseases In some embodiments, the subject is a mammal.

[0042] In some embodiments, the subject is a human.

[0043] In some embodiments, the subject is a mouse.

[0044] In some embodiments, the subject is a rat.

[0045] In some embodiments, the subject is a dog.

[0046] In some embodiments, the subject is a monkey.

[0047] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the BRAF gene.

[0048] It is understood that a cancer characterized by at least one oncogenic mutation in the BRAF gene is typically a cancer associated with at least one oncogenic mutation in the BRAF gene, including, but not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the BRAF gene.

[0049] In some embodiments, the cancer is characterized by at least one oncogenic variant of B-Raf.

[0050] It is understood that a cancer characterized by at least one oncogenic variant of B-Raf is typically a cancer associated with at least one oncogenic variant of B-Raf, and includes, but is not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of B-Raf.

[0051] An oncogenic variant of B-Raf is understood to be a B-Raf protein that contains at least one oncogenic mutation and that is produced as a result of expression of a BRAF gene that contains at least one oncogenic mutation.

[0052] In some embodiments, the subject has at least one oncogenic mutation in the BRAF gene.

[0053] In some embodiments, the subject has at least one tumor and / or cancerous cell that expresses an oncogenic variant of B-Raf.

[0054] As will be understood by those skilled in the art, in the context of a gene (e.g., BRAF), oncogenic mutations include, but are not limited to, mutations that result in the substitution of one amino acid for another at a specific position in B-Raf, mutations that result in the substitution of one or more amino acids for one or more amino acids between two specific positions in B-Raf, mutations that result in the insertion of one or more amino acids between two positions in B-Raf, mutations that result in the deletion of another amino acid between two positions in B-Raf, and mutations that result in the fusion of B-Raf or a portion thereof with another protein or portion thereof, or any combination thereof. As will be understood by those skilled in the art, oncogenic mutations in the context of a gene can include, but are not limited to, missense mutations, nonsynonymous mutations, insertions of one or more nucleotides, deletions of one or more nucleotides, inversions, and deletion-insertions. As will be understood by those skilled in the art, in the context of a gene (e.g., BRAF), a gene can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations.

[0055] As will be appreciated by those skilled in the art, in the context of a protein (e.g., B-Raf), an oncogenic mutation includes, but is not limited to, a substitution of one amino acid for another at a specific position within B-Raf, a substitution of one or more amino acids for one or more amino acids between two specific positions within B-Raf, an insertion of one or more amino acids between two positions within B-Raf, a deletion of another amino acid between two positions within B-Raf, and a fusion of B-Raf, or a portion thereof, with another protein or portion thereof, or any combination thereof. As will be appreciated by those skilled in the art, in the context of a protein (e.g., B-Raf), a protein can have one or more of the foregoing types of oncogenic mutations, including a combination of different types of oncogenic mutations.

[0056] In some embodiments, the oncogenic mutation in B-Raf can be any of the B-Raf mutations presented in Table 1a. The oncogenic variant in B-Raf can include one or more of the oncogenic mutations presented in Table 1a, in any combination. In a non-limiting example, the oncogenic variant in B-Raf can include the oncogenic mutations K601E and S363F. [Table 1]

[0057] As will be understood by one of skill in the art, L485-P490>Y and L485-P490Y refer to the substitution of residues L485 through P490 of B-Raf (SEQ ID NO: 1) with a tyrosine (Y) residue.

[0058] In some embodiments, oncogenic mutations in B-Raf may comprise any combination of deletions of one or more amino acids between L485 and P490 of B-Raf (SEQ ID NO: 1). In some embodiments, oncogenic mutations in B-Raf may comprise any combination of deletions of one or more amino acids between L485 and Q494 of B-Raf (SEQ ID NO: 1). In some embodiments, oncogenic mutations in B-Raf may comprise any combination of deletions of one or more amino acids between A481 and Q494 of B-Raf (SEQ ID NO: 1). In some embodiments, oncogenic mutations in B-Raf may comprise any combination of deletions 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 may further comprise any combination of one or more substitutions and / or insertions within the specified residue ranges.

[0059] In some embodiments, an oncogenic mutation "deletion around 487-493" refers to a deletion of one or more amino acids between residues 487±3 and 498±3 (e.g., a deletion between residues 489 and 497).

[0060] The sequence of wild-type B-Raf of the present disclosure may comprise, consist essentially of, or consist of the following amino acid sequence: 1 MAALSGGGGG GAEPGQALFN GDMEPEAGAG AGAAASSAAD PAIPEEVWNI 51 KQMIKLTQEH IEALLDKFGG EHNPPSIYLE AYEEYTSKLD ALQQREQQLL 101 ESLGNGTDFS VSSSASMDTV TSSSSSSLSV LPSSLSVFQN PTDVARSNPK 151 SPQKPIVRVF LPNKQRTVVP ARCGVTVRDS LKKALMMRGL IPECCAVYRI 201 QDGEKKPIGW DTDISWLTGE ELHVEVLENV PLTTHNFVRK TFFTLAFCDF 251 CRKLLFQGFR CQTCGYKFHQ RCSTEVPLMC VNYDQLDLLF VSKFFEHHPI 301 PQEEASLAET ALTSGSSPSA PASDSIGPQI LTSPSPSKSI PIPQPFRPAD 351 EDHRNQFGQR DRSSSAPNVH INTIEPVNID DLIRDQGFRG DGGSTTGLSA 401 TPPASLPGSL TNVKALQKSP GPQRERKSSS SSEDRNRMKT LGRRDSSDDW 451 EIPDGQITVG QRIGSGSFGT VYKGKWHGDV AVKMLNVTAP TPQQLQAFKN 501 EVGVLRKTRH VNILLFMGYS TKPQLAIVTQ WCEGSSLYHH LHIIETKFEM 551 IKLIDIARQT AQGMDYLHAK SIIHRDLKSN NIFLHEDLTV KIGDFGLATV 601 KSRWSGSHQF EQLSGSILWM APEVIRMQDK NPYSFQSDVY AFGIVLYELM 651 TGQLPYSNIN NRDQIIFMVG RGYLSPDLSK VRSNCPKAMK RLMAECLKKK 701 RDERPLFPQI LASIELLARS LPKIHRSASE PSLNRAGFQT EDFSLYACAS 751 PKTPIQAGGY GAFPVH (SEQ ID NO: 1)

[0061] 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.

[0062] 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.

[0063] 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.

[0064] In some embodiments, the oncogenic variant of B-Raf can be any of the B-Raf variants presented in Table 1b. Any of the variants presented in Table 1b can be combined with any 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. [Table 2]

[0065] In some embodiments, oncogenic variants of B-Raf may comprise any combination of deletions of one or more amino acids between L485 and P490 of B-Raf (SEQ ID NO: 1). In some embodiments, oncogenic variants of B-Raf may comprise any combination of deletions of one or more amino acids between L485 and Q494 of B-Raf (SEQ ID NO: 1). In some embodiments, oncogenic variants of B-Raf may comprise any combination of deletions of one or more amino acids between A481 and Q494 of B-Raf (SEQ ID NO: 1). In some embodiments, oncogenic variants of B-Raf may comprise any combination of deletions 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 may further comprise any combination of one or more substitutions and / or insertions within the specified residue ranges.

[0066] As will be understood by those skilled in the art, B-Raf-ex10-18dup refers to an oncogenic variant of B-Raf containing a duplication of exons 10 to 18 (see, e.g., Kemper et al. Cell Rep. 2016 Jun 28;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 can appear after treatment with a BRAF inhibitor and / or a MEK inhibitor. Without wishing to be bound by theory, B-Raf-ex10-18dup can mediate resistance to a BRAF inhibitor and / or a MEK inhibitor.

[0067] In some embodiments, an oncogenic variant of B-Raf can contain both a duplication of exons 10-18 and a V600E mutation (B-Raf-V600E+ex10-18dup).

[0068] In some embodiments, the subject has at least one tumor and / or cancerous cells expressing 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 may be selected from N-Ras, K-Ras, and neurofibromin 1 (NF1). In some embodiments, the at least one mutation in the at least one additional protein may be an oncogenic mutation.

[0069] In some embodiments, the subject has at least one tumor or cancerous cell expressing an oncogenic variant of B-Raf and an N-Ras protein containing at least one mutation. 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 cancerous cell expressing B-Raf-D594G and N-Ras-G12D.

[0070] In some embodiments, the subject has at least one tumor or cancerous cell expressing an oncogenic variant of B-Raf and a K-Ras protein comprising at least one mutation, which may 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.

[0071] In some embodiments, the subject has at least one tumor or cancerous cell expressing an oncogenic variant of B-Raf and an NF1 protein containing at least one mutation. Exemplary mutations in the NF1 protein include, but are not limited to, missense mutations, nonsense mutations, frameshift mutations, splice site mutations, insertions, deletions, and translocations.

[0072] 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, hi some embodiments, the at least one protein in the RAF and / or MAPK / ERK signaling pathway may be selected from N-Ras, K-Ras, and NF1.

[0073] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the KRAS gene.

[0074] It is understood that a cancer characterized by at least one oncogenic mutation in the KRAS gene is typically a cancer associated with at least one oncogenic mutation in the KRAS gene, and includes, but is not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the KRAS gene.

[0075] In some embodiments, oncogenic mutations in the KRAS gene induce the formation of one or more homodimers and / or heterodimers of Raf proteins. In a non-limiting example, oncogenic mutations in the KRAS gene can induce the formation of A-Raf homodimers. In a non-limiting example, oncogenic mutations in the KRAS gene can induce the formation of B-Raf homodimers. In a non-limiting example, oncogenic mutations in the KRAS gene can induce the formation of C-Raf homodimers. In a non-limiting example, oncogenic mutations 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.

[0076] In some embodiments, the cancer is characterized by at least one oncogenic variant of K-Ras.

[0077] In some embodiments, an oncogenic variant of K-Ras induces the formation of one or more homodimers and / or heterodimers of Raf proteins. In a non-limiting example, at least one oncogenic variant of K-Ras can induce the formation of A-Raf homodimers. In a non-limiting example, at least one oncogenic variant of K-Ras can induce the formation of B-Raf homodimers. In a non-limiting example, at least one oncogenic variant of K-Ras can induce the formation of C-Raf homodimers. In a non-limiting example, 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.

[0078] It is understood that a cancer characterized by at least one oncogenic variant of K-Ras is generally a cancer associated with at least one oncogenic variant of K-Ras, including, but not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of K-Ras.

[0079] An oncogenic variant of K-Ras is understood to be a K-Ras protein that contains at least one oncogenic mutation and that is produced as a result of expression of a KRAS gene that contains at least one oncogenic mutation.

[0080] In some embodiments, the subject has at least one oncogenic mutation in the KRAS gene.

[0081] In some embodiments, the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of K-Ras.

[0082] In some embodiments, the oncogenic K-Ras mutation may 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 K-Ras mutation may be a mutation that induces constitutive RAF dimer activation. In some embodiments, the oncogenic K-Ras mutation is a mutation other than K-Ras-G12C. In some embodiments, the oncogenic K-Ras mutation may be K-Ras-G12D. In some embodiments, the oncogenic K-Ras mutation may be K-Ras-G12V.

[0083] In some embodiments, the subject has at least one oncogenic mutation in the KRAS gene, and the at least one oncogenic mutation in the KRAS gene induces the formation of one or more homodimers and / or heterodimers of Raf proteins. In a non-limiting example, the at least one oncogenic mutation in the KRAS gene can induce the formation of A-Raf homodimers. In a non-limiting example, the at least one oncogenic mutation in the KRAS gene can induce the formation of B-Raf homodimers. In a non-limiting example, the at least one oncogenic mutation in the KRAS gene can induce the formation of C-Raf homodimers. In a non-limiting example, the 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.

[0084] In some embodiments, the subject has at least one tumor and / or cancer cells expressing 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 a non-limiting example, the oncogenic variant of K-Ras can induce the formation of A-Raf homodimers. In a non-limiting example, the oncogenic variant of K-Ras can induce the formation of B-Raf homodimers. In a non-limiting example, the oncogenic variant of K-Ras can induce the formation of C-Raf homodimers. In a non-limiting example, 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.

[0085] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the NRAS gene.

[0086] It is understood that a cancer characterized by at least one oncogenic mutation in the NRAS gene is typically a cancer associated with at least one oncogenic mutation in the NRAS gene, and includes, but is not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the NRAS gene.

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

[0088] It is understood that a cancer characterized by at least one oncogenic variant of N-Ras is generally a cancer associated with at least one oncogenic variant of N-Ras, including, but not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of N-Ras.

[0089] An oncogenic variant of N-Ras is understood to be an N-Ras protein that contains at least one oncogenic mutation and that is produced as a result of expression of an NRAS gene that contains at least one oncogenic mutation.

[0090] In some embodiments, the subject has at least one oncogenic mutation in the NRAS gene.

[0091] In some embodiments, the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of N-Ras.

[0092] In some embodiments, the oncogenic N-Ras mutation 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 N-Ras mutation can be a mutation that induces constitutive RAF dimer activation.

[0093] 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.

[0094] It is understood that a cancer characterized by at least one oncogenic mutation in the NF1 gene is typically a cancer associated with at least one oncogenic mutation in the NF1 gene, and includes, but is not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the NF1 gene.

[0095] In some embodiments, the cancer is characterized by at least one oncogenic variant of NF1.

[0096] It is understood that a cancer characterized by at least one oncogenic variant of NF1 is typically a cancer associated with at least one oncogenic variant of NF1, including, but not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of N-Ras.

[0097] An oncogenic variant of NF1 is understood to be an NF1 protein that contains at least one oncogenic mutation and is produced as a result of expression of an NF1 gene that contains at least one oncogenic mutation. In some embodiments, the oncogenic mutation in the NF1 protein can be a loss-of-function mutation in the NF1 protein.

[0098] In some embodiments, the subject has at least one oncogenic mutation in the NF1 gene.

[0099] In some embodiments, the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of NF1.

[0100] 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 mutations in can be any of the oncogenic mutations described herein.

[0101] 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.

[0102] In some embodiments, the cancer is characterized by at least one oncogenic mutation in a gene encoding a RAS GTPase.

[0103] It is understood that a cancer characterized by at least one oncogenic mutation in a gene encoding a RAS GTPase is typically a cancer associated with at least one oncogenic mutation in a gene encoding a RAS GTPase, and includes, but is not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in a gene encoding a RAS GTPase.

[0104] In some embodiments, the cancer is characterized by at least one oncogenic variant of a RAS GTPase.

[0105] It is understood that a cancer characterized by at least one oncogenic variant of a RAS GTPase is typically a cancer associated with at least one oncogenic variant of a RAS GTPase, including, but not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of a RAS GTPase.

[0106] An oncogenic variant of a RAS GTPase is understood to be a RAS GTPase protein that contains at least one oncogenic mutation and that is produced as a result of expression of a gene encoding a RAS GTPase that contains at least one oncogenic mutation.

[0107] In some embodiments, the subject has at least one oncogenic mutation in a gene encoding a RAS GTPase.

[0108] In some embodiments, the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of a RAS GTPase.

[0109] In some embodiments, the RAS GTPase can be NRAS, KRAS, or HRAS.

[0110] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the HRAS gene.

[0111] It is understood that a cancer characterized by at least one oncogenic mutation in the HRAS gene is typically a cancer associated with at least one oncogenic mutation in the HRAS gene, and includes, but is not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the HRAS gene.

[0112] In some embodiments, the cancer is characterized by at least one oncogenic variant of H-Ras.

[0113] It is understood that a cancer characterized by at least one oncogenic variant of H-Ras is typically a cancer associated with at least one oncogenic variant of H-Ras, including, but not limited to, a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of H-Ras.

[0114] An oncogenic variant of H-Ras is understood to be an H-Ras protein that contains at least one oncogenic mutation and that is produced as a result of expression of an HRAS gene that contains at least one oncogenic mutation.

[0115] In some embodiments, the subject has at least one oncogenic mutation in the HRAS gene.

[0116] In some embodiments, the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of H-Ras.

[0117] In some embodiments, the oncogenic mutation of H-Ras may be H-Ras-G13D.

[0118] 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, kidney cancer, renal 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 cavity cancer, pharyngeal cancer, or colorectal cancer.

[0119] In some embodiments, the cancer is adrenocortical carcinoma, urothelial carcinoma of the bladder, invasive breast carcinoma, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, bile duct carcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, chromophobe cell carcinoma of the kidney, clear cell carcinoma of the kidney, papillary cell carcinoma of the kidney, acute myeloid leukemia, low-grade glioma of the brain, hepatocellular carcinoma of the liver, adenocarcinoma of the lung, squamous cell carcinoma of the lung, mesothelioma, serous cystadenocarcinoma of the ovary, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, or uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal 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, biliary tract cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary site (CUP), cancer that has metastasized to the bone, cancer that has metastasized to the brain, cancer that has metastasized to the liver, cancer that has metastasized to the lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, stomach cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia , head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, gastric fibroblastic fibrositis, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral cavity and oropharyngeal cancer, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's 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 cancer, secondary cancers, signet ring cell carcinoma, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymic cancer, tongue cancer, tonsil cancer, adrenal gland tumors, uterine cancer These include vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer (womb cancer), and gynecological cancers.

[0120] 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, chromocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0121] In some embodiments, the cancer is a blood cancer.

[0122] In some embodiments, the cancer is a solid cancer (also called a solid malignant tumor or solid tumor).

[0123] 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.

[0124] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, thyroid cancer, histiocytosis, small intestine cancer, gastrointestinal neuroendocrine carcinoma, carcinoma of unknown primary origin, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid carcinoma, or glioblastoma.

[0125] 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 carcinoma.

[0126] In some embodiments, the cancer is a histiocytic neoplasm. In some embodiments, the histiocytic neoplasm is Langerhans cell histiocytosis (LCH). In some embodiments, the histiocytic neoplasm is Erdheim-Chester disease (ECD). In some embodiments, the cancer is a histiocytic and dendritic cell neoplasm.

[0127] In some embodiments, the cancer is melanoma.

[0128] In some embodiments, the cancer is thyroid cancer.

[0129] In some embodiments, the cancer is thyroid carcinoma.

[0130] In some embodiments, the cancer is colorectal cancer.

[0131] In some embodiments, the cancer is colorectal carcinoma.

[0132] In some embodiments, the cancer is glioma.

[0133] In some embodiments, the cancer is astrocytoma, brain stem glioma, ependymoma, oligoastrocytoma, oligodendroglioma, or optic pathway glioma.

[0134] In some embodiments, the cancer is a low-grade glioma (eg, a glioma arising from astrocytes and / or oligodendrocytes).

[0135] In some embodiments, the cancer is glioma (e.g., low-grade glioma) in a subject aged 18 years or older.

[0136] In some embodiments, the cancer is a glioma (e.g., a low-grade glioma) in a subject under 18 years of age.

[0137] In some embodiments, the cancer is glioblastoma.

[0138] In some embodiments, the cancer is a recurrent cancer.

[0139] In some embodiments, the cancer is an advanced cancer.

[0140] In some embodiments, the cancer is a metastatic cancer.

[0141] In some embodiments, the tumor is a recurrent tumor.

[0142] In some embodiments, the tumor is an advanced tumor.

[0143] In some embodiments, the tumor is a metastatic tumor.

[0144] In some embodiments, the cancer is brain cancer.

[0145] In some embodiments, the cancer is recurrent brain cancer.

[0146] In some embodiments, the cancer is advanced brain cancer.

[0147] In some embodiments, the cancer is metastatic brain cancer.

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

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

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

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

[0152] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0153] In some embodiments, the cancer is recurrent non-small cell lung cancer (NSCLC).

[0154] In some embodiments, the cancer is advanced non-small cell lung cancer (NSCLC).

[0155] In some embodiments, the cancer is metastatic non-small cell lung cancer (NSCLC).

[0156] In some embodiments, the cancer is NSCLC, and the subject has at least one tumor and / or cancerous cells expressing an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein comprising at least one class I mutation. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein comprising at least one class II mutation. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein comprising 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.

[0157] In some embodiments, the cancer is NSCLC, and the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of K-Ras. In some embodiments, the oncogenic variant of K-Ras is a K-Ras protein that includes an oncogenic mutation other than K-Ras-G12C. In some embodiments, the NSCLC can be recurrent, advanced, metastatic, or any combination thereof.

[0158] In some embodiments, the cancer is a histiocytic neoplasm and the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that includes 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 neoplasm and the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of N-Ras. In some embodiments, the histiocytic neoplasm may be recurrent.

[0159] In some embodiments, the cancer is melanoma, and the subject has at least one tumor and / or cancerous cells expressing an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein containing 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, progressive, metastatic, or any combination thereof.

[0160] In some embodiments, the cancer is melanoma, and the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of N-Ras. In some embodiments, the melanoma can be recurrent, progressive, metastatic, or any combination thereof.

[0161] In some embodiments, the cancer is thyroid carcinoma and the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that includes at least one Class I mutation, at least one Class II mutation, at least one Class III mutation, or any combination thereof.

[0162] In some embodiments, the cancer is colorectal carcinoma and the subject has at least one tumor and / or cancerous cells that express an oncogenic variant of B-Raf. In some aspects, the oncogenic variant of B-Raf is a B-Raf protein that includes at least one class II mutation, at least one class III mutation, or any combination thereof.

[0163] In some embodiments, administration of a compound of the present disclosure does not induce aberrant activation of wild-type B-Raf.

[0164] In some embodiments, administration of a compound of the present disclosure does not substantially increase the amount of p-ERK in a subject.

[0165] In some embodiments, administration of a compound of the present disclosure results in an amount of p-ERK in a subject that is at least about 10% lower, at least about 20% lower, at least about 30% lower, at least about 40% lower, at least about 50% lower, at least about 60% lower, at least about 70% lower, at least about 80% lower, at least about 90% lower, or at least about 95% lower, compared to a comparable subject administered vemurafenib or encorafenib.

[0166] In some embodiments, administration of a compound of the present disclosure results in an amount of p-ERK in a subject that is at least about 10% lower, at least about 20% lower, at least about 30% lower, at least about 40% lower, at least about 50% lower, at least about 60% lower, at least about 70% lower, at least about 80% lower, at least about 90% lower, or at least about 95% lower compared to a comparable subject that is not administered the compound.

[0167] In some embodiments, administration of a compound of the present disclosure reduces 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%.

[0168] In some embodiments, the cancer is insensitive or resistant to treatment with one or more inhibitors of the MAPK pathway.

[0169] In some embodiments, the cancer is insensitive or resistant to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0170] In some embodiments, the cancer is insensitive or resistant to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0171] In some embodiments, the cancer is insensitive to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0172] In some embodiments, the cancer is resistant to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0173] In some embodiments, the subject has an adverse reaction to treatment with one or more inhibitors of the MAPK pathway.

[0174] In some embodiments, the subject has an adverse reaction to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0175] In some embodiments, the subject has an adverse reaction to treatment with a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0176] In some embodiments, the adverse reaction is a new cancer (e.g., skin cancer), bleeding, gastrointestinal effects, kidney and / or liver effects, eye problems, lung problems, fever, or any combination thereof.

[0177] In some embodiments, the subject has previously been administered one or more inhibitors of the MAPK pathway, and the subject experienced disease progression despite the previous administration.

[0178] In some embodiments, the subject has previously been administered a BRAF inhibitor, a MEK inhibitor, or a combination thereof, and the subject experienced disease progression despite the previous administration.

[0179] In some embodiments, the subject has previously been administered a combination comprising a BRAF inhibitor and a MEK inhibitor, and the subject experienced disease progression despite the previous administration.

[0180] 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.

[0181] In some embodiments, the subject does not have central nervous system metastases.

[0182] In some embodiments, the subject has at least one brain metastasis. In some embodiments, the at least one brain metastasis is stable.

[0183] In some embodiments, the subject does not have brain metastases.

[0184] In some embodiments, the subject has histiocytosis.

[0185] MAPK pathway inhibitors In some embodiments, the one or more inhibitors of the MAPK pathway comprise a BRAF inhibitor, a MEK inhibitor, or any combination thereof.

[0186] In some embodiments, the one or more inhibitors of the MAPK pathway comprise a combination comprising a BRAF inhibitor and a MEK inhibitor.

[0187] In some embodiments, the BRAF inhibitor is vemurafenib, dabrafenib, or encorafenib.

[0188] In some embodiments, the BRAF inhibitor is vemurafenib.

[0189] In some embodiments, the BRAF inhibitor is dabrafenib.

[0190] In some embodiments, the BRAF inhibitor is encorafenib.

[0191] In some embodiments, the MEK inhibitor is trametinib, cobimetinib, or binimetinib.

[0192] In some embodiments, the MEK inhibitor is trametinib.

[0193] In some embodiments, the MEK inhibitor is cobimetinib.

[0194] In some embodiments, the MEK inhibitor is binimetinib.

[0195] Compound administration In some embodiments, the compound is administered to the subject by oral or parenteral administration.

[0196] In some embodiments, the compound is administered to the subject by oral administration.

[0197] In some embodiments, a pharmaceutical composition comprising the compound is administered to the subject.

[0198] In some embodiments, the pharmaceutical composition is an oral formulation.

[0199] In some embodiments, the pharmaceutical composition is a tablet or capsule.

[0200] In some embodiments, the pharmaceutical composition comprises a unit dose of the compound.

[0201] 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.

[0202] 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.

[0203] In some embodiments, the compound is administered in 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 The dose is administered at 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).

[0204] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0205] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0206] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0207] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0208] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0209] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0210] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0211] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0212] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0213] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0214] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0215] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0216] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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., 1200 mg).

[0217] In some embodiments, the compound is administered in 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); 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 The compound is administered at 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).

[0218] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0219] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0220] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0221] In some embodiments, the compound is administered in 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); 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 The compound is administered at 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).

[0222] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0223] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0224] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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).

[0225] In some embodiments, the pharmaceutical composition has a unit dose strength of 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.

[0226] In some embodiments, the compound is administered with one or more drug holidays.

[0227] In some embodiments, the compound is administered without a drug holiday.

[0228] In some embodiments, prior to administration, the subject fasts 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.

[0229] In some embodiments, 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 prior to administration.

[0230] In some embodiments, the compound is administered once daily (QD).

[0231] In some embodiments, the compound is administered twice daily (BID).

[0232] 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.

[0233] In some embodiments, the compound is administered for more than 210 days.

[0234] In some embodiments, the compound is administered until cancer progression or adverse effects (eg, intolerable toxicity) are observed.

[0235] Combination therapy In some aspects, the present disclosure provides combinations comprising a compound of the present disclosure and one or more additional therapeutic agents.

[0236] In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the methods 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).

[0237] 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).

[0238] In some aspects, the present disclosure provides combinations comprising a compound of the present disclosure and one or more additional therapeutic agents for treating or preventing cancer in a subject.

[0239] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more additional therapeutic agents for treating cancer in a subject.

[0240] In some aspects, the present disclosure provides compounds of the present disclosure for use in combination with one or more additional therapeutic agents in the treatment of cancer in a subject.

[0241] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and one or more additional therapeutic agents in the manufacture of a medicament for treating or preventing cancer in a subject.

[0242] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and one or more additional therapeutic agents in the manufacture of a medicament for treating or preventing cancer in a subject.

[0243] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and an additional therapeutic agent in the manufacture of a medicament for treating cancer in a subject.

[0244] 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 chemotherapeutics, one or more EGFR (epidermal growth factor receptor) inhibitors, one or more MET (mesenchymal-epithelial transition) inhibitors, one or more TEAD (transcription enhancer-associated 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.

[0245] In some embodiments, the one or more additional therapeutic agents comprise one or more SHP2 inhibitors.

[0246] In some embodiments, the one or more SHP2 inhibitors comprise JAB-3068, JAB-3312, TNO-155, RLY-1971, or RMC-4630.

[0247] In some embodiments, the one or more additional therapeutic agents comprise one or more SOS1 inhibitors.

[0248] In some embodiments, the one or more SOS1 inhibitors comprise BI-1701963, BI-1703880, or MRTX0902.

[0249] In some embodiments, the one or more additional therapeutic agents comprise one or more KRAS inhibitors.

[0250] In some embodiments, the one or more KRAS inhibitors comprise sotorasib, adagrasib, LY3537982, zivalasib, JDQ443, BI-1823911, MRTX1133, RMC-9805, or RMC-6236.

[0251] In some embodiments, the one or more additional therapeutic agents comprise one or more ERK inhibitors.

[0252] In some embodiments, the one or more ERK inhibitors comprise ulixertinib, MK-8353, LY3214996, ASTX029, ASN007, LTT462, or KO-947.

[0253] In some embodiments, the one or more additional therapeutic agents comprise one or more immune checkpoint inhibitors.

[0254] In some embodiments, the one or more immune checkpoint inhibitors comprise pembrolizumab, ipilimumab, nivolumab, or atezolizumab.

[0255] In some embodiments, the one or more additional therapeutic agents comprise one or more chemotherapeutics.

[0256] In some embodiments, the one or more chemotherapeutic agents include oxaliplatin or irinotecan.

[0257] In some embodiments, the one or more additional therapeutic agents comprise one or more EGFR inhibitors.

[0258] In some embodiments, the one or more EGFR inhibitors comprise erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, or vandetanib.

[0259] In some embodiments, the one or more additional therapeutic agents comprise one or more MET inhibitors.

[0260] 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.

[0261] In some embodiments, the one or more additional therapeutic agents comprise one or more TEAD inhibitors.

[0262] In some embodiments, the one or more TEAD inhibitors include VT3989, IK-930, or IAG933.

[0263] In some embodiments, the one or more additional therapeutic agents comprise one or more YAP inhibitors.

[0264] In some embodiments, the one or more YAP inhibitors comprise verteporfin.

[0265] In some embodiments, the one or more additional therapeutic agents comprise one or more PI3K inhibitors.

[0266] In some embodiments, the one or more PI3K inhibitors comprise idelalisib, alpelisib, alpelisib, leniolisib, duvelisib, or copanlisib.

[0267] In some embodiments, the one or more additional therapeutic agents comprise one or more mTOR inhibitors.

[0268] In some embodiments, the one or more mTOR inhibitors comprise everolimus, sirolimus, temsirolimus, everolimus, sirolimus, sirolimus protein-bound, or everolimus.

[0269] In some embodiments, the one or more additional therapeutic agents include one or more metabolic inhibitors.

[0270] In some embodiments, the one or more metabolic inhibitors comprise trifluridine, gemcitabine, fluorouracil, pentostatin, clofarabine, azacitidine, cytarabine, mercaptopurine, fludarabine, or capecitabine.

[0271] In some embodiments, the one or more metabolic inhibitors comprise one or more MEK inhibitors.

[0272] In some embodiments, the one or more MEK inhibitors comprise trametinib, cobimetinib, or binimetinib.

[0273] 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.

[0274] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and one or more MEK inhibitors.

[0275] In some aspects, the present disclosure provides: a compound of the present disclosure; and and one or more of trametinib, cobimetinib, or binimetinib.

[0276] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and trametinib.

[0277] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and cobimetinib.

[0278] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and binimetinib.

[0279] In some aspects, the present disclosure provides methods 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).

[0280] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising: a compound of the present disclosure (e.g., in a therapeutically effective amount); and administering to the subject a combination comprising one or more of trametinib, cobimetinib, or binimetinib (e.g., in a therapeutically effective amount).

[0281] 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 trametinib (e.g., in a therapeutically effective amount).

[0282] 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 cobimetinib (e.g., in a therapeutically effective amount).

[0283] 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 binimetinib (e.g., in a therapeutically effective amount).

[0284] 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 one or more inhibitors of the MAPK pathway (e.g., in a therapeutically effective amount).

[0285] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising: a compound of the present disclosure (e.g., in a therapeutically effective amount); and administering to the subject a combination comprising one or more of trametinib, cobimetinib, or binimetinib (e.g., in a therapeutically effective amount).

[0286] 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 trametinib (e.g., in a therapeutically effective amount).

[0287] 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).

[0288] 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).

[0289] 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 for treating or preventing cancer in a subject.

[0290] In some aspects, the present disclosure provides: a compound of the present disclosure; and and one or more of trametinib, cobimetinib, or binimetinib, Provided for treating or preventing cancer in a subject.

[0291] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and trametinib for treating or preventing cancer in a subject.

[0292] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and cobimetinib for treating or preventing cancer in a subject.

[0293] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and binimetinib for treating or preventing cancer in a subject.

[0294] 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 for treating cancer in a subject.

[0295] In some aspects, the present disclosure provides: a compound of the present disclosure; and and one or more of trametinib, cobimetinib, or binimetinib, Provided for treating cancer in a subject.

[0296] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and trametinib for treating cancer in a subject.

[0297] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and cobimetinib for treating cancer in a subject.

[0298] In some aspects, the present disclosure provides a combination comprising a compound of the present disclosure and binimetinib for treating cancer in a subject.

[0299] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway in the manufacture of a medicament for treating or preventing cancer in a subject.

[0300] In some aspects, the present disclosure provides: a compound of the present disclosure; and and one or more of trametinib, cobimetinib, or binimetinib, In the manufacture of a medicament for treating or preventing cancer in a subject.

[0301] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and trametinib in the manufacture of a medicament for treating or preventing cancer in a subject.

[0302] In some aspects, the present disclosure provides use of a combination comprising a compound of the present disclosure and cobimetinib in the manufacture of a medicament for treating or preventing cancer in a subject.

[0303] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and binimetinib in the manufacture of a medicament for treating or preventing cancer in a subject.

[0304] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and one or more inhibitors of the MAPK pathway in the manufacture of a medicament for treating cancer in a subject.

[0305] In some aspects, the present disclosure provides: a compound of the present disclosure; and and one or more of trametinib, cobimetinib, or binimetinib, In the manufacture of a medicament for treating cancer in a subject.

[0306] In some aspects, the present disclosure provides for the use of a combination comprising a compound of the present disclosure and trametinib in the manufacture of a medicament for treating cancer in a subject.

[0307] In some aspects, the present disclosure provides use of a combination comprising a compound of the present disclosure and cobimetinib in the manufacture of a medicament for treating cancer in a subject.

[0308] In some aspects, the present disclosure provides use of a combination comprising a compound of the present disclosure and binimetinib in the manufacture of a medicament for treating cancer in a subject.

[0309] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered simultaneously.

[0310] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered in a co-formulation.

[0311] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered in separate formulations.

[0312] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered sequentially or alternatingly.

[0313] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered sequentially.

[0314] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered closely in time.

[0315] In some embodiments, the compound is administered prior to administration of one or more inhibitors of the MAPK pathway.

[0316] In some embodiments, the compound is administered closely in time prior to the administration of one or more inhibitors of the MAPK pathway.

[0317] 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 administration of one or more inhibitors of the MAPK pathway.

[0318] In some embodiments, one or more inhibitors of the MAPK pathway are administered prior to administration of the compound.

[0319] In some embodiments, one or more inhibitors of the MAPK pathway are administered closely in time prior to the administration of the compound.

[0320] In some embodiments, the 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 prior to administration of the compound.

[0321] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered in alternation.

[0322] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered by the same route of administration.

[0323] In some embodiments, the compound and the one or more inhibitors of the MAPK pathway are administered by different routes of administration.

[0324] In some embodiments, at least two inhibitors of the MAPK pathway are administered.

[0325] In some embodiments, binimetinib is administered once daily.

[0326] In some embodiments, binimetinib is administered twice daily.

[0327] In some embodiments, the compound is administered at a dose of 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±0.1 mg (e.g., about 6 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 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± administered at a dose (e.g., a daily dose) of about 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); Binimetinib may be administered at doses of 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±2 0 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± 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).

[0328] In some embodiments, the compound is administered at a dose of 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±0.1 mg (e.g., about 6 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 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± administered at a dose (e.g., a daily dose) of about 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0329] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0330] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0331] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0332] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0333] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0334] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0335] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0336] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0337] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0338] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0339] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0340] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0341] In some embodiments, the compound is administered at a dose (e.g., a daily dose) of 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); Binimetinib is administered at a dose (e.g., a daily dose) of 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).

[0342] Other additional therapeutic agents In some embodiments, the one or more additional therapeutic agents include agents known to regulate other pathways, or other components of the same pathway, or overlapping sets of target enzymes.

[0343] In some embodiments, the one or more additional therapeutic agents include a chemotherapeutic agent, a therapeutic antibody, and radiation therapy.

[0344] Currently, many chemotherapeutic agents are known in the art. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, 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 include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as numerous chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM™); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaolamide, and trimethylolmelamine. ethyleneimines and methylamelamines, including amines; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin Antibiotics such as cin, keramicin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; acitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and estrogen Pyrimidine analogues such as nocitabine and floxuridine; androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elfomitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxybenzoates Urea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxanes, such as paclitaxel and docetaxel; retinoic acid; esperamycin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0345] Suitable chemotherapy cell conditioners also include antihormonal agents that act to regulate or inhibit hormone action on tumors, such as tamoxifen, Nolvadex, T n), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifen, keoxifen, LY Antiestrogens, including 117018, onapristone, and toremifene (Fareston); and antiandrogens, 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); the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO), and the like.

[0346] In some embodiments, the one or more additional therapeutic agents are Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione 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 anticancer agent, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, rutotecan, mafosfamili These include commonly prescribed anticancer drugs such as fluconazole, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swansonine, talaporfin, tariquidar, tegaflu-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0347] In some embodiments, the one or more additional therapeutic agents comprise radiation therapy to inhibit abnormal cell growth or treat a hyperproliferative disorder in a mammal. Techniques for administering radiation therapy are known in the art.

[0348] Radiation therapy can be administered via one or a combination of several methods, including, but not limited to, external radiation therapy, internal radiation therapy, implant radiation therapy, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy administered via a spatially confined radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. This term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as cell conditioners of the present disclosure include both solid and liquid sources. By way of non-limiting example, the radioactive source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material may also be any solution of the radionuclide, e.g., a fluid made from a solution of I-125 or I-131, or a radioactive fluid may be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198, Y-90, etc. Additionally, the radionuclide may be incorporated into a gel or radioactive microspheres.

[0349] In some embodiments, the one or more additional therapeutic agents comprise one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0350] Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in conjunction with the compounds of the present disclosure and the pharmaceutical compositions described herein. Antiangiogenic agents 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 include those described in WO96 / 33172, WO96 / 27583, European Patent Publication No. EP0818442, European Patent Publication No. EP1004578, WO98 / 07697, WO98 / 03516, WO98 / 34918, W98 / 34915, W98 / 33768, W98 / 30566, European Patent Publication No. 606046, European Patent Publication No. 931 788, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO1999007675, European Patent Publication No. EP1786785, European Patent Publication No. EP1181017, U.S. Publication No. US20090012085, U.S. Publication No. 5,863,949, U.S. Publication No. 5,861,510, and European Patent Publication No. EP0780386, all of which are incorporated herein by reference in their entireties. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferably, they 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 RS 13-0830.

[0351] In some embodiments, the one or more additional therapeutic agents are acemannan, ararubicin, aldesleukin, alemtuzumab, aliretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, anserine, ancestim, aruglavin, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosefate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dextrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflomitin, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination drug, glucuronide Lycopene, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-N3, interferon alphacon-1, interferon alpha, natural type, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural type interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570 Octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium etidronate 186, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, Remifen, tositumomab-iodine 131, trastuzumab, threosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, native form, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulence, zinostatin stimulant, or zoledronic acid, abarelix, AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziconazole, EL532 (Elan), EM800 (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, iproxifen, LDI 200 (Milkhaus), religistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafine gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 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 (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolytic vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle Hospital), or anti-tumor drugs such as valspodar.

[0352] In some embodiments, the one or more additional therapeutic agents comprise a VEGFR inhibitor, including compounds described in the following patents and patent applications: U.S. Patent No. 6,258,812, U.S. Patent No. 2003 / 0105091, WO / 2001 / 037820, U.S. Patent No. 6,235,764, WO / 2001 / 032651, U.S. Patent Nos. 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, and 5,747,498, Nos. 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.

[0353] In some embodiments, the one or more additional therapeutic agents include at least one anti-angiogenic agent. Agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, can act to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or halting cell proliferation.

[0354] Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C 225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), 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™ or VEGF-TRAP™, 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™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind thereto or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). Pharmaceutical compositions of the invention may also include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, 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."

[0355] Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Publication No. 2003 / 0162712, U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., antibodies or antigen-binding regions that specifically bind, or soluble TWEAK receptor antagonists; see Wiley, U.S. Patent No. 6,727,225), ADAM disintegrin domains that antagonize binding of integrins to their ligands (Fanslow et al., U.S. Publication No. 2003 / 0162712, U.S. Patent No. 6,413,932), and agonists of TWEAK receptor agonism (e.g., antibodies or antigen-binding regions that specifically bind, or soluble TWEAK receptor antagonists; see Wiley, U.S. Patent No. 6,727,225). al., U.S. Publication No. 2002 / 0042368), specifically binding anti-eph receptor and / or anti-ephrin antibodies or antigen binding regions (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124, and patent family members thereof), and anti-PDGF-BB antagonists (e.g., antibodies or antigen binding regions that specifically bind), as well as antibodies or antigen binding regions that specifically bind PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto).

[0356] Additional antiangiogenic / antitumor 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. 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); alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab, (Crucell, Netherlands); DAC: antiangiogenic, (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, (EntreMed, USA); angiogenesis inhibitor, (Tripep, Sweden); mastapine, (Sosei, Japan); 2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan); TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan JP 02233610); platelet factor 4, (RepliGen, USA EP 407122);Vascular endothelial growth factor antagonists, (Borean, Denmark); bevacizumab (pINN), (Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha 5 beta 3 integrin, second generation, (Applied Molecular Evolution, USA and MediImmune, USA); gene therapy, retinopathy, (Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC1, (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitors, (Alchemia, Australia); VEGF antagonists, (Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic agents (XOMA, USA); PI88 (Progen, Australia); cilengitide (pINN) (Merck KGaA, Germany; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); cetuximab (INN) (Aventis, France); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); endostatin (Boston Children's Hospital, USA); ATN161 (Attenuon, USA); angiostatin (Boston Children's Hospital, USA); 2-methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI2458 (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK), vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany);Tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei University, South Korea); gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX103 (University of California at San Diego, USA); PX478 (ProlX, USA); metastatin (EntreMed, USA); troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC381, (Harvard University, USA); AE 941, (Aeterna, Canada); Vaccine, Angiogenesis, (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor, (Dendreon, USA); Oglufanide (pINN), (Melmotte, USA); HIF-1 alpha inhibitor, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, Korea); GW2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP868596, (Pfizer, USA); CP 564959, (OSI, USA);CP 547632, (Pfizer, USA);786034, (GlaxoSmithKline, UK);KRN 633, (Kirin Brewery, Japan), drug delivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA); Anginex, (Maastricht University, The Netherlands, and University of Minnesota, USA); ABT510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor alpha inhibitor, (National Institute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN, USA); ABT518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems, USA); MAb, alpha5beta1, (Protein Design, USA); KDR kinase inhibitor, (Celltech Group, UK and Johnson & Johnson, USA); GFB116, (University of South Florida, USA and Yale University, USA); CS706, (Sankyo, Japan); combretastatin A4 prodrug, (Arizona State University, USA); chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM 1470, (Harvard University, USA, Takeda, 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, Korea); MAb, vascular endothelial growth factor, (Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG 13577, (Aventis, France); WX360, (Wilex, Germany); Squalamine (pINN), (Genaera, USA); RPI 4610, (Sirna, USA);Cancer therapy, (Marinova, Australia); heparanase inhibitor, (InSight, Israel); KL3106, (Kolon, South Korea); honokiol, (Emory University, USA); ZK CDK, (Schering AG, Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis, Switzerland, and Schering AG, Germany); XMP300, (XOMA, USA); VGA 1102, (Taisho, Japan); VEGF receptor modulator, (Pharmacopeia, USA); VE-cadherin-2 antagonist, (ImClone Systems, USA); vasostatin, (National Institutes of Health, USA); vaccine, Flk-1, (ImClone Systems, USA); TZ93, (Tsumura, Japan); TumStatin, (Beth Israel Hospital, USA); cleaved soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0357] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibitory algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used.

[0358] In some embodiments, the one or more additional therapeutic agents comprise epoetin alfa, darbepoetin alfa, panitumumab, pegfilgrastim, palifermin, filgrastim, denosumab, ancestim, AMG 102, AMG 386, AMG 479, AMG 655, AMG 745, AMG 951, AMG 706, or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments, the one or more additional therapeutic agents comprise a chemotherapeutic agent. Suitable chemotherapeutic agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparagine-containing L-asparaginase, which metabolizes asparagine systemically and deprives cells that do not have the ability to synthesize it themselves of asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines 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), trazene-dacarbazine (DTIC), folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguaiacol, Antiproliferative / antimitotic antimetabolites such as benzodiazepines (e.g., benzodiazepines, 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, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH589, 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), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and other anti-cancer drugs such as leukotrienes (LNCA). Hormonal agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN163L), 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., 17 AAG and KOS 953), PI3K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zamestra™), 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., Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or analog or derivative variants of any of the foregoing.

[0360] In some embodiments, the one or more additional therapeutic agents include radiation therapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0361] In some embodiments, the one or more additional therapeutic agents comprise a steroid. Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone ... These include lometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednivar, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof. In certain embodiments, the compounds of the present invention can also be used in combination with additional pharmaceutically active agents that treat nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or a pharmaceutically acceptable salt thereof.

[0362] 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 agents selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and 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 BiTEs.

[0363] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA.Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab.Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and recently lapatinib (TykerB). See, e.g., 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.

[0364] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, including all pharmaceutically acceptable salts of such EGFR inhibitors: European Patent Application No. EP 520722, published December 30, 1992; European Patent Application No. EP 566226, published October 20, 1993; PCT International Publication No. WO 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, issued May 5, 1998; PCT International Publication No. WO 96 / 30347, published October 3, 1996; and European Patent Application No. EP 96 / 30347, published August 6, 1997. 787772, PCT International Publication No. WO97 / 30034 published August 21, 1997, PCT International Publication No. WO97 / 30044 published August 21, 1997, PCT International Publication No. WO97 / 38994 published October 23, 1997, PCT International Publication No. WO97 / 49688 published December 31, 1997, European Patent Application No. EP837063, PCT International Publication No. WO98 / 02434 published January 22, 1998, PCT International Publication No. WO97 / 38983 published October 23, 1997, PCT International Publication No. WO95 / 19774 published July 27, 1995, PCT International Publication No. WO95 / 19970 published July 27, 1995, PCT International Publication No. WO95 / 19970 published April 17, 1997 PCT International Publication No. WO97 / 13771, published January 22, 1998, PCT International Publication No. WO98 / 02437, published January 22, 1998, PCT International Publication No. WO98 / 02438, published January 22, 1998, PCT International Publication No. WO97 / 32881, published September 12, 1997, German Patent Application No. DE19629652, published January 29, 1998, PCT International Publication No. DE19629652, published August 6, 1998 PCT International Publication No. WO98 / 33798, PCT International Publication No. WO97 / 32880, published September 12, 1997, European Patent Application No. EP682027, published November 15, 1995, PCT International Publication No. WO97 / 02266, published January 23, 1997, PCT International Publication No. WO97 / 27199, published July 31, 1997,PCT International Publication No. WO98 / 07726, published February 26, 1998; PCT International Publication No. WO97 / 34895, published September 25, 1997; PCT International Publication No. WO96 / 31510, published October 10, 1996; PCT International Publication No. WO98 / 14449, published April 9, 1998; PCT International Publication No. WO98 / 14450, published April 9, 1998; PCT International Publication No. WO98 / 14451, published April 9, 1998; PCT International Publication No. WO95 / 09847, published April 13, 1995; PCT International Publication No. WO97 / 190, published May 29, 1997 65, PCT International Publication No. WO98 / 17662 published April 30, 1998, U.S. Patent No. 5,789,427 issued August 4, 1998, U.S. Patent No. 5,650,415 issued July 22, 1997, U.S. Patent No. 5,656,643 issued August 12, 1997, PCT International Publication No. WO99 / 35146 published July 15, 1999, PCT International Publication No. WO99 / 35132 published July 15, 1999, PCT International Publication No. WO99 / 07701 published February 18, 1999, and PCT International Publication No. WO92 / 20642 published November 26, 1992. Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.

[0365] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the EGFR activation caused by its natural ligand.Non-limiting examples of antibody-based EGFR inhibitors include those described in 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, SM, et al., 1999, Cancer Res.15:59(8):1935-40 and Yang, X., et al., 1999, Cancer Res.59:1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0366] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0367] PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxywortmannin 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, described in PCT Publication Nos. 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]propionitrile (also known as BEZ 235 or NVP-BEZ 235, described in PCT Publication Nos. WO 09 / 036,082 and WO 09 / 055,730), and 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, described in PCT Publication Nos. WO 09 / 036,082 and WO 09 / 055,730). 06 / 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 No. WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride available from Axon Medchem), PIK 75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide available from Axon Medchem), GDC-0941 bismesylate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate available from Axon Medchem). available from Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione available from Axon Medchem), and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one available from Axon Medchem), XL-765, and XL-147. Other PI3K inhibitors include demethoxyviridine, 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.

[0368] AKT inhibitors include 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-carbinol 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., which 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. Drug 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

[0369] TOR inhibitors include, but are not limited to, ATP-competitive TORC1 / TORC2 inhibitors such as APAP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, PI-103, PP242, PP30, and torin-1. Other TOR inhibitors in the FKBP12 enhancer include rapamycin and its derivatives, such as CCI-779 (temsirolimus), RAD001 (everolimus, WO9409010), and AP23573; e.g., the rapalogs disclosed in WO98 / 02441 and WO01 / 14387, e.g., AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)propanoic acid methyl]-rapamycin (also known as CC1779), 40-epi-(tetrazolyt)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin, and those disclosed in WO Other derivatives disclosed in U.S. Pat. No. 5,258,389, WO 94 / 090101, WO 92 / 05179, U.S. Pat. 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 Nos. 96 / 41807 and 5,256,790, phosphorus-containing rapamycin derivatives (e.g., WO 05016252), 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0370] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is an important anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression as well as resistance to conventional chemotherapy and targeted therapeutic agents, including BCL-2 inhibitors such as ABT-263.

[0371] SHP inhibitors include, but are not limited to, SHP099.

[0372] Proteasome inhibitors include, but are not limited to, Kyprolis® (carfilzomib), Velcade® (bortezomib), and oprozomib.

[0373] 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.

[0374] Monoclonal antibodies include, but are not limited to, Darzalex® (daratumumab), Herceptin® (trastuzumab), Avastin® (bevacizumab), Rituxan® (rituximab), and Lucentis® (ranibizumab).

[0375] Fusion proteins include, but are not limited to, Eylea® (aflibercept).

[0376] Immunomodulatory drugs (IMiDs) are a class of immunomodulatory agents (drugs that modulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0377] Exemplary anti-PD-1 antibodies and methods of their use are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (Publication No. WO 2006 / 121168 No. A1), each of which is expressly incorporated herein by reference, and includes Yervoy™ (ipilimumab) 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), and other chemotherapeutic agents. Immunotherapies include: 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), and ipilumumab (against CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0378] In some embodiments, the one or more additional therapeutic agents comprises an anti-PD-1 antibody.

[0379] In some embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises one, two, three, four, five, or all six of the complementarity-determining region (CDR) amino acid sequences of SEQ ID NOs: 2-7 (representing, in order, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3). In specific embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises all six of the CDR amino acid sequences of SEQ ID NOs: 2-7.

[0380] 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 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 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.

[0381] 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 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 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.

[0382] In some embodiments, the antibody comprises one, two, three, four, five, or all six CDRs (representing, in order, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3) encoded by the nucleic acids of SEQ ID NOs: 12-17. In some embodiments, the antibody comprises all six CDRs encoded by the nucleic acids of SEQ ID NOs: 12-17.

[0383] 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 by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least 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 by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least 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 variable region encoded by SEQ ID NO: 18 and a light chain variable region encoded by SEQ ID NO: 19.

[0384] 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 by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least 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 by only 1, 2, 3, 4, 5, or 6 nucleic acids or has at least 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.

[0385] Exemplary anti-PD-1 antibody sequences are provided in Table 2. [Table 3-1] [Table 3-2] [Table 3-3]

[0386] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as those described in U.S. Pat. No. 6,111,090 box.c, European Patent No. 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos. WO2010 / 003118 and 2011 / 090754, or those described in U.S. Pat. No. 7,025,962, European Patent No. 1947183B1, U.S. Pat. Nos. 7,812,135, 8,388,967, 8,591,886, European Patent No. EP 1866339, PCT Publication No. WO 2011 / 028683, PCT Publication No. WO 2013 / 039954, PCT Publication No. WO 2005 / 007190, PCT Publication No. WO 2007 / 133822, PCT Publication No. WO 2005 / 055808, PCT Publication No. WO 99 / 40196, PCT Publication No. WO 2001 / 03720, PCT Publication No. WO 99 / 20758, PCT Publication No. WO 2006 / 083289, PCT Publication No. WO 2005 / 115451, U.S. Patent No. 7,618,632, and PCT Publication No. WO 2011 / 051726.

[0387] Compounds of the Disclosure In some aspects, the present disclosure provides a compound of formula (0): [ka] or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X is CR X or N, R Xis H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH; W 1 is N or CR W1 and R W1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; W 2 is N or CR W2 and R W2 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halogens; W 3 is N or CR W3 and R W3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; W 4 is N or CR W4 and 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, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10The aryl or 5- to 10-membered heteroaryl may optionally be one or more R 1a is replaced by Each R 1a are 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, 3-12 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 atoms therebetween form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo; 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 the bond to A, R X1 are independently H, S(=O)2R X1a, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R X1a is replaced by Each R X1a are independently halogen, C1-C6 alkyl, or 3-12 membered heterocycloalkyl, wherein C1-C6 alkyl or 3-12 membered heterocycloalkyl is optionally substituted with one or more halogens; A is C1-C6 alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), wherein C1-C6 alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C-C alkyl)-(5- to 10-membered heteroaryl), optionally with one or more R A is replaced by Each R A are 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, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A1 is replaced by Each R A1 are 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, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A2 is replaced by Each R A2 are independently halogen, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; In the formula, R A3 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0388] In some aspects, the present disclosure provides a compound of formula (I'): [ka] The isomers thereof, or pharmaceutically acceptable salts thereof are provided.

[0389] In some aspects, the present disclosure provides a compound of formula (I): [ka] The isomers thereof, or pharmaceutically acceptable salts thereof are provided.

[0390] In some aspects, the present disclosure provides a compound of formula (II'): [ka] The isomers thereof, or pharmaceutically acceptable salts thereof are provided.

[0391] 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 be selected from the groups described herein, where applicable, and 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 Any group described herein for any 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 It is understood that one or more of the residues of may be combined with any group described herein.

[0392] Variables X and R X 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.

[0393] In some embodiments, R Xis H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH. X is H, halogen, cyano, oxo, or OH. In some embodiments, R X is H. In some embodiments, R X is a 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, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH. X is C1-C6 alkoxy optionally substituted with one or more OH. In some embodiments, R X is C alkoxy optionally substituted with one or more OH. In some embodiments, R X is a C alkoxy optionally substituted with one or more OH. In some embodiments, R X is a C alkoxy optionally substituted with one or more OH. In some embodiments, R X is a C4 alkoxy optionally substituted with one or more OH. In some embodiments, R X is a C5 alkoxy optionally substituted with one or more OH. In some embodiments, R Xis a C6 alkoxy optionally substituted with one or more OH.

[0394] Variable W 1 , R W1 , W 2 , R W2 , W 3 , R W3 , W 4 , R W4 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.

[0395] In some embodiments, R W1 is H, halogen, C-C alkyl, C-C alkenyl, or C-C alkynyl. W1 is H or halogen. In some embodiments, R W1 is H. In some embodiments, R W1 is a 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. W1 is C1-C6 alkyl. In some embodiments, R W1 is C alkyl. In some embodiments, R W1 is C alkyl. In some embodiments, R W1 is C alkyl. In some embodiments, R W1 is C4 alkyl. In some embodiments, R W1is a C alkyl. In some embodiments, R W1 is C alkyl. In some embodiments, R W1 is CH3.

[0396] 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).

[0397] In some embodiments, R W2 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halogens.

[0398] In some embodiments, R W2 is H or 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, a C2-C6 alkenyl, or a C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halogens. W2 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. W2is C1-C6 alkyl. In some embodiments, R W2 is C alkyl. In some embodiments, R W2 is C alkyl. In some embodiments, R W2 is C alkyl. In some embodiments, R W2 is C4 alkyl. In some embodiments, R W2 is a C alkyl. In some embodiments, R W2 is C alkyl. In some embodiments, R W2 is CH3.

[0399] In some embodiments, W 3 is N or CR W3 In some embodiments, W 3 is N. In some embodiments, W 3 is CR W3 In some embodiments, W 3 is CH.

[0400] In some embodiments, R W3 is H, halogen, C-C alkyl, C-C alkenyl, or C-C alkynyl. W3 is H or halogen. In some embodiments, R W3 is H. In some embodiments, R W3 is a 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. W3 is C1-C6 alkyl. In some embodiments, R W3 is C alkyl. In some embodiments, R W3 is C alkyl. In some embodiments, R W3is C alkyl. In some embodiments, R W3 is C4 alkyl. In some embodiments, R W3 is a C alkyl. In some embodiments, R W3 is a C6 alkyl.

[0401] 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.

[0402] In some embodiments, R W4 is H, halogen, C-C alkyl, C-C alkenyl, C-C alkynyl, or S(C-C alkyl). W4 is H or halogen. In some embodiments, R W4 is H. In some embodiments, R W4 is a 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.

[0403] In some embodiments, R W4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or S(C1-C6 alkyl).

[0404] In some embodiments, R W4 is C1-C6 alkyl. In some embodiments, R W4 is C alkyl. In some embodiments, R W4 is C alkyl. In some embodiments, R W4 is C alkyl. In some embodiments, R W4is C4 alkyl. In some embodiments, R W4 is a C alkyl. In some embodiments, R W4 is C alkyl. In some embodiments, W 1 is CR W1 and W 2 is CR W2 and W 3 is CR W3 and W 4 is CR W4 is.

[0405] In some embodiments, W 1 is CH and W 2 is CH and W 3 is CH, and W 4 is CH. In some embodiments, W 1 is CH and W 2 is C(CH3) and W 3 is CH, and W 4 is CH. In some embodiments, W 1 is CR W1 and W 2 is CR W2 and W 3 is N, and W 4 is CR W4 In some embodiments, W 1 is CH and W 2 is C(CH3) and W 3 is N, and W 4 is CH. In some embodiments, W 1 is CR W1 and W 2 is N and W 3 is N, and W 4 is CR W4 In some embodiments, W 1 is CR W1 and W 2 is CR W2 and W 3 is N, and W 4 is N.

[0406] Variable R 1 , R 1a , R 2 , R 3 In some embodiments, R 1 is H, 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 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R 1a In some embodiments, R 1 is H. In some embodiments, R 1 is C1-C6 alkyl, wherein the C1-C6 alkyl is selected from one or more R 1a In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is C4 alkyl. In some embodiments, R 1 is a C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is CH3. In some embodiments, R 1 is CH2CH3.

[0407] In some embodiments, each R 1ais 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-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl. In some embodiments, R 1a is halogen, cyano, oxo, OH, or NH. In some embodiments, R 1a is cyano. In some embodiments, R 1a is 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, 3-8 membered heterocycloalkyl, C6-C 10 It is aryl, or 5- to 10-membered heteroaryl.

[0408] In some embodiments, R 2 is H, cyano, oxo, OH, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxy. 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. 2 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0409] In some embodiments, R 3 is H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0410] In some embodiments, R 1 and R 3 together with the atoms therebetween form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo.

[0411] Variable X 1 , R X1 , R X1a , A, R A , R A1 , R A2 , R A3 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 -*, -NR X1 C(=O)NR X1 -*, -S(=O)2NR X1 -* or -NR X1 S(=O)2-*, where * indicates a bond 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 the bond to A. In some embodiments, is -NR X1In some embodiments, X is -*, where * indicates a bond to A. In some embodiments, X is -NH-*, where * indicates a bond to A. In some embodiments, X is -NH-*, where * indicates a bond to A. 1 But -C(=O)NR X1 -* or -NR X1 C(=O)-*, where * indicates a bond to A. In some embodiments, X 1 But -C(=O)NR X1 -*, where * indicates a bond to A. In some embodiments, X 1 is —C(═O)NH—*, where * indicates a bond to A. In some embodiments, X 1 But, -NR X1 C(=O)-*, where * indicates a bond to A. In some embodiments, X 1 is —NHC(═O)—*, where * indicates a bond to A. In some embodiments, X 1 But, -NR X1 C(=NH)-*, where * indicates a bond to A. In some embodiments, X 1 is -NHC(=NH)-*, where * indicates the bond to A.

[0412] 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, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be 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 X1is 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 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be 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 aryl, or 5-10 membered heteroaryl. In some embodiments, R X1 is C1-C6 alkyl. In some embodiments, R X1 is CH3.

[0413] In some embodiments, R X1a is halogen, C1-C6 alkyl, or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more halogens. X1a is a halogen. In some embodiments, R X1a is C1-C6 alkyl optionally substituted with one or more halogens. In some embodiments, R X1a is a 3-8 membered heterocycloalkyl optionally substituted with one or more halogens.

[0414] In some embodiments, A is C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10Aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), -(C1-C6 alkyl)-(3-8 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), wherein C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), -(C1-C6 alkyl)-(3-8 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C-C alkyl)-(5- to 10-membered heteroaryl), optionally with one or more R A In some embodiments, A is substituted with C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A In some embodiments, A is substituted with C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A In some embodiments, A is C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more R AIn some embodiments, A is substituted with one or more R A In some embodiments, A is a 3-8 membered heterocycloalkyl optionally substituted with one or more R A In some embodiments, A is tetrahydropyranyl optionally substituted with one or more R A In some embodiments, A is piperidinyl optionally substituted with C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A In some embodiments, A is substituted with one or more R A C6-C optionally substituted with 10 In some embodiments, A is C-C 10 In some embodiments, A is aryl. In some embodiments, A is phenyl. In some embodiments, A is one or more R A In some embodiments, A is phenyl optionally substituted with one or more R AIn some embodiments, A is a 5-10 membered heteroaryl optionally substituted with R. In some embodiments, A is a 5-10 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]pyridyl. In some embodiments, A is 2,3-dihydrofuro[2,3-c]pyridyl. In some embodiments, A is 2,3-dihydrofuro[3,2-b]pyridyl. In some embodiments, A is 3,4-dihydro-1H-pyrano[3,4-c]pyridyl. In some embodiments, A is 4,5,6,7-tetrahydrobenzo[d]isoxazolyl. In some embodiments, A is selected from the group consisting of one or more R A In some embodiments, A is pyridyl optionally substituted with one or more R A In some embodiments, A is triazolyl optionally substituted with one or more R A In some embodiments, A is pyrazolyl optionally substituted with one or more R A In some embodiments, A is imidazolyl optionally substituted with one or more R A In some embodiments, A is oxazolyl optionally substituted with one or more R A In some embodiments, A is imidazo[1,5-a]pyridyl optionally substituted with one or more R A In some embodiments, A is 2,3-dihydrofuro[2,3-c]pyridyl optionally substituted with one or more R A In some embodiments, A is 2,3-dihydrofuro[3,2-b]pyridyl optionally substituted with one or more R A In some embodiments, A is 3,4-dihydro-1H-pyrano[3,4-c]pyridyl optionally substituted with one or more R AIn some embodiments, A is 4,5,6,7-tetrahydrobenzo[d]isoxazolyl optionally substituted with -(C1-C6 alkyl)-(C3-C8 cycloalkyl), -(C1-C6 alkyl)-(3-8 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), wherein -(C1-C6 alkyl)-(C3-C8 cycloalkyl), -(C1-C6 alkyl)-(3-8 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl) optionally may be joined by one or more R A In some embodiments, A is -(C1-C6 alkyl)-(3-8 membered heterocycloalkyl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), wherein -(C1-C6 alkyl)-(3-8 membered heterocycloalkyl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl) is optionally substituted with one or more R A In some embodiments, A is substituted with one or more R A In some embodiments, A is -(C1-C6 alkyl)-(3- to 8-membered heterocycloalkyl) optionally substituted with one or more R A In some embodiments, A is -(C alkyl)-(tetrahydropyranyl) optionally substituted with one or more R A In some embodiments, A is -(C alkyl)-(piperidinyl) optionally substituted with one or more R AIn some embodiments, A is -(C1-C6 alkyl)-(5-10 membered heteroaryl) optionally substituted with one or more R A In some embodiments, A is -(C alkyl)-(triazolyl) optionally substituted with one or more R A is -(C alkyl)-(triazolyl) optionally substituted with

[0415] In some embodiments, X 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is phenyl optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is phenyl optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is phenyl optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is pyridyl optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is pyridyl optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is pyridyl optionally substituted with 1is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is triazolyl optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is triazolyl optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is triazolyl optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is tetrahydropyranyl optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is tetrahydropyranyl optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is tetrahydropyranyl optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is piperidinyl optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is piperidinyl optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is piperidinyl optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R AIn some embodiments, X is -(C alkyl)-(tetrahydropyranyl) optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(tetrahydropyranyl) optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(tetrahydropyranyl) optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(piperidinyl) optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(piperidinyl) optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(piperidinyl) optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(triazolyl) optionally substituted with 1 is —C(═O)NH—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(triazolyl) optionally substituted with 1 is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(triazolyl) optionally substituted with 1is —NHC(═O)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(triazolyl) optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A In some embodiments, X is -(C alkyl)-(triazolyl) optionally substituted with 1 is —NHC(═NH)—*, where * indicates a bond to A, and A is one or more R A is -(C alkyl)-(triazolyl) optionally substituted with

[0416] In some embodiments, R A is 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, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be 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 a halogen. In some embodiments, R A is fluorine. In some embodiments, R A is chlorine. In some embodiments, R Ais 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 one or more R A2 In some embodiments, R is O(C-C alkyl) optionally substituted with A is NHR A1 In some embodiments, R A is N(R A1 )2. In some embodiments, R A is N(CH). 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 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A1 In some embodiments, R A is C1-C6 alkyl. In some embodiments, R A is C alkyl. In some embodiments, R A is C alkyl. In some embodiments, R A is C alkyl. In some embodiments, R A is C4 alkyl. In some embodiments, R A is a C alkyl. In some embodiments, R A is C alkyl. In some embodiments, R A is one or more R A1 In some embodiments, R is C1-C6 alkyl optionally substituted with Ais one or more R A1 In some embodiments, R is a C alkyl optionally substituted with A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is C1-C6 alkyl optionally substituted with one or more halogens. In some embodiments, R A is a C alkyl optionally substituted with one or more halogens. In some embodiments, R A is a C alkyl optionally substituted with one or more halogens. In some embodiments, R A is CH3. In some embodiments, R A is CF3.

[0417] In some embodiments, R A is C(CH3)2CN. In some embodiments, R A is C1-C6 alkoxy. In some embodiments, R A is C alkoxy. In some embodiments, R A is C2 alkoxy. In some embodiments, R A is C alkoxy. In some embodiments, R A is C4 alkoxy. In some embodiments, R A is C5 alkoxy. In some embodiments, R A is C6 alkoxy. In some embodiments, RA is one or more R A1 In some embodiments, R is C1-C6 alkoxy optionally substituted with A is one or more R A1 In some embodiments, R is C alkoxy optionally substituted with A is one or more R A1 In some embodiments, R is a C alkoxy optionally substituted with A is one or more R A1 In some embodiments, R is a C alkoxy optionally substituted with A is one or more R A1 In some embodiments, R is a C4 alkoxy optionally substituted with A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is C-C cycloalkyl. In some embodiments, R A is C cycloalkyl. In some embodiments, R A is C4 cycloalkyl. In some embodiments, R A is C cycloalkyl. In some embodiments, R A is Ccycloalkyl. In some embodiments, R A is C cycloalkyl. In some embodiments, R A is a C8 cycloalkyl.

[0418] In some embodiments, R A is one or more R A1 In some embodiments, R is a C-C cycloalkyl optionally substituted with A is one or more R A1 In some embodiments, R is a C cycloalkyl optionally substituted with A is one or more R A1In some embodiments, R A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is one or more R A1 In some embodiments, R A is one or more R A1 is a C cycloalkyl optionally substituted with

[0419] 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, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be 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 a halogen. In some embodiments, R A1 is fluorine. In some embodiments, R A1 is chlorine. In some embodiments, R A1is 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 NH. 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 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A2 In some embodiments, R A1 is C1-C6 alkyl. In some embodiments, R A1 is C alkyl. In some embodiments, R A1 is C alkyl. In some embodiments, R A1 is C alkyl. In some embodiments, R A1 is C4 alkyl. In some embodiments, R A1 is a C alkyl. In some embodiments, R A1 is C alkyl. In some embodiments, R A1 is one or more R A2 In some embodiments, R is C1-C6 alkyl optionally substituted with A1 is one or more R A2 In some embodiments, R is a C alkyl optionally substituted with A1 is one or more R A2 In some embodiments, R A1is one or more R A2 In some embodiments, R A1 is one or more R A2 In some embodiments, R A1 is one or more R A2 In some embodiments, R A1 is one or more R A2 is a C6 alkyl optionally substituted with

[0420] In some embodiments, R A is C1-C6 alkyl, and R A1 is a halogen. In some embodiments, R A is a C1 alkyl, and R A1 is fluorine. In some embodiments, R A is C1-C6 alkyl, and R A1 is cyano. In some embodiments, R A is a C1 alkyl, and R A1 is cyano.

[0421] In some embodiments, R A2 are halogens, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. A2 are halogens, 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 A2is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. A2 is C1-C6 alkyl. In some embodiments, R A2 is C alkyl. In some embodiments, R A2 is C alkyl. In some embodiments, R A2 is C alkyl. In some embodiments, R A2 is C4 alkyl. In some embodiments, R A2 is a C alkyl. In some embodiments, R A2 is a C6 alkyl.

[0422] In some embodiments, R A3 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0423] In some embodiments, the compound is a compound of formula (Ia), (Ib), (Ic), (Id), or (If): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0424] In some embodiments, the compound is a compound of the following formula (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), or (It): [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0425] In some embodiments, the compound is a compound of formula (Iu), (Iv), (Iw), or (Ix): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0426] In some embodiments, the compound is a compound of the following formula (Iai), (Ibi), (Ici), (Idi), or (Ifi): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0427] In some embodiments, the compound is a compound of the following formula (Igi), (Ihi), (Iii), (Iji), (Iki), (Ili), (Imi), (Ini), (Ioi), (Ipi), (Iqi), (Iri), (Isi), or (Iti): [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0428] In some embodiments, the compound is a compound of the following formula (Iui), (Ivi), (Iwi), or (Ixi): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0429] In some embodiments, the compound is a compound of the following formula (Ia-ii), (Ib-ii), (Ic-ii), (Id-ii), (Ie-ii), (If-ii), (Ig-ii), (Ih-ii), (Ii-ii), (Ij-ii), (Ik-ii), (Il-ii), (Im-ii), (In-ii), (Io-ii), or (Ip-ii): [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0430] In some embodiments, the compound is a compound of the following formula (Iq-ii), (Ir-ii), (Is-ii), (It-ii), (Iu-ii), (Iv-ii), (Iw-ii), (Ix-ii), (Iy-ii), (Iz-ii), (I-aa-ii), (I-bb-ii), (I-cc-ii), or (I-dd-ii): [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0431] In some embodiments, the compound is a compound of the following formula (I-ee-ii), (I-ff-ii), (I-gg-ii), or (I-hh-ii): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0432] In some embodiments, the compound is selected from the compounds set forth in Table I, and pharmaceutically acceptable salts and stereoisomers thereof.

[0433] In some embodiments, the compound is selected from the compounds set forth in Table I, and pharmaceutically acceptable salts thereof.

[0434] In some embodiments, the compound is selected from the compounds set forth in Table I. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25 Table 4-26 Table 4-27 Table 4-28 Table 4-29 Table 4-30 Table 4-31 Table 4-32 Table 4-33 Table 4-34 Table 4-35 Table 4-36 Table 4-37 Table 4-38 Table 4-39 Table 4-40 Table 4-41 Table 4-42 Table 4-43 Table 4-44 Table 4-45 Table 4-46 Table 4-47 Table 4-48 Table 4-49 Table 4-50 Table 4-51 Table 4-52 Table 4-53 Table 4-54 Table 4-55 Table 4-56 Table 4-57 Table 4-58 Table 4-59 Table 4-60 Table 4-61 Table 4-62 Table 4-63 Table 4-64 Table 4-65 Table 4-66 Table 4-67 Table 4-68 Table 4-69 Table 4-70 Table 4-71 Table 4-72 Table 4-73 Table 4-74 Table 4-75 Table 4-76

[0435] In some embodiments, the compound is Compound No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 44, 49, 52, 53, 55, 56, 57, 58, 59, 60, 62, 63, 65, 66, 68, 71, 75, 77, 78, 79, 153, 154, 173, 174, 175, 176, 191, 193, 194, 200, 201, 202, 203, 204, 206, 214, 215, 217, 218, 220, 221, 222, 223, 225, 226, 227, 229, 230, 231, 233, 234, 235, 236, 237, 238, 242, 243, 245, 247, 248, 249, 252, 253, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 271, 272, 274, 275, and 276, and pharmaceutically acceptable salts and stereoisomers thereof.

[0436] In some embodiments, the compound is Compound No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 44, 49, 52, 53, 55, 56, 57, 58, 59, 60, 62, 63, 65, 66, 68, 71, 75, 77, 78, 79, 153, 154, 173, 174, 175, 176, 191, 193, 194, 200, 201, 202, 203, 204, 206, 214, 215, 217, 218, 220, 221, 222, 223, 225, 226, 227, 229, 230, 231, 233, 234, 235, 236, 237, 238, 242, 243, 245, 247, 248, 249, 252, 253, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 271, 272, 274, 275, and 276, and pharmaceutically acceptable salts thereof.

[0437] In some embodiments, the compound is Compound No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 44, 49, 52, 53, 55, 56, 57, 58, 59, 60, 62, 63, 65, 66, 68, 71, 75, 77, 78, 79, 153, 154, 173, 174, 175, 176, 191, 193 , 194, 200, 201, 202, 203, 204, 206, 214, 215, 217, 218, 220, 221, 222, 223, 225, 226, 227, 229, 230, 231, 233, 234, 235, 236, 237, 238, 242, 243, 245, 247, 248, 249, 252, 253, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 271, 272, 274, 275, and 276.

[0438] In some embodiments, the compound is selected from Compound Nos. 1, 3, 4, 6, 7, 9, 10, 14, 16, 17, 18, 19, 20, 24, 27, 29, 32, 33, 49, 52, 55, 57, 60, 79, 154, 193, 200, 203, 204, 261, 263, 265, 267, 274, and 276, and pharmaceutically acceptable salts and stereoisomers thereof.

[0439] In some embodiments, the compound is selected from Compound Nos. 1, 3, 4, 6, 7, 9, 10, 14, 16, 17, 18, 19, 20, 24, 27, 29, 32, 33, 49, 52, 55, 57, 60, 79, 154, 193, 200, 203, 204, 261, 263, 265, 267, 274, and 276, and pharmaceutically acceptable salts thereof.

[0440] In some embodiments, the compound is selected from compound numbers 1, 3, 4, 6, 7, 9, 10, 14, 16, 17, 18, 19, 20, 24, 27, 29, 32, 33, 49, 52, 55, 57, 60, 79, 154, 193, 200, 203, 204, 261, 263, 265, 267, 274, and 276.

[0441] In some embodiments, the compound is Compound No. 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0442] In some embodiments, the compound is Compound No. 1, or a pharmaceutically acceptable salt thereof.

[0443] In some embodiments, the compound is Compound No. 1.

[0444] In some embodiments, the compound is Compound No. 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0445] In some embodiments, the compound is Compound No. 2, or a pharmaceutically acceptable salt thereof.

[0446] In some embodiments, the compound is Compound No. 2.

[0447] In some embodiments, the compound is Compound No. 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0448] In some embodiments, the compound is Compound No. 3, or a pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the compound is Compound No. 3.

[0450] In some embodiments, the compound is Compound No. 4, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0451] In some embodiments, the compound is Compound No. 4, or a pharmaceutically acceptable salt thereof.

[0452] In some embodiments, the compound is Compound No. 4.

[0453] In some embodiments, the compound is Compound No. 5, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0454] In some embodiments, the compound is Compound No. 5, or a pharmaceutically acceptable salt thereof.

[0455] In some embodiments, the compound is Compound No. 5.

[0456] In some embodiments, the compound is Compound No. 6, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0457] In some embodiments, the compound is Compound No. 6, or a pharmaceutically acceptable salt thereof.

[0458] In some embodiments, the compound is Compound No. 6.

[0459] In some embodiments, the compound is Compound No. 7, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0460] In some embodiments, the compound is Compound No. 7, or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the compound is Compound No. 7.

[0462] In some embodiments, the compound is Compound No. 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0463] In some embodiments, the compound is Compound No. 8, or a pharmaceutically acceptable salt thereof.

[0464] In some embodiments, the compound is Compound No. 8.

[0465] In some embodiments, the compound is Compound No. 9, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0466] In some embodiments, the compound is Compound No. 9, or a pharmaceutically acceptable salt thereof.

[0467] In some embodiments, the compound is Compound No. 9.

[0468] In some embodiments, the compound is Compound No. 10, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0469] In some embodiments, the compound is Compound No. 10, or a pharmaceutically acceptable salt thereof.

[0470] In some embodiments, the compound is Compound No. 10.

[0471] In some embodiments, the compound is Compound No. 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0472] In some embodiments, the compound is Compound No. 11, or a pharmaceutically acceptable salt thereof.

[0473] In some embodiments, the compound is Compound No. 11.

[0474] In some embodiments, the compound is Compound No. 12, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0475] In some embodiments, the compound is Compound No. 12, or a pharmaceutically acceptable salt thereof.

[0476] In some embodiments, the compound is Compound No. 12.

[0477] In some embodiments, the compound is Compound No. 14, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0478] In some embodiments, the compound is Compound No. 14, or a pharmaceutically acceptable salt thereof.

[0479] In some embodiments, the compound is Compound No. 14.

[0480] In some embodiments, the compound is Compound No. 15, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0481] In some embodiments, the compound is Compound No. 15, or a pharmaceutically acceptable salt thereof.

[0482] In some embodiments, the compound is Compound No. 15.

[0483] In some embodiments, the compound is Compound No. 16, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0484] In some embodiments, the compound is Compound No. 16, or a pharmaceutically acceptable salt thereof.

[0485] In some embodiments, the compound is Compound No. 16.

[0486] In some embodiments, the compound is Compound No. 17, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0487] In some embodiments, the compound is Compound No. 17, or a pharmaceutically acceptable salt thereof.

[0488] In some embodiments, the compound is Compound No. 17.

[0489] In some embodiments, the compound is Compound No. 18, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0490] In some embodiments, the compound is Compound No. 18, or a pharmaceutically acceptable salt thereof.

[0491] In some embodiments, the compound is Compound No. 18.

[0492] In some embodiments, the compound is Compound No. 19, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0493] In some embodiments, the compound is Compound No. 19, or a pharmaceutically acceptable salt thereof.

[0494] In some embodiments, the compound is Compound No. 19.

[0495] In some embodiments, the compound is Compound No. 20, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0496] In some embodiments, the compound is Compound No. 20, or a pharmaceutically acceptable salt thereof.

[0497] In some embodiments, the compound is Compound No. 20.

[0498] In some embodiments, the compound is Compound No. 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0499] In some embodiments, the compound is Compound No. 21, or a pharmaceutically acceptable salt thereof.

[0500] In some embodiments, the compound is Compound No. 21.

[0501] In some embodiments, the compound is Compound No. 22, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0502] In some embodiments, the compound is Compound No. 22, or a pharmaceutically acceptable salt thereof.

[0503] In some embodiments, the compound is Compound No. 22.

[0504] In some embodiments, the compound is Compound No. 23, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0505] In some embodiments, the compound is Compound No. 23, or a pharmaceutically acceptable salt thereof.

[0506] In some embodiments, the compound is Compound No. 23.

[0507] In some embodiments, the compound is Compound No. 24, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0508] In some embodiments, the compound is Compound No. 24, or a pharmaceutically acceptable salt thereof.

[0509] In some embodiments, the compound is Compound No. 24.

[0510] In some embodiments, the compound is Compound No. 25, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0511] In some embodiments, the compound is Compound No. 25, or a pharmaceutically acceptable salt thereof.

[0512] In some embodiments, the compound is Compound No. 25.

[0513] In some embodiments, the compound is Compound No. 26, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0514] In some embodiments, the compound is Compound No. 26, or a pharmaceutically acceptable salt thereof.

[0515] In some embodiments, the compound is Compound No. 26.

[0516] In some embodiments, the compound is Compound No. 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0517] In some embodiments, the compound is Compound No. 27, or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, the compound is Compound No. 27.

[0519] In some embodiments, the compound is Compound No. 29, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0520] In some embodiments, the compound is Compound No. 29, or a pharmaceutically acceptable salt thereof.

[0521] In some embodiments, the compound is Compound No. 29.

[0522] In some embodiments, the compound is Compound No. 30, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0523] In some embodiments, the compound is Compound No. 30, or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the compound is Compound No. 30.

[0525] In some embodiments, the compound is Compound No. 31, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0526] In some embodiments, the compound is Compound No. 31, or a pharmaceutically acceptable salt thereof.

[0527] In some embodiments, the compound is Compound No. 31.

[0528] In some embodiments, the compound is Compound No. 32, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0529] In some embodiments, the compound is Compound No. 32, or a pharmaceutically acceptable salt thereof.

[0530] In some embodiments, the compound is Compound No. 32.

[0531] In some embodiments, the compound is Compound No. 33, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0532] In some embodiments, the compound is Compound No. 33, or a pharmaceutically acceptable salt thereof.

[0533] In some embodiments, the compound is Compound No. 33.

[0534] In some embodiments, the compound is Compound No. 34, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0535] In some embodiments, the compound is Compound No. 34, or a pharmaceutically acceptable salt thereof.

[0536] In some embodiments, the compound is Compound No. 34.

[0537] In some embodiments, the compound is Compound No. 35, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0538] In some embodiments, the compound is Compound No. 35, or a pharmaceutically acceptable salt thereof.

[0539] In some embodiments, the compound is Compound No. 35.

[0540] In some embodiments, the compound is Compound No. 37, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0541] In some embodiments, the compound is Compound No. 37, or a pharmaceutically acceptable salt thereof.

[0542] In some embodiments, the compound is Compound No. 37.

[0543] In some embodiments, the compound is Compound No. 38, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0544] In some embodiments, the compound is Compound No. 38, or a pharmaceutically acceptable salt thereof.

[0545] In some embodiments, the compound is Compound No. 38.

[0546] In some embodiments, the compound is Compound No. 39, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0547] In some embodiments, the compound is Compound No. 39, or a pharmaceutically acceptable salt thereof.

[0548] In some embodiments, the compound is Compound No. 39.

[0549] In some embodiments, the compound is Compound No. 40, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0550] In some embodiments, the compound is Compound No. 40, or a pharmaceutically acceptable salt thereof.

[0551] In some embodiments, the compound is Compound No. 40.

[0552] In some embodiments, the compound is Compound No. 41, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0553] In some embodiments, the compound is Compound No. 41, or a pharmaceutically acceptable salt thereof.

[0554] In some embodiments, the compound is Compound No. 41.

[0555] In some embodiments, the compound is Compound No. 42, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0556] In some embodiments, the compound is Compound No. 42, or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, the compound is Compound No. 42.

[0558] In some embodiments, the compound is Compound No. 43, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0559] In some embodiments, the compound is Compound No. 43, or a pharmaceutically acceptable salt thereof.

[0560] In some embodiments, the compound is Compound No. 43.

[0561] In some embodiments, the compound is Compound No. 44, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0562] In some embodiments, the compound is Compound No. 44, or a pharmaceutically acceptable salt thereof.

[0563] In some embodiments, the compound is Compound No. 44.

[0564] In some embodiments, the compound is Compound No. 49, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0565] In some embodiments, the compound is Compound No. 49, or a pharmaceutically acceptable salt thereof.

[0566] In some embodiments, the compound is Compound No. 49.

[0567] In some embodiments, the compound is Compound No. 52, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0568] In some embodiments, the compound is Compound No. 52, or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, the compound is Compound No. 52.

[0570] In some embodiments, the compound is Compound No. 53, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0571] In some embodiments, the compound is Compound No. 53, or a pharmaceutically acceptable salt thereof.

[0572] In some embodiments, the compound is Compound No. 53.

[0573] In some embodiments, the compound is Compound No. 55, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0574] In some embodiments, the compound is Compound No. 55, or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments, the compound is Compound No. 55.

[0576] In some embodiments, the compound is Compound No. 56, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0577] In some embodiments, the compound is Compound No. 56, or a pharmaceutically acceptable salt thereof.

[0578] In some embodiments, the compound is Compound No. 56.

[0579] In some embodiments, the compound is Compound No. 57, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0580] In some embodiments, the compound is Compound No. 57, or a pharmaceutically acceptable salt thereof.

[0581] In some embodiments, the compound is Compound No. 57.

[0582] In some embodiments, the compound is Compound No. 58, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0583] In some embodiments, the compound is Compound No. 58, or a pharmaceutically acceptable salt thereof.

[0584] In some embodiments, the compound is Compound No. 58.

[0585] In some embodiments, the compound is Compound No. 59, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0586] In some embodiments, the compound is Compound No. 59, or a pharmaceutically acceptable salt thereof.

[0587] In some embodiments, the compound is Compound No. 59.

[0588] In some embodiments, the compound is Compound No. 60, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0589] In some embodiments, the compound is Compound No. 60, or a pharmaceutically acceptable salt thereof.

[0590] In some embodiments, the compound is Compound No. 60.

[0591] In some embodiments, the compound is Compound No. 62, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0592] In some embodiments, the compound is Compound No. 62, or a pharmaceutically acceptable salt thereof.

[0593] In some embodiments, the compound is Compound No. 62.

[0594] In some embodiments, the compound is Compound No. 63, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0595] In some embodiments, the compound is Compound No. 63, or a pharmaceutically acceptable salt thereof.

[0596] In some embodiments, the compound is Compound No. 63.

[0597] In some embodiments, the compound is Compound No. 65, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0598] In some embodiments, the compound is Compound No. 65, or a pharmaceutically acceptable salt thereof.

[0599] In some embodiments, the compound is Compound No. 65.

[0600] In some embodiments, the compound is Compound No. 66, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0601] In some embodiments, the compound is Compound No. 66, or a pharmaceutically acceptable salt thereof.

[0602] In some embodiments, the compound is Compound No. 66.

[0603] In some embodiments, the compound is Compound No. 68, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0604] In some embodiments, the compound is Compound No. 68, or a pharmaceutically acceptable salt thereof.

[0605] In some embodiments, the compound is Compound No. 68.

[0606] In some embodiments, the compound is Compound No. 71, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0607] In some embodiments, the compound is Compound No. 71, or a pharmaceutically acceptable salt thereof.

[0608] In some embodiments, the compound is Compound No. 71.

[0609] In some embodiments, the compound is Compound No. 75, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0610] In some embodiments, the compound is Compound No. 75, or a pharmaceutically acceptable salt thereof.

[0611] In some embodiments, the compound is Compound No. 75.

[0612] In some embodiments, the compound is Compound No. 77, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0613] In some embodiments, the compound is Compound No. 77, or a pharmaceutically acceptable salt thereof.

[0614] In some embodiments, the compound is Compound No. 77.

[0615] In some embodiments, the compound is Compound No. 78, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0616] In some embodiments, the compound is Compound No. 78, or a pharmaceutically acceptable salt thereof.

[0617] In some embodiments, the compound is Compound No. 78.

[0618] In some embodiments, the compound is Compound No. 79, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0619] In some embodiments, the compound is Compound No. 79, or a pharmaceutically acceptable salt thereof.

[0620] In some embodiments, the compound is Compound No. 79.

[0621] In some embodiments, the compound is Compound No. 153, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0622] In some embodiments, the compound is Compound No. 153, or a pharmaceutically acceptable salt thereof.

[0623] In some embodiments, the compound is Compound No. 153.

[0624] In some embodiments, the compound is Compound No. 154, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0625] In some embodiments, the compound is Compound No. 154, or a pharmaceutically acceptable salt thereof.

[0626] In some embodiments, the compound is Compound No. 154.

[0627] In some embodiments, the compound is Compound No. 173, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0628] In some embodiments, the compound is Compound No. 173, or a pharmaceutically acceptable salt thereof.

[0629] In some embodiments, the compound is Compound No. 173.

[0630] In some embodiments, the compound is Compound No. 174, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0631] In some embodiments, the compound is Compound No. 174, or a pharmaceutically acceptable salt thereof.

[0632] In some embodiments, the compound is Compound No. 174.

[0633] In some embodiments, the compound is Compound No. 175, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0634] In some embodiments, the compound is Compound No. 175, or a pharmaceutically acceptable salt thereof.

[0635] In some embodiments, the compound is Compound No. 175.

[0636] In some embodiments, the compound is Compound No. 176, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0637] In some embodiments, the compound is Compound No. 176, or a pharmaceutically acceptable salt thereof.

[0638] In some embodiments, the compound is Compound No. 176.

[0639] In some embodiments, the compound is Compound No. 191, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0640] In some embodiments, the compound is Compound No. 191, or a pharmaceutically acceptable salt thereof.

[0641] In some embodiments, the compound is Compound No. 191.

[0642] In some embodiments, the compound is Compound No. 193, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0643] In some embodiments, the compound is Compound No. 193, or a pharmaceutically acceptable salt thereof.

[0644] In some embodiments, the compound is Compound No. 193.

[0645] In some embodiments, the compound is Compound No. 194, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0646] In some embodiments, the compound is Compound No. 194, or a pharmaceutically acceptable salt thereof.

[0647] In some embodiments, the compound is Compound No. 194.

[0648] In some embodiments, the compound is Compound No. 200, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0649] In some embodiments, the compound is Compound No. 200, or a pharmaceutically acceptable salt thereof.

[0650] In some embodiments, the compound is Compound No. 200.

[0651] In some embodiments, the compound is Compound No. 201, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0652] In some embodiments, the compound is Compound No. 201, or a pharmaceutically acceptable salt thereof.

[0653] In some embodiments, the compound is Compound No. 201.

[0654] In some embodiments, the compound is Compound No. 202, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0655] In some embodiments, the compound is Compound No. 202, or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments, the compound is Compound No. 202.

[0657] In some embodiments, the compound is Compound No. 203, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0658] In some embodiments, the compound is Compound No. 203, or a pharmaceutically acceptable salt thereof.

[0659] In some embodiments, the compound is Compound No. 203.

[0660] In some embodiments, the compound is Compound No. 204, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0661] In some embodiments, the compound is Compound No. 204, or a pharmaceutically acceptable salt thereof.

[0662] In some embodiments, the compound is Compound No. 204.

[0663] In some embodiments, the compound is Compound No. 206, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0664] In some embodiments, the compound is Compound No. 206, or a pharmaceutically acceptable salt thereof.

[0665] In some embodiments, the compound is Compound No. 206.

[0666] In some embodiments, the compound is Compound No. 214, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0667] In some embodiments, the compound is Compound No. 214, or a pharmaceutically acceptable salt thereof.

[0668] In some embodiments, the compound is Compound No. 214.

[0669] In some embodiments, the compound is Compound No. 215, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0670] In some embodiments, the compound is Compound No. 215, or a pharmaceutically acceptable salt thereof.

[0671] In some embodiments, the compound is Compound No. 215.

[0672] In some embodiments, the compound is Compound No. 217, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0673] In some embodiments, the compound is Compound No. 217, or a pharmaceutically acceptable salt thereof.

[0674] In some embodiments, the compound is Compound No. 217.

[0675] In some embodiments, the compound is Compound No. 218, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0676] In some embodiments, the compound is Compound No. 218, or a pharmaceutically acceptable salt thereof.

[0677] In some embodiments, the compound is Compound No. 218.

[0678] In some embodiments, the compound is Compound No. 220, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0679] In some embodiments, the compound is Compound No. 220, or a pharmaceutically acceptable salt thereof.

[0680] In some embodiments, the compound is Compound No. 220.

[0681] In some embodiments, the compound is Compound No. 221, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0682] In some embodiments, the compound is Compound No. 221, or a pharmaceutically acceptable salt thereof.

[0683] In some embodiments, the compound is Compound No. 221.

[0684] In some embodiments, the compound is Compound No. 222, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0685] In some embodiments, the compound is Compound No. 222, or a pharmaceutically acceptable salt thereof.

[0686] In some embodiments, the compound is Compound No. 222.

[0687] In some embodiments, the compound is Compound No. 223, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0688] In some embodiments, the compound is Compound No. 223, or a pharmaceutically acceptable salt thereof.

[0689] In some embodiments, the compound is Compound No. 223.

[0690] In some embodiments, the compound is Compound No. 225, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0691] In some embodiments, the compound is Compound No. 225, or a pharmaceutically acceptable salt thereof.

[0692] In some embodiments, the compound is Compound No. 225.

[0693] In some embodiments, the compound is Compound No. 226, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0694] In some embodiments, the compound is Compound No. 226, or a pharmaceutically acceptable salt thereof.

[0695] In some embodiments, the compound is Compound No. 226.

[0696] In some embodiments, the compound is Compound No. 227, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0697] In some embodiments, the compound is Compound No. 227, or a pharmaceutically acceptable salt thereof.

[0698] In some embodiments, the compound is Compound No. 227.

[0699] In some embodiments, the compound is Compound No. 229, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0700] In some embodiments, the compound is Compound No. 229, or a pharmaceutically acceptable salt thereof.

[0701] In some embodiments, the compound is Compound No. 229.

[0702] In some embodiments, the compound is Compound No. 230, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0703] In some embodiments, the compound is Compound No. 230, or a pharmaceutically acceptable salt thereof.

[0704] In some embodiments, the compound is Compound No. 230.

[0705] In some embodiments, the compound is Compound No. 231, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0706] In some embodiments, the compound is Compound No. 231, or a pharmaceutically acceptable salt thereof.

[0707] In some embodiments, the compound is Compound No. 231.

[0708] In some embodiments, the compound is Compound No. 233, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0709] In some embodiments, the compound is Compound No. 233, or a pharmaceutically acceptable salt thereof.

[0710] In some embodiments, the compound is Compound No. 233.

[0711] In some embodiments, the compound is Compound No. 234, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0712] In some embodiments, the compound is Compound No. 234, or a pharmaceutically acceptable salt thereof.

[0713] In some embodiments, the compound is Compound No. 234.

[0714] In some embodiments, the compound is Compound No. 235, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0715] In some embodiments, the compound is Compound No. 235, or a pharmaceutically acceptable salt thereof.

[0716] In some embodiments, the compound is Compound No. 235.

[0717] In some embodiments, the compound is Compound No. 236, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0718] In some embodiments, the compound is Compound No. 236, or a pharmaceutically acceptable salt thereof.

[0719] In some embodiments, the compound is Compound No. 236.

[0720] In some embodiments, the compound is Compound No. 237, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0721] In some embodiments, the compound is Compound No. 237, or a pharmaceutically acceptable salt thereof.

[0722] In some embodiments, the compound is Compound No. 237.

[0723] In some embodiments, the compound is Compound No. 238, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0724] In some embodiments, the compound is Compound No. 238, or a pharmaceutically acceptable salt thereof.

[0725] In some embodiments, the compound is Compound No. 238.

[0726] In some embodiments, the compound is Compound No. 242, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0727] In some embodiments, the compound is Compound No. 242, or a pharmaceutically acceptable salt thereof.

[0728] In some embodiments, the compound is Compound No. 242.

[0729] In some embodiments, the compound is Compound No. 243, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0730] In some embodiments, the compound is Compound No. 243, or a pharmaceutically acceptable salt thereof.

[0731] In some embodiments, the compound is Compound No. 243.

[0732] In some embodiments, the compound is Compound No. 245, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0733] In some embodiments, the compound is Compound No. 245, or a pharmaceutically acceptable salt thereof.

[0734] In some embodiments, the compound is Compound No. 245.

[0735] In some embodiments, the compound is Compound No. 247, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0736] In some embodiments, the compound is Compound No. 247, or a pharmaceutically acceptable salt thereof.

[0737] In some embodiments, the compound is Compound No. 247.

[0738] In some embodiments, the compound is Compound No. 248, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0739] In some embodiments, the compound is Compound No. 248, or a pharmaceutically acceptable salt thereof.

[0740] In some embodiments, the compound is Compound No. 248.

[0741] In some embodiments, the compound is Compound No. 249, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0742] In some embodiments, the compound is Compound No. 249, or a pharmaceutically acceptable salt thereof.

[0743] In some embodiments, the compound is Compound No. 249.

[0744] In some embodiments, the compound is Compound No. 252, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0745] In some embodiments, the compound is Compound No. 252, or a pharmaceutically acceptable salt thereof.

[0746] In some embodiments, the compound is Compound No. 252.

[0747] In some embodiments, the compound is Compound No. 253, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0748] In some embodiments, the compound is Compound No. 253, or a pharmaceutically acceptable salt thereof.

[0749] In some embodiments, the compound is Compound No. 253.

[0750] In some embodiments, the compound is Compound No. 255, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0751] In some embodiments, the compound is Compound No. 255, or a pharmaceutically acceptable salt thereof.

[0752] In some embodiments, the compound is Compound No. 255.

[0753] In some embodiments, the compound is Compound No. 256, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0754] In some embodiments, the compound is Compound No. 256, or a pharmaceutically acceptable salt thereof.

[0755] In some embodiments, the compound is Compound No. 256.

[0756] In some embodiments, the compound is Compound No. 257, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0757] In some embodiments, the compound is Compound No. 257, or a pharmaceutically acceptable salt thereof.

[0758] In some embodiments, the compound is Compound No. 257.

[0759] In some embodiments, the compound is Compound No. 258, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0760] In some embodiments, the compound is Compound No. 258, or a pharmaceutically acceptable salt thereof.

[0761] In some embodiments, the compound is Compound No. 258.

[0762] In some embodiments, the compound is Compound No. 259, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0763] In some embodiments, the compound is Compound No. 259, or a pharmaceutically acceptable salt thereof.

[0764] In some embodiments, the compound is Compound No. 259.

[0765] In some embodiments, the compound is Compound No. 260, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0766] In some embodiments, the compound is Compound No. 260, or a pharmaceutically acceptable salt thereof.

[0767] In some embodiments, the compound is Compound No. 260.

[0768] In some embodiments, the compound is Compound No. 261, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0769] In some embodiments, the compound is Compound No. 261, or a pharmaceutically acceptable salt thereof.

[0770] In some embodiments, the compound is Compound No. 261.

[0771] In some embodiments, the compound is Compound No. 262, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0772] In some embodiments, the compound is Compound No. 262, or a pharmaceutically acceptable salt thereof.

[0773] In some embodiments, the compound is Compound No. 262.

[0774] In some embodiments, the compound is Compound No. 263, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0775] In some embodiments, the compound is Compound No. 263, or a pharmaceutically acceptable salt thereof.

[0776] In some embodiments, the compound is Compound No. 263.

[0777] In some embodiments, the compound is Compound No. 264, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0778] In some embodiments, the compound is Compound No. 264, or a pharmaceutically acceptable salt thereof.

[0779] In some embodiments, the compound is Compound No. 264.

[0780] In some embodiments, the compound is Compound No. 265, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0781] In some embodiments, the compound is Compound No. 265, or a pharmaceutically acceptable salt thereof.

[0782] In some embodiments, the compound is Compound No. 265.

[0783] In some embodiments, the compound is Compound No. 266, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0784] In some embodiments, the compound is Compound No. 266, or a pharmaceutically acceptable salt thereof.

[0785] In some embodiments, the compound is Compound No. 266.

[0786] In some embodiments, the compound is Compound No. 267, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0787] In some embodiments, the compound is Compound No. 267, or a pharmaceutically acceptable salt thereof.

[0788] In some embodiments, the compound is Compound No. 267.

[0789] In some embodiments, the compound is Compound No. 271, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0790] In some embodiments, the compound is Compound No. 271, or a pharmaceutically acceptable salt thereof.

[0791] In some embodiments, the compound is Compound No. 271.

[0792] In some embodiments, the compound is Compound No. 272, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0793] In some embodiments, the compound is Compound No. 272, or a pharmaceutically acceptable salt thereof.

[0794] In some embodiments, the compound is Compound No. 272.

[0795] In some embodiments, the compound is Compound No. 274, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0796] In some embodiments, the compound is Compound No. 274, or a pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the compound is Compound No. 274.

[0798] In some embodiments, the compound is Compound No. 275, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0799] In some embodiments, the compound is Compound No. 275, or a pharmaceutically acceptable salt thereof.

[0800] In some embodiments, the compound is Compound No. 275.

[0801] In some embodiments, the compound is Compound No. 276, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0802] In some embodiments, the compound is Compound No. 276, or a pharmaceutically acceptable salt thereof.

[0803] In some embodiments, the compound is Compound No. 276.

[0804] Compounds of the present disclosure containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts thereof, are within the scope of the present disclosure. 2 Substitution with H) may result in certain therapeutic benefits resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0805] For the avoidance of doubt, when a group is modified herein by "as described herein," it is to be understood that the group includes the broadest definition appearing first, as well as each and every specific definition for that group.

[0806] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, triethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0807] It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0808] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0809] As used herein, the term "chiral center" refers to a carbon atom bonded to four non-identical substituents.

[0810] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0811] As used herein, the term "geometric isomer" refers to diastereomers whose presence hinders rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0812] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. 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 it is understood that the naming of the compound does not exclude any isomeric form, and it is understood that not all isomers may have the same level of activity.

[0813] It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof, and it is also understood that not all atropisomers have the same level of activity.

[0814] As used herein, an "atropisomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers restrict rotation by hindering the rotation of large groups around a central bond. However, such atropisomers usually exist as mixtures, although recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers in selected cases.

[0815] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the interchange of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomeric sets in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, the simultaneous shift of electrons and hydrogen atoms occurs. Cyclic-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) form, such as that exhibited by glucose.

[0816] It is understood that the compounds of the present application may be represented as different tautomeric forms. It should also be understood that, if a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present application, and the name of the compound does not exclude any tautomeric form. It will be understood that certain tautomers may have higher levels of activity than others.

[0817] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space 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." For example, if a compound has an asymmetric center and is bonded to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0818] The compounds of the present disclosure may have one or more asymmetric centers, and therefore, such compounds can be produced as individual (R) 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 both individual enantiomers and their racemates or other mixtures. Methods for the determination of stereochemistry and the separation of 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, 2001), for example, by synthesis from optically active starting materials or resolution of racemates. Some of the compounds of the present disclosure may have geometric isomeric centers (E and Z isomers). It should be understood that the present disclosure encompasses all optical, diastereomeric, and geometric isomers and mixtures thereof that possess antitumor activity.

[0819] The present disclosure also includes compounds of the present disclosure, as defined herein, that contain one or more isotopic substitutions.

[0820] Any compound of any formula described herein is understood to include, where applicable, the compound itself, as well as its salts and solvates.Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on the substituted compound disclosed herein.Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0821] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts may also be formed between a cation and a negatively charged group (e.g., carboxylic acid) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0822] It is understood that the compounds of the present disclosure, for example, the salts of compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules.Non-limiting examples of hydrates include monohydrates and dihydrates.Non-limiting examples of solvates include ethanol solvates and acetone solvates.

[0823] As used herein, "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as HO.

[0824] As used herein, the term "analog" refers to a compound that is structurally similar to another but differs slightly in composition (such as by replacing one atom with an atom of a different element, or by the presence of a particular functional group, or by replacing one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not in structure or origin.

[0825] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0826] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another broadly similar atom or group of atoms. The purpose of bioisostere substitution is to create a new compound with similar biological properties to the parent compound. Bioisostere substitution may be physicochemical or topologically based. 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.

[0827] It should also be understood that certain compounds of the present disclosure can exist in solvated and unsolvated forms, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that the present disclosure encompasses all such solvated forms that have antitumor activity.

[0828] It should also be understood that certain compounds of the present disclosure may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have antitumor activity. It is generally known that crystalline substances can be analyzed using conventional techniques, such as powder X-ray diffraction analysis, differential scanning calorimetry, thermogravimetry, 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 substances can be determined by Karl Fischer analysis.

[0829] The compounds of the present disclosure may exist in many different tautomeric forms, and reference to a compound of the present disclosure includes all such forms. For the avoidance of doubt, even if a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are encompassed by the disclosed formula. Examples of tautomers include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro. [ka]

[0830] Compounds of the present disclosure containing an amine functional group can also form N-oxides. Reference herein to compounds disclosed herein containing an amine functional group also includes N-oxides. When a compound contains multiple amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or the N-oxides of nitrogen atoms in 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., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), which involves reacting an amine compound with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0831] The compounds of the present disclosure can be administered in the form of prodrugs, which are decomposed in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to change 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 property-modifying group can be added. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents on the sulfonylurea group in any one of the compounds of the formulas disclosed herein.

[0832] Thus, the present disclosure includes the compounds of the present disclosure as previously defined when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes compounds of the present disclosure produced by organic synthetic means, as well as compounds produced in the human or animal body by metabolism of a precursor compound, i.e., the compounds of the present disclosure may be synthetically produced compounds or metabolically produced compounds.

[0833] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs are described in, for example, the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard, pp. 113-191 (1991); 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. al.,Chem.Pharm.Bull.,32,692(1984), g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14, and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0834] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compounds of the present disclosure containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C1-C2 esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Alkanoyl groups, such as C1-C6 alkyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups 10 Examples of ring substituents on the phenylacetyl group and benzoyl group 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 hydroxyl groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0835] Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure having a carboxy group include, for example, their in vivo cleavable amides, e.g., amines such as ammonia, C, e.g., methylamine, etc. 1-4 amides formed with amines such as alkylamines, for example (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 its esters.

[0836] Suitable pharmaceutically acceptable prodrugs of the disclosed compounds having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 and amides formed with alkanoyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0837] The in vivo effects of the compounds of the present disclosure may be exerted in part by one or more metabolic products formed in the human or animal body after administration of the compounds of the present disclosure. As previously described herein, the in vivo effects of the compounds of the present disclosure may also be exerted by metabolism of precursor compounds (prodrugs).

[0838] Synthesis method In some aspects, the disclosure provides methods of preparing the compounds disclosed herein.

[0839] In some aspects, the present disclosure provides methods of preparing compounds, comprising one or more steps described herein.

[0840] In some aspects, the disclosure provides compounds obtainable by, obtained by, or obtained directly by the methods for preparing compounds described herein.

[0841] In some aspects, the present disclosure provides intermediates suitable for use in the methods for preparing the compounds described herein.

[0842] The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying examples.

[0843] In the description of synthetic methods described herein, and in any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and work-up procedures, can be selected by one of ordinary skill in the art.

[0844] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0845] It will be understood that during the synthesis of the compounds of the present disclosure or during the synthesis of certain starting materials in the processes defined herein, it may be desirable to protect certain substituents to prevent their undesired reactions. A skilled chemist will understand when such protection is necessary and how to place and subsequently remove such protecting groups. For examples of protecting groups, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any conventional method described in the literature or known to skilled chemists that is suitable for removing the protecting group in question, and such methods are selected to result in the removal of the protecting group while minimizing interference with groups elsewhere in the molecule. Thus, when reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0846] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium on carbon, or by treatment with a Lewis acid, e.g., boron tris(trifluoroacetic acid). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0847] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl, aroyl groups, for example, benzoyl, or arylmethyl groups, for example, benzyl. The deprotection conditions for the above-mentioned protecting groups will necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed by hydrolysis using a suitable base, such as an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation using a catalyst, such as palladium on carbon.

[0848] Suitable protecting groups for carboxy groups are, for example, esterifying groups, for example, a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example, a tert-butyl group which may be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example, a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0849] Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the process may then further comprise the additional steps of: (i) removing any protecting groups present, (ii) converting the compound of the present disclosure to another compound of the present disclosure, (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof, and / or (iv) forming a prodrug thereof.

[0850] The resulting compounds of this disclosure can be isolated and purified using techniques well known in the art.

[0851] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or diisopropyl ether. 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 butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the above solvents, or mixtures with water.

[0852] The reaction temperature is preferably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0853] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of each compound and the reaction conditions. The appropriate reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature described above, the suitable reaction time is generally in the range of 10 minutes to 48 hours.

[0854] Moreover, by utilizing the procedures described herein in conjunction with procedures in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0855] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are readily accessible by a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize which types of reagents and reaction conditions to use to obtain the compounds of the present disclosure, and how they should be applied and adapted whenever necessary or useful in any particular case. Furthermore, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, e.g., by converting one specific functional group present in the compounds of the present disclosure or a suitable precursor molecule thereof into another by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, which are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or protecting) groups whenever necessary or useful. 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).

[0856] General routes for making the compounds of the present application are depicted in Schemes I-X. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0857] Biological assays Once compounds designed, selected, and / or optimized by the above-described methods are produced, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0858] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0859] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0860] In some embodiments, the biological assay may involve the production of retrovirus.

[0861] In some embodiments, the fusion mutant (e.g., BRAF-KIAA1549) may be subcloned into a retroviral expression vector (e.g., pMXs-IRES-Blasticidin), in which case the retrovirus may be produced by transfecting cells (e.g., HEK293T) with a retroviral plasmid (e.g., a retroviral BRAF mutant expression vector).

[0862] In some embodiments, cells (e.g., HEK293T) may be seeded and incubated. In some embodiments, a retroviral plasmid (e.g., a BRAF-KIAA fusion mutant) may be added to a transfection reagent, which may then be added to cells (e.g., HEK293T). In this case, the cells may be harvested.

[0863] In some embodiments, the biological assay may involve the production of a fusion-stable cell line (eg, a BRAF-KIAA1549 fusion-stable cell line).

[0864] In some embodiments, cells (e.g., BaF3) may be transduced with the viral supernatant (e.g., BRAF-KIAA1549 fusion viral supernatant) and the cells may be sampled for viability testing (e.g., by a luminescent cell viability assay such as CellTiterGlo). In some embodiments, the fusion-stable cell line may undergo cell banking and sequence confirmation (e.g., Sanger sequencing).

[0865] In some embodiments, the biological assay is an assay for cell proliferation.

[0866] In some embodiments, cells (e.g., BaF3 BRAF-KIAA1549 fusion cells) are suspended and distributed into plates. In some embodiments, to determine the effect of a compound of the present disclosure on cell proliferation, cells (e.g., BaF3 BRAF-KIAA1549 fusion cells) may be incubated in the presence of a vehicle control (e.g., DMSO) or in the presence of various concentrations of a compound of the present disclosure, and inhibition of cell proliferation may be determined by luminescence quantification (e.g., intracellular ATP content using CellTiterGlo) according to the manufacturer's protocol. In some embodiments, IC 50 To determine values, vehicle-treated cells were normalized as live cells and analyzed using software (e.g., CDD Vault (Collaborative Drug Discovery, Burlingame, CA)) that uses an algorithm (e.g., the Levenberg-Marquardt algorithm; Levenberg, K., 1994; Marquardt, D., 1963).

[0867] Pharmaceutical Composition In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient.

[0868] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table I and Table II. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table I. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table II.

[0869] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0870] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. The compounds of the present disclosure can also be formulated for intravenous (bolus injection or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0871] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0872] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as 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.

[0873] Any suitable chelating agent can be used, examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0874] Any suitable preservative can be used, including, for example, quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0875] The aqueous vehicle may also contain a tonicity agent to adjust the tonicity (osmotic pressure), which may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0876] The aqueous vehicle also preferably contains a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of crosslinked acrylic acid with polyalkenyl ethers or divinyl glycol (Carbopols, e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0877] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifier. The pH modifier is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifiers are added to adjust the formulation to a target acceptable pH range. Therefore, depending on the formulation, it is not necessary to use both an acid and a base; the addition of either an acid or a base may be sufficient to bring the mixture into the desired pH range.

[0878] The aqueous vehicle may also contain a buffering agent to stabilize the pH. If used, the buffering agent is selected from the group consisting of phosphate buffers (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or salts thereof, including disodium tetraborate), citrate buffers (e.g., citric acid or salts thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0879] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0880] Oral compositions generally contain an inert diluent or edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of therapeutic oral administration, active compound can be mixed with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is orally applied, rinsed and expectorated, or swallowed.Pharmaceutical compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0881] 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, in combination with a pharmaceutically acceptable diluent or carrier.

[0882] Compositions of the disclosure may be in a form 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), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0883] The compositions of the present disclosure can 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, sweeteners, flavoring agents and / or preservatives.

[0884] The magnitude of a therapeutic or prophylactic dose of a compound of the present disclosure will, of course, vary depending on the nature and severity of the disease, the age and sex of the animal, subject, or patient, and the route of administration, in accordance with well-known principles of medicine.

[0885] Exemplary Embodiments Exemplary embodiment number 1. 1. A method of treating or preventing cancer in a subject, comprising administering to a subject a compound according to formula (0): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is CR X or N, R Xis H, halogen, cyano, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH; W 1 is N or CR W1 and R W1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; W 2 is N or CR W2 and R W2 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halogens; W 3 is N or CR W3 and R W3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; W 4 is N or CR W4 and 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, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10The aryl or 5- to 10-membered heteroaryl may optionally be one or more R 1a is replaced by Each R 1a are 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, 3-12 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 atoms therebetween form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo; 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 the bond to A; R X1 are independently H, S(=O)2R X1a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R X1a is replaced by Each R X1a are independently halogen, C1-C6 alkyl, or 3-12 membered heterocycloalkyl, wherein C1-C6 alkyl or 3-12 membered heterocycloalkyl is optionally substituted with one or more halogens; A is C1-C6 alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), wherein C1-C6 alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C-C alkyl)-(5- to 10-membered heteroaryl), optionally with one or more R A is replaced by Each R A are independently halogen, cyano, oxo, OH, OR A1 , NH2, NHR A1 , N(R A1 )2, (=N)RA1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A1 is replaced by Each R A1 are 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, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl may optionally be one or more R A2 is replaced by Each R A2 are independently halogen, cyano, OH, NH2, N(R A3 )2, C(=O)R A3 , C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; In the formula, R A3 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0886] Exemplary embodiment number 2. A compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject.

[0887] Exemplary embodiment number 3. 10. Use of a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject.

[0888] Exemplary embodiment number 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.

[0889] Exemplary embodiment number 5. A method of treating or preventing cancer in a subject, 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.

[0890] Exemplary embodiment number 6. 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 treating or preventing cancer in a subject.

[0891] Exemplary embodiment number 7. 1. 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 in the manufacture of a medicament for treating or preventing cancer in a subject.

[0892] Exemplary embodiment number 8. The method, compound, combination or use of any one of exemplary embodiments 1 to 7, wherein the subject is a human.

[0893] Exemplary embodiment number 9. The method, compound, combination or use according to any one of exemplary embodiments 1 to 8, wherein the cancer is characterized by at least one oncogenic mutation in the BRAF gene.

[0894] Exemplary embodiment number 10. The method, compound, combination or use according to any one of exemplary embodiments 1 to 9, wherein the cancer is characterized by at least one oncogenic variant of B-Raf.

[0895] Exemplary embodiment number 11. The method, compound, combination or use according to any one of exemplary embodiments 1 to 10, wherein the subject has at least one oncogenic mutation in the BRAF gene.

[0896] Exemplary embodiment number 12. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 11, wherein the subject has at least one tumor and / or cancerous cell that expresses an oncogenic variant of B-Raf.

[0897] Exemplary embodiment number 13. The method, compound, combination or use according to any one of exemplary embodiments 1 to 12, wherein the oncogenic mutation in B-Raf is any of the B-Raf mutations presented in Table 1a.

[0898] Exemplary embodiment number 14. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 13, wherein the oncogenic variant of B-Raf can be any of the B-Raf variants presented in Table 1b.

[0899] Exemplary embodiment number 15. 15. The method, compound, combination or use according to any one of exemplary embodiments 1 to 14, wherein the cancer is characterized by at least one oncogenic mutation in the KRAS gene.

[0900] Exemplary embodiment number 16. 16. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 15, wherein the cancer is characterized by at least one oncogenic variant of K-Ras.

[0901] Exemplary embodiment number 17. 17. The method, compound, combination or use according to any one of exemplary embodiments 1 to 16, wherein the subject has at least one oncogenic mutation in the KRAS gene.

[0902] Exemplary embodiment number 18. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 17, wherein the subject has at least one tumor and / or cancerous cell that expresses an oncogenic variant of K-Ras.

[0903] Exemplary embodiment number 19. The method, compound, combination or use according to any one of exemplary embodiments 1 to 18, wherein the cancer is characterized by at least one oncogenic mutation in the NRAS gene.

[0904] Exemplary embodiment number 20. 20. The method, compound, combination, or use of any one of exemplary embodiments 1-19, wherein the cancer is characterized by at least one oncogenic variant of N-Ras.

[0905] Exemplary embodiment number 21. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 20, wherein the subject has at least one oncogenic mutation in the NRAS gene.

[0906] Exemplary embodiment number 22. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 21, wherein the subject has at least one tumor and / or cancerous cell that expresses an oncogenic variant of N-Ras.

[0907] Exemplary embodiment number 23. 23. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 22, wherein the cancer is characterized by at least one oncogenic mutation in the NF1 gene.

[0908] Exemplary embodiment number 24. The method, compound, combination, or use of any one of exemplary embodiments 1-23, wherein the cancer is characterized by at least one oncogenic variant of NF1.

[0909] Exemplary embodiment number 25. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 24, wherein the subject has at least one oncogenic mutation in the NF1 gene.

[0910] Exemplary embodiment number 26. The method, compound, combination, or use of any one of exemplary embodiments 1-25, wherein the subject has at least one tumor and / or cancerous cell that expresses an oncogenic variant of NF1.

[0911] Exemplary embodiment number 27. 27. The method, compound, combination, or use according to any one of exemplary embodiments 1-26, 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 cavity cancer, pharyngeal cancer, or colorectal cancer.

[0912] Exemplary embodiment number 28. 28. The method, compound, combination, or use of any one of exemplary embodiments 1-27, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, bile duct carcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe cell carcinoma, kidney clear cell carcinoma, kidney papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer, or gastric cancer. Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumor, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary (CUP), cancer metastasized to bone, cancer metastasized to brain, cancer metastasized to liver, cancer metastasized to lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell Alveolar sarcoma, gallbladder cancer, gastric cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, gastric fibroblastic fibrosis, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumors, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral cavity and oropharyngeal cancer, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's 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 cancer, secondary cancers, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumors, uterine cancer, including vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and gynecological cancer. 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, chromocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0913] Exemplary embodiment number 29. The method, compound, combination, or use of any one of exemplary embodiments 1-28, wherein the cancer is a blood cancer.

[0914] Exemplary embodiment number 30. The method, compound, combination, or use of any one of exemplary embodiments 1-29, wherein the cancer is a solid cancer.

[0915] Exemplary embodiment number 31. The method, compound, combination, or use of any one of exemplary embodiments 1-30, wherein the cancer is melanoma, breast cancer, head and neck cancer, esophagogastric cancer, gastric and small intestinal 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.

[0916] Exemplary embodiment number 32. The method, compound, combination, or use according to any one of exemplary embodiments 1-31, wherein the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, thyroid cancer, histiocytosis, small intestine cancer, gastrointestinal neuroendocrine cancer, carcinoma of unknown primary, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid cancer, or glioblastoma.

[0917] Exemplary embodiment number 33. The method, compound, combination, or use of any one of exemplary embodiments 1-32, wherein the cancer is glioma.

[0918] Exemplary embodiment number 34. The method, compound, combination, or use of any one of exemplary embodiments 1-33, wherein the cancer is low-grade glioma.

[0919] Exemplary embodiment number 35. The method, compound, combination, or use of any one of exemplary embodiments 1-34, wherein the cancer is glioblastoma.

[0920] Exemplary embodiment number 36. The method, compound, combination, or use according to any one of exemplary embodiments 1-35, wherein the cancer is insensitive or resistant to treatment with one or more inhibitors of the MAPK pathway.

[0921] Exemplary embodiment number 37. The method, compound, combination, or use of any one of exemplary embodiments 1-36, wherein the cancer is insensitive or resistant to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0922] Exemplary embodiment number 38. The method, compound, combination, or use according to any one of exemplary embodiments 1-37, wherein the subject has an adverse reaction to treatment with one or more inhibitors of the MAPK pathway.

[0923] Exemplary embodiment number 39. The method, compound, combination, or use of any one of exemplary embodiments 1-38, wherein the subject has an adverse reaction to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0924] Exemplary embodiment number 40. The method, compound, combination, or use of any one of exemplary embodiments 1-39, wherein the subject has previously been administered one or more inhibitors of the MAPK pathway, and the subject has experienced disease progression despite the previous administration.

[0925] Exemplary embodiment number 41. The method, compound, combination, or use of any one of exemplary embodiments 1-40, wherein the subject has previously been administered a BRAF inhibitor, a MEK inhibitor, or a combination thereof, and the subject has experienced disease progression despite the previous administration.

[0926] Exemplary embodiment number 42. The method, compound, combination, or use of any one of exemplary embodiments 1-41, wherein the BRAF inhibitor is vemurafenib, dabrafenib, or encorafenib.

[0927] Exemplary embodiment number 43. The method, compound, combination, or use according to any one of exemplary embodiments 1-42, wherein the MEK inhibitor is trametinib, cobimetinib, or binimetinib.

[0928] Exemplary embodiment number 44. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 43, wherein the compound is administered to the subject by oral or parenteral administration.

[0929] Exemplary embodiment number 45. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 44, wherein a pharmaceutical composition comprising the compound is administered to the subject.

[0930] Exemplary embodiment number 46. 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 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 46. ​​The method, compound, combination, or use of any one of exemplary embodiments 1-45, wherein the compound is administered at 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).

[0931] Exemplary embodiment number 47. The method, compound, or use according to any one of exemplary embodiments 1 to 46, wherein one or more inhibitors of the MAPK pathway are further administered to the subject.

[0932] Exemplary embodiment number 48. The method, compound, combination, or use according to any one of exemplary embodiments 1-47, wherein the compound and the one or more inhibitors of the MAPK pathway are administered simultaneously.

[0933] Exemplary embodiment number 49. The method, compound, combination, or use according to any one of exemplary embodiments 1-48, wherein the compound and the one or more inhibitors of the MAPK pathway are administered sequentially.

[0934] Exemplary embodiment number 50. The method, compound, combination, or use according to any one of exemplary embodiments 1-49, wherein the compound and the one or more inhibitors of the MAPK pathway are administered in close temporal proximity.

[0935] Exemplary embodiment number 51. The method, compound, combination, or use according to any one of exemplary embodiments 1-50, wherein the compound and the one or more inhibitors of the MAPK pathway are administered in alternation.

[0936] Exemplary embodiment number 52. The method, compound, combination, or use according to any one of exemplary embodiments 1-51, wherein the compound and the one or more inhibitors of the MAPK pathway are administered by the same route of administration.

[0937] Exemplary embodiment number 53. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 52, wherein at least two inhibitors of the MAPK pathway are administered.

[0938] Exemplary embodiment number 54. The method, compound, combination, or use of any one of exemplary embodiments 1-53, wherein the MEK inhibitor is binimetinib.

[0939] Exemplary embodiment number 55. The compound may be administered in an amount of 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 1 2±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 100 0±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 g, about 1200±40 mg, about 1200±30 mg, about 1200±20 mg, or about 1200±10 mg (e.g., about 1200 mg), and binimetinib is administered at a dose (e.g., daily dose) of 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 7 55. The method, compound, combination, or use of any one of exemplary embodiments 1-54, wherein the compound is administered at a dose (e.g., a daily dose) of about 5±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). ;

[0940] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0941] As will be understood by those skilled in the art, the BRAF gene is commonly referred to as one of the following: BRAF, B-RAF1, BRAF1, NS7, RAFB1, B-Raf proto-oncogene, proto-oncogene B-raf, v-Raf murine sarcoma viral oncogene homolog B, and v-Raf murine sarcoma viral oncogene homolog B1. Accordingly, these terms are used interchangeably herein to refer to the BRAF gene.

[0942] As will be understood by those skilled in the art, the B-Raf protein encoded by the BRAF gene is commonly referred to as one of the following: BRAF, B-Raf, serine / threonine-protein kinase B-Raf, proto-oncogene B-Raf, p94, and v-Raf murine sarcoma viral oncogene homolog B1. Accordingly, these terms are used interchangeably herein to refer to the B-Raf gene.

[0943] While not intending to be limited by this description, various options for variables are described herein, and the present disclosure is intended to encompass workable embodiments having combinations of options, the present disclosure may be construed to exclude inoperable embodiments caused by a particular combination of options.

[0944] It should be under...

Claims

1. 1. A method of treating or preventing cancer in a subject, comprising administering to a subject a compound according to formula (0): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: X is CR Ｘ or N, R Ｘ is H, halogen, cyano, oxo, OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or C １ -C ６ Alkoxy, wherein the C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or C １ -C ６ The alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH; W １ is N or CR Ｗ１ and R Ｗ１ is H, halogen, C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ is alkynyl, W ２ is N or CR Ｗ２ and R Ｗ２ is H, halogen, C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ alkynyl, wherein C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ The alkynyl is optionally substituted with one or more halogens; W ３ is N or CR Ｗ３ and R Ｗ３ is H, halogen, C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ is alkynyl, W ４ is N or CR Ｗ４ and R Ｗ４ is H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or S(C １ -C ６ alkyl), R １ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ The aryl or 5- to 10-membered heteroaryl may optionally be one or more R １ａ is replaced by Each R １ａ are independently halogen, cyano, oxo, OH, NH ２ ,NHC(=O)O(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 5-10 membered heteroaryl; R ２ is H, halogen, cyano, oxo, OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or C １ -C ６ is an alkoxy; R ３ is H, halogen, cyano, oxo, OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or C １ -C ６ is alkoxy, or R １ and R ３ together with the atoms therebetween form a 4- to 12-membered heterocycloalkyl optionally substituted with one or more oxo; 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) ２ NR Ｘ１ -* or -NR Ｘ１ S (= O) ２ -*, where * indicates the bond to A, R Ｘ１ are independently H, S(=O) ２ R Ｘ１ａ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ The aryl or 5- to 10-membered heteroaryl may optionally be one or more R Ｘ１ａ is replaced by Each R Ｘ１ａ are independently halogen, C １ -C ６ alkyl, or 3- to 12-membered heterocycloalkyl, wherein １ -C ６ the alkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more halogens; A is C １ -C ６ Alkyl, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, -(C １ -C ６ alkyl)-(C ３ -C １２ cycloalkyl), -(C １ -C ６ alkyl)-(3- to 12-membered heterocycloalkyl), -(C １ -C ６ alkyl)-(C ６ -C １０ aryl), or -(C １ -C ６ alkyl)-(5- to 10-membered heteroaryl), wherein １ -C ６ Alkyl, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, -(C １ -C ６ alkyl)-(C ３ -C １２ cycloalkyl), -(C １ -C ６ alkyl)-(3- to 12-membered heterocycloalkyl), -(C １ -C ６ alkyl)-(C ６ -C １０ aryl), or -(C １ -C ６ alkyl)-(5- to 10-membered heteroaryl) optionally includes one or more R Ａ is replaced by Each R Ａ are independently halogen, cyano, oxo, OH, OR Ａ１ , N.H. ２ , N.H.R. Ａ１ , N(R Ａ１ ) ２ , (=N)R Ａ１ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ The aryl or 5- to 10-membered heteroaryl may optionally be one or more R Ａ１ is replaced by Each R Ａ１ are independently halogen, cyano, oxo, OH, OR Ａ２ , N.H. ２ , N.H.R. Ａ２ , N(R Ａ２ ) ２ , C(=O)R Ａ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ -C １０ The aryl or 5- to 10-membered heteroaryl may optionally be one or more R Ａ２ is replaced by Each R Ａ２ are independently halogen, cyano, OH, NH ２ , N(R Ａ３ ) ２ , C(=O)R Ａ３ , C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ is alkynyl, In the formula, R Ａ３ is C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ The method is alkynyl.

2. A compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject.

3. 10. Use of a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject.

4. A combination comprising: (i) a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof; and (ii) one or more additional therapeutic agents.

5. A method of treating or preventing cancer in a subject, 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 additional therapeutic agents.

6. A combination comprising (i) a compound of formula (0), an isomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more additional therapeutic agents, for treating or preventing cancer in a subject.

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 additional therapeutic agents in the manufacture of a medicament for treating or preventing cancer in a subject.

8. The method, compound, combination or use of any one of claims 1 to 7, wherein the subject is a human.

9. 9. The method, compound, combination or use of any one of claims 1 to 8, 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, kidney cancer, renal 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 cavity cancer, pharyngeal cancer or colorectal cancer.

10. 10. The method, compound, combination or use of any one of claims 1 to 9, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, bile duct carcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe cell carcinoma, kidney clear cell carcinoma, kidney papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, or uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer, or gastric cancer. Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumor, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary (CUP), cancer metastasized to bone, cancer metastasized to brain, cancer metastasized to liver, cancer metastasized to lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell Alveolar sarcoma, gallbladder cancer, stomach cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, gastric fibroids, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumors, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral cavity and oropharyngeal cancer, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's 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 cancer, secondary cancer, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumors, and uterine cancer. Examples of cancer include vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer (Womb cancer), and gynecological cancer. 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, chromic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

11. 11. The method, compound, combination or use of any one of claims 1 to 10, wherein the cancer is a blood cancer.

12. 12. The method, compound, combination or use of any one of claims 1 to 11, wherein the cancer is a solid cancer.

13. 13. The method, compound, combination or use of any one of claims 1 to 12, wherein the cancer is melanoma, breast cancer, head and neck cancer, esophagogastric cancer, gastric and small intestinal 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.

14. 14. The method, compound, combination or use of any one of claims 1 to 13, wherein the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, thyroid cancer, histiocytosis, small intestine cancer, gastrointestinal neuroendocrine cancer, carcinoma of unknown primary, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid cancer, or glioblastoma.

15. 15. The method, compound, combination or use of any one of claims 1 to 14, wherein said cancer is glioma.

16. 16. The method, compound, combination or use of any one of claims 1 to 15, wherein said cancer is glioblastoma.

17. 17. The method, compound, combination or use of any one of claims 1 to 16, wherein the cancer is lung cancer.

18. 18. The method, compound, combination or use of any one of claims 1 to 17, wherein the cancer is non-small cell lung cancer (NSCLC).

19. 19. The method, compound, combination or use of any one of claims 1 to 18, wherein said compound is administered to said subject by oral or parenteral administration.

20. 20. The method, compound, combination or use of any one of claims 1 to 19, wherein a pharmaceutical composition comprising said compound is administered to said subject.

21. The compound is administered in 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 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 21. The method, compound, combination, or use of any one of claims 1 to 20, wherein the compound is administered at 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. 22. The method, compound, combination, or use of any one of claims 1 to 21, 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 chemotherapeutics, one or more EGFR (epidermal growth factor receptor) inhibitors, one or more MET (mesenchymal-epithelial transition) inhibitors, one or more TEAD (transcription enhancer associated 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 one or more additional therapeutic agents comprise one or more SHP2 inhibitors; 23. The method, compound, combination or use of any one of claims 1 to 22, optionally wherein the one or more SHP2 inhibitors comprise JAB-3068, JAB-3312, TNO-155, RLY-1971, or RMC-4630.

24. the one or more additional therapeutic agents comprise one or more SOS1 inhibitors; 24. The method, compound, combination or use of any one of claims 1 to 23, optionally wherein the one or more SOS1 inhibitors comprise BI-1701963, BI-1703880, or MRTX0902.

25. the one or more additional therapeutic agents comprise one or more KRAS inhibitors; 25. The method, compound, combination or use of any one of claims 1 to 24, optionally wherein the one or more KRAS inhibitors comprise sotorasib, adagrasib, LY3537982, zivalasib, JDQ443, BI-1823911, MRTX1133, RMC-9805, or RMC-6236.

26. the one or more additional therapeutic agents comprise one or more ERK inhibitors; 26. The method, compound, combination or use of any one of claims 1 to 25, optionally wherein the one or more ERK inhibitors comprise ulixertinib, MK-8353, LY3214996, ASTX029, ASN007, LTT462, or KO-947.

27. the one or more additional therapeutic agents comprise one or more immune checkpoint inhibitors; 27. The method, compound, combination or use of any one of claims 1 to 26, optionally wherein said one or more immune checkpoint inhibitors comprise pembrolizumab, ipilimumab, nivolumab, or atezolizumab.

28. the one or more additional therapeutic agents include one or more chemotherapeutic agents; 28. The method, compound, combination or use of any one of claims 1 to 27, optionally wherein said one or more chemotherapeutic agents comprises oxaliplatin or irinotecan.

29. the one or more additional therapeutic agents comprise one or more EGFR inhibitors; 29. The method, compound, combination or use of any one of claims 1 to 28, optionally wherein the one or more EGFR inhibitors comprise erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, or vandetanib.

30. the one or more additional therapeutic agents comprise one or more MET inhibitors; Optionally, the one or more MET inhibitors are crizotinib, capmatinib, tepotinib, savolitinib.

30. The method, compound, combination or use of any one of claims 1 to 29 comprising cabozantinib, glesatinib, foretinib, merestinib, tivantinib, SAR125844, onartuzumab, telisotuzumab, or JNJ-61186372.

31. the one or more additional therapeutic agents comprise one or more TEAD inhibitors; 31. The method, compound, combination, or use of any one of claims 1 to 30, optionally wherein the one or more TEAD inhibitors comprise VT3989, IK-930, or IAG933.

32. the one or more additional therapeutic agents comprise one or more YAP inhibitors; 32. The method, compound, combination or use of any one of claims 1 to 31, optionally wherein the one or more YAP inhibitors comprises verteporfin.

33. the one or more additional therapeutic agents comprise one or more PI3K inhibitors; 33. The method, compound, combination or use of any one of claims 1 to 32, optionally wherein the one or more PI3K inhibitors comprise idelalisib, alpelisib, alpelisib, leniolisib, duvelisib, or copanlisib.

34. the one or more additional therapeutic agents comprise one or more mTOR inhibitors; 34. The method, compound, combination or use of any one of claims 1 to 33, optionally wherein the one or more mTOR inhibitors comprise everolimus, sirolimus, temsirolimus, everolimus, sirolimus, sirolimus protein-bound, or everolimus.

35. the one or more additional therapeutic agents include one or more metabolic inhibitors; 35. The method, compound, combination or use of any one of claims 1 to 34, optionally wherein said one or more metabolic inhibitors comprise trifluridine, gemcitabine, fluorouracil, pentostatin, clofarabine, azacitidine, cytarabine, mercaptopurine, fludarabine, or capecitabine.

36. the one or more metabolic inhibitors include one or more MEK inhibitors; 36. The method, compound, combination or use of any one of claims 1 to 35, optionally wherein said one or more MEK inhibitors comprises trametinib, cobimetinib, or binimetinib.

Images