JP2025536257A - Methods of treating cancer using isoquinoline or 6-AZA-quinoline derivatives - Google Patents

Abstract

The present disclosure relates to a method for treating or preventing cancer using a compound of formula (0): JPEG2025536257000121.jpg3972 or a pharmaceutically acceptable salt thereof. The present disclosure also relates to pharmaceutical compositions and pharmaceutical kits suitable for the treatment or prevention.

Description

RELATED APPLICATIONS This application claims priority to and 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.

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.

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 through administration of protein kinase inhibitors has been used to treat a variety of cancers in many patients. However, a proportion of patients treated with these therapies fail to respond, ultimately relapse, or experience recurrence of secondary lesions/pathways. More specifically, many existing B-Raf-targeting kinase inhibitors have low specificity for B-Raf, resulting in undesirable off-target effects, or target only specific subsets of BRAF/B-Raf mutations. Thus, there is a long-felt 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.

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).

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).

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

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

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

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

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

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

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 additional therapeutic agents (e.g., in a therapeutically effective amount).

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.

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

In some aspects, the present disclosure provides 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.

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.

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.

In some aspects, the present disclosure provides 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.

In some aspects, the present disclosure provides 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.

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 hereby 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.

Features and advantages of the present disclosure will become apparent from the following detailed description and claims.

FIG. 1 is a graph showing a schematic of an exemplary study of compounds of the present disclosure. FIG. 2 is a graph depicting the anti-tumor activity of a compound of the present disclosure (“Compound”) in combination with binimetinib in a mouse-bearing KRAS G12D NSCLC patient-derived xenograft (PDX) model. 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.

This disclosure relates to methods of using compounds, as well as 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 such methods.

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.

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). Activated MAPKKKs then activate MAP kinase kinases (MAPKKs). Activated MAPKKs then activate MAP kinases (MAPKs). Activated MAPK then activates downstream effectors, including transcription factors, thereby causing changes in gene expression and regulating various cellular processes mentioned above, including but not limited to cell growth, proliferation, differentiation, and apoptosis.

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.

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 autoinhibition of the kinase domain. CR2 is a flexible linker that functions as a hinge for connecting CR1 and CR3. CR3 is the enzyme kinase domain.

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 uncouple. RAS-GTP then binds to B-Raf's CR1, causing CR1 to release CR3. The overall effect is that the autoinhibitory properties of the kinase domain of B-Raf 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.

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.

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

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 intermediate to high levels of kinase activity, although their activity levels are typically lower than those of the RAS-independent active monomers produced by class I BRAF mutations.

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. BRAF Class III mutations typically result in B-Raf with reduced kinase activity or dysfunctional function.

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.

Methods and Uses of the Disclosure In some aspects, the disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of the disclosure (e.g., in a therapeutically effective amount).

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).

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

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

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

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

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

Suitable Subjects and Diseases In some embodiments, the subject is a mammal.

In some embodiments, the subject is a human.

In some embodiments, the subject is a mouse.

In some embodiments, the subject is a rat.

In some embodiments, the subject is a dog.

In some embodiments, the subject is a monkey.

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

Cancers characterized by at least one oncogenic mutation in the BRAF gene are generally cancers associated with at least one oncogenic mutation in the BRAF gene, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the BRAF gene.

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

Cancers characterized by at least one oncogenic variant of B-Raf are generally cancers associated with at least one oncogenic variant of B-Raf, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of B-Raf.

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

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

In some embodiments, the subject has at least one tumor and/or cancerous cells that express an oncogenic variant of B-Raf.

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 resulting in the substitution of one amino acid for another at a specific position in B-Raf, mutations resulting in the substitution of one or more amino acids for one or more amino acids between two specific positions in B-Raf, mutations resulting in the insertion of one or more amino acids between two positions in B-Raf, mutations resulting in the deletion of another amino acid between two positions in B-Raf, and mutations resulting 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), the gene can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations.

As will be understood by those skilled in the art, in the context of a protein (e.g., B-Raf), oncogenic mutations include, but are 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 understood 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 aforementioned types of oncogenic mutations, including a combination of different types of oncogenic mutations.

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.

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

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.

In some embodiments, an oncogenic mutation "deletion near 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).

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)

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.

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.

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.

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.

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.

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 may mediate resistance to a BRAF inhibitor and/or a MEK inhibitor.

In some aspects, oncogenic variants of B-Raf may contain both a duplication of exons 10-18 and a V600E mutation (B-Raf-V600E+ex10-18dup).

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 comprises 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.

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 comprising at least one mutation. In some embodiments, the N-Ras protein comprising at least one mutation can be N-Ras-G12D, N-Ras-Q61K, and/or N-Ras-Q61R. In some embodiments, the N-Ras protein comprising 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.

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. In some embodiments, the K-Ras protein comprising at least one mutation 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.

In some embodiments, the subject has at least one tumor or cancerous cell that expresses 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.

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

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

Cancers characterized by at least one oncogenic mutation in the KRAS gene are generally cancers associated with at least one oncogenic mutation in the KRAS gene, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the KRAS gene.

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.

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

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.

Cancers characterized by at least one oncogenic variant of K-Ras are generally cancers associated with at least one oncogenic variant of K-Ras, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of K-Ras.

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

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

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

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 that is not 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.

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.

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.

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

Cancers characterized by at least one oncogenic mutation in the NRAS gene are generally cancers associated with at least one oncogenic mutation in the NRAS gene, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the NRAS gene.

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

Cancers characterized by at least one oncogenic variant of N-Ras are generally cancers associated with at least one oncogenic variant of N-Ras, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of N-Ras.

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

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

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

In some embodiments, the oncogenic mutation in N-Ras may be selected from N-Ras-G12D, N-Ras-Q61K, N-Ras-Q61R, N-Ras-Q61L, and N-Ras-G13D. In some embodiments, the oncogenic mutation in N-Ras may be a mutation that induces constitutive RAF dimer activation.

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.

Cancers characterized by at least one oncogenic mutation in the NF1 gene are generally cancers associated with at least one oncogenic mutation in the NF1 gene, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is thought to be driven by at least one oncogenic mutation in the NF1 gene.

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

Cancers characterized by at least one oncogenic variant of NF1 are generally cancers associated with at least one oncogenic variant of NF1, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is thought to be driven by at least one oncogenic variant of N-Ras.

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 aspects, the oncogenic mutation in the NF1 protein can be a loss-of-function mutation in the NF1 protein.

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

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

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 the NRAS gene may be any of the oncogenic mutations described herein.

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.

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

Cancers characterized by at least one oncogenic mutation in a gene encoding RAS GTPase are generally cancers associated with at least one oncogenic mutation in a gene encoding RAS GTPase, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is thought to be driven by at least one oncogenic mutation in a gene encoding RAS GTPase.

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

Cancers characterized by at least one oncogenic variant of RAS GTPase are generally cancers associated with at least one oncogenic variant of RAS GTPase, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is thought to be driven by at least one oncogenic variant of RAS GTPase.

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

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

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

In some embodiments, the RAS GTPase may be NRAS, KRAS, or HRAS.

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

Cancers characterized by at least one oncogenic mutation in the HRAS gene are generally cancers associated with at least one oncogenic mutation in the HRAS gene, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is thought to be driven by at least one oncogenic mutation in the HRAS gene.

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

Cancers characterized by at least one oncogenic variant of H-Ras are generally cancers associated with at least one oncogenic variant of H-Ras, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of H-Ras.

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

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

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

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

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.

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 cancer, 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 (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 fibrosis, Liver cancer, Lung cancer, Lymphoma, Malignant neurilemmoma, Mediastinal germ cell tumor, Melanoma skin cancer, Cancer in men, 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 These include T-cell childhood 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, gastric cancer, T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymic cancer, tongue cancer, tonsil cancer, adrenal gland tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, womb cancer, and gynecological cancers.

Examples of cancer also include, but are not limited to, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, 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.

In some embodiments, the cancer is a blood cancer.

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

In some embodiments, 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.

In some embodiments, 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 site, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid cancer, or glioblastoma.

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.

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.

In some embodiments, the cancer is melanoma.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is thyroid carcinoma.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is colorectal carcinoma.

In some embodiments, the cancer is glioma.

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

In some embodiments, the cancer is a low-grade glioma (e.g., a glioma arising from astrocytes and/or oligodendrocytes).

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

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

In some embodiments, the cancer is glioblastoma.

In some embodiments, the cancer is a recurrent cancer.

In some embodiments, the cancer is advanced cancer.

In some embodiments, the cancer is metastatic cancer.

In some embodiments, the tumor is a recurrent tumor.

In some embodiments, the tumor is an advanced tumor.

In some embodiments, the tumor is a metastatic tumor.

In some embodiments, the cancer is brain cancer.

In some embodiments, the cancer is recurrent brain cancer.

In some embodiments, the cancer is advanced brain cancer.

In some embodiments, the cancer is metastatic brain cancer.

In some embodiments, the cancer is lung cancer.

In some embodiments, the cancer is recurrent lung cancer.

In some embodiments, the cancer is advanced lung cancer.

In some embodiments, the cancer is metastatic lung cancer.

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

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

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

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

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.

In some embodiments, the cancer is NSCLC and the subject has at least one tumor and/or cancerous cells expressing 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 that is not K-Ras-G12C. In some embodiments, the NSCLC can be recurrent, advanced, metastatic, 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 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, 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 expressing an oncogenic variant of N-Ras. In some embodiments, the histiocytic neoplasm may be recurrent.

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 comprising at least one class I mutation, at least one class II mutation, at least one class III mutation, or any combination thereof. In some embodiments, the oncogenic variant is B-Raf-V600E. In some embodiments, the melanoma can be recurrent, advanced, metastatic, or any combination thereof.

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.

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.

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.

In some embodiments, administration of the disclosed compounds does not induce aberrant activation of wild-type B-Raf.

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

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.

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 not administered the compound.

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%.

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

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

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

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

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

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

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

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

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

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.

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.

In some embodiments, the subject has previously received a combination comprising a BRAF inhibitor and a MEK inhibitor, and the subject experienced disease progression despite the previous administration.

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.

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

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

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

In some embodiments, the subject has histiocytosis.

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

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

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

In some embodiments, the BRAF inhibitor is vemurafenib.

In some embodiments, the BRAF inhibitor is dabrafenib.

In some embodiments, the BRAF inhibitor is encorafenib.

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

In some embodiments, the MEK inhibitor is trametinib.

In some embodiments, the MEK inhibitor is cobimetinib.

In some embodiments, the MEK inhibitor is binimetinib.

Administration of the Compound In some embodiments, the compound is administered to the subject by oral or parenteral administration.

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

In some embodiments, a pharmaceutical composition containing the compound is administered to a subject.

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

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

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

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.

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.

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

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).

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).

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).

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).

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).

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).

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).

In some embodiments, the compound is administered at a dose (e.g., 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).

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).

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).

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).

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).

In some embodiments, the compound is administered at a dose (e.g., 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).

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).

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).

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).

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).

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).

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).

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).

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).

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.

In some embodiments, the compound is administered with one or more drug-free periods.

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

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.

In some embodiments, the subject is fed 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.

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

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

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.

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

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

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

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

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).

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.

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

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.

In some aspects, the present disclosure provides 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.

In some aspects, the present disclosure provides 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.

In some aspects, the present disclosure provides 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.

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.

In some embodiments, the one or more additional therapeutic agents include one or more SHP2 inhibitors.

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

In some embodiments, the one or more additional therapeutic agents include one or more SOS1 inhibitors.

In some embodiments, the one or more SOS1 inhibitors include BI-1701963, BI-1703880, or MRTX0902.

In some embodiments, the one or more additional therapeutic agents include one or more KRAS inhibitors.

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

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

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

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

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

In some embodiments, the one or more additional therapeutic agents include one or more chemotherapeutic agents.

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

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

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

In some embodiments, the one or more additional therapeutic agents include one or more MET inhibitors.

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

In some embodiments, the one or more additional therapeutic agents include one or more TEAD inhibitors.

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

In some embodiments, the one or more additional therapeutic agents include one or more YAP inhibitors.

In some embodiments, the one or more YAP inhibitors include verteporfin.

In some embodiments, the one or more additional therapeutic agents include one or more PI3K inhibitors.

In some embodiments, the one or more PI3K inhibitors include idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib.

In some embodiments, the one or more additional therapeutic agents include one or more mTOR inhibitors.

In some embodiments, the one or more mTOR inhibitors include everolimus, sirolimus, temsirolimus, everolimus, sirolimus, sirolimus protein-bound, or everolimus.

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

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

In some embodiments, the one or more metabolic inhibitors include one or more MEK inhibitors.

In some embodiments, the one or more MEK inhibitors include trametinib, cobimetinib, or binimetinib.

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

In some aspects, the present disclosure provides combinations comprising a compound of the present disclosure and one or more MEK inhibitors.

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

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

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

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

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

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).

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

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

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

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).

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 one or more of trametinib, cobimetinib, or binimetinib (e.g., in a therapeutically effective amount), to the subject.

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).

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).

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).

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.

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.

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.

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.

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.

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.

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.

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

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

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

In some aspects, the present disclosure provides 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.

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.

In some aspects, the present disclosure provides 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.

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.

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 or preventing cancer in a subject.

In some aspects, the present disclosure provides 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.

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.

In some aspects, the present disclosure provides 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.

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.

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.

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

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

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

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

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

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

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

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

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 prior to administration of one or more inhibitors of the MAPK pathway.

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

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

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.

In some embodiments, the compound and one or more inhibitors of the MAPK pathway are administered in alternating fashion.

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

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

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

In some embodiments, binimetinib is administered once daily.

In some embodiments, binimetinib is administered twice daily.

In some embodiments, the compound is 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 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); ±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±4 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±3 00 mg, about 600±200 mg, about 600±100 mg, about 600±90 mg, about 600±80 mg, about 600±70 mg, about 600±60 mg, about 600±50 mg, about 600±40 mg, about 600±30 mg, about 600±20 mg, or about 600±10 mg (e.g., about 600 mg); about 800±400 mg, about 800±300 mg, about 800±200 mg, about 800±100 mg, about 800±90 mg, about 800±80 mg, about 800±70 mg, about 800±60 mg, about 800± 50 mg, about 800±40 mg, about 800±30 mg, about 800±20 mg, or about 800±10 mg (e.g., about 800 mg); about 1000±500 mg, about 1000±400 mg, about 1000±300 mg, about 1000±200 mg, about 1000±100 mg, about 1000±90 mg, about 1000±80 mg, about 1000±70 mg, about 1000±60 mg, about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, or about 1000±10 mg (e.g., about 1000 mg); or about 1200±600 mg, about 1200±500 mg, about 1200±400 mg, about 1200±300 mg, about 1200±200 mg, about 1200±100 mg, about 1200±90 mg, about 1200±80 mg, about 1200±70 mg, about 1200±60 mg, about 1200±50 mg, about 1200±40 mg, about 1200±30 mg, about 1200±20 mg, or about 1200±10 mg (e.g., about 1200 mg),
Binimetinib is available in 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).

In some embodiments, the compound is 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 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); ±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±4 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±3 00 mg, about 600±200 mg, about 600±100 mg, about 600±90 mg, about 600±80 mg, about 600±70 mg, about 600±60 mg, about 600±50 mg, about 600±40 mg, about 600±30 mg, about 600±20 mg, or about 600±10 mg (e.g., about 600 mg); about 800±400 mg, about 800±300 mg, about 800±200 mg, about 800±100 mg, about 800±90 mg, about 800±80 mg, about 800±70 mg, about 800±60 mg, about 800± 50 mg, about 800±40 mg, about 800±30 mg, about 800±20 mg, or about 800±10 mg (e.g., about 800 mg); about 1000±500 mg, about 1000±400 mg, about 1000±300 mg, about 1000±200 mg, about 1000±100 mg, about 1000±90 mg, about 1000±80 mg, about 1000±70 mg, about 1000±60 mg, about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, or about 1000±10 mg (e.g., about 1000 mg); or about 1200±600 mg, about 1200±500 mg, about 1200±400 mg, about 1200±300 mg, about 1200±200 mg, about 1200±100 mg, about 1200±90 mg, about 1200±80 mg, about 1200±70 mg, about 1200±60 mg, about 1200±50 mg, about 1200±40 mg, about 1200±30 mg, about 1200±20 mg, or about 1200±10 mg (e.g., about 1200 mg),
Binimetinib is administered in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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 in 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).

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.

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

Many chemotherapeutic agents are currently 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, antiangiogenic agents, 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 other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; altretamine, triethylenediamine, thiazolinone ... Ethylenimines and methylamelamines, including melamine, triethylenephosphoramide, triethylenethiophosphaolamide, and trimethylolomelamine; chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine, Nitrogen mustards such as thiamin oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trophosfamide, and uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, and calabimycin. , carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rhodolubicin, streptomycin, Antibiotics such as ptonigrin, 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, and citabine. Pyrimidine analogues such as tarabin, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; Bestravsil; Visa Nthren; Edatraxate; Defofamine; Demecolcine; Diazicon; Elfomitine; Elliptinium acetate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Toxic Examples include reazicon; 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.

Also suitable chemotherapy cell conditioners include antihormonal agents that act to regulate or inhibit hormone action on tumors, such as tamoxifen, (Nolvadex ^Tn ), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifen, ketoxifen, 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.

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, alpharazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, anti-tumor 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, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, rutotecan, mafosfami These include commonly prescribed anticancer drugs such as fluoxetine, 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.

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.

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 spatially confined radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. The 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.

In some embodiments, the one or more additional therapeutic agents include 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.

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 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 disclosed in WO 96/33172, WO 96/27583, European Patent Publication No. EP 0 818 442, European Patent Publication No. EP 1 004 578, WO 98/07697, WO 98/03516, WO 98/34918, W98/34915, W98/33768, W98/30566, European Patent Publication No. 606 046, European Patent Publication No. 931 788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 1999007675, European Patent Publication No. EP 1786785, European Patent Publication No. EP 1181017, U.S. Publication No. US 20090012085, U.S. Publication No. 5,863,949, U.S. Publication No. 5,861,510, and European Patent Publication No. EP 0780386, 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 compared 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.

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, glucan 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, LC 9018 (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, Osateron, 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, Rasburyembodiment, Rhenium etidronate Re 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, natural 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, diazicon, EL 532 (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), relidistim, 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, mitsumomab, motexafine gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL These include antineoplastic agents such as 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 valspodar.

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. Pat. No. 6,258,812, U.S. Pat. No. 2003/0105091, WO/2001/037820, U.S. Pat. No. 6,235,764, WO/2001/032651, U.S. Pat. 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.

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 act to inhibit or stimulate their targets (e.g., activation or inhibition of receptors or enzymes), thereby promoting cell death or halting cell proliferation.

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 ligand binding regions thereof) 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 present 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."

Other antiangiogenic agents include Campath, IL-8, B-FGF, and 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; Wiley, U.S. Patent No. 6,727,225), and ADAM disintegrin domains that antagonize the binding of integrins to their ligands (Fanslow et al., 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., specifically binding antibodies or antigen-binding regions), as well as antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., specifically binding antibodies or antigen-binding regions thereof).

Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer, USA), cilengitide (Merck KGaA, Germany, EPO 770622); pegaptanib octasodium (Gilead Sciences, USA), alphastatin (BioActa, UK), M-PGA (Celgene, USA, U.S. 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); Masterpin (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 antagonist, (Borean, Denmark); Bevacizumab (pINN), (Genentech, USA); Angiogenesis inhibitor, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha5beta3 integrin, second generation, (Applied Molecular Evolution, USA and MedImmune, USA); gene therapy, retinopathy, (Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC1, (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia, Australia); VEGF antagonist, (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, Korea); gene-based vaccine, VEGF-2, (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, 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 Longchang, 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, (South Florida University, 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 treatment, (Marinova, Australia); heparanase inhibitor, (InSight, Israel); KL3106, (Kolon, 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).

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 that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), may also be used.

In some embodiments, the one or more additional therapeutic agents include 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.

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), alkylsulfonates (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, benzophenone, 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, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., Zalypsis), 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 Hormonal agonists such as tinnitus hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38 MAPK 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 any analog or derivative variant of the foregoing.

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.

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, fluocortin ... Examples of suitable antihistamines include lometron, 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.

In some embodiments, the one or more additional therapeutic agents include compounds that disrupt or inhibit the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways. In other such combinations, the additional pharmaceutically active compounds are PD-1 and PD-L1 antagonists. The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

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 more recently, lapatinib (TykerB). See, e.g., Yan L, et al. See, for example, Paez J G, et al., Pharmacogenetics and Pharmacogenomics in Oncology Therapeutic Antibody Development, BioTechniques 2005;39(4):565-8, and Paez J G, et al., EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy, Science 2004;304(5676):1497-500.

Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts of 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 566226, published August 6, 1997. PCT International Publication No. WO97/30034 published on August 21, 1997, PCT International Publication No. WO97/30044 published on August 21, 1997, PCT International Publication No. WO97/38994 published on October 23, 1997, PCT International Publication No. WO97/49688 published on December 31, 1997, European Patent Application No. EP 837063 published on April 22, PCT International Publication No. WO 98/02434 published on January 22, 1998, PCT International Publication No. WO 97/38983 published on October 23, 1997, PCT International Publication No. WO 95/19774 published on July 27, 1995, PCT International Publication No. WO 96/19774 published on July 27, 1995, PCT International Publication No. WO95/19970, PCT International Publication No. WO97/13771 published on April 17, 1997, PCT International Publication No. WO98/02437 published on January 22, 1998, PCT International Publication No. WO98/02438 published on January 22, 1998, PCT International Publication No. WO97/32881 published on September 12, 1997, German Patent Application No. DE 19629652 published on January 29, 1998, PCT International Publication No. WO 98/33798 published on August 6, 1998, PCT International Publication No. WO 97/32880 published on September 12, 1997, and European Patent Application No. EP 682027 published on 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. WO97/34896 published October 10, 1996, PCT International Publication No. WO96/31510' published on April 9, 1998, PCT International Publication No. WO98/14449 published on April 9, 1998, PCT International Publication No. WO98/14450 published on April 9, 1998, PCT International Publication No. WO98/14451 published on April 9, 1998, PCT International Publication No. WO95/098 published on April 13, 1995, No. 47, PCT International Publication No. WO97/19065 published May 29, 1997, PCT International Publication No. WO98/17662 published April 30, 1998, U.S. Pat. No. 5,789,427 issued August 4, 1998, U.S. Pat. No. 5,650,415 issued July 22, 1997, U.S. Pat. No. No. 5,656,643, PCT International Publication No. WO 99/35146 published July 15, 1999, PCT International Publication No. WO 99/35132 published July 15, 1999, PCT International Publication No. WO 99/07701 published February 18, 1999, and PCT International Publication No. WO 92/20642 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.

Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation 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, S. M., 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.

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

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 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 (available from 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.

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).

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, WO 9409010), and AP23573; for example, the rapalogs disclosed in WO 98/02441 and WO 01/14387, such as 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 WO Other derivatives disclosed in US Pat. No. 5,258,389, WO 94/090101, WO 92/05179, US 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 These include derivatives disclosed in US Patent Nos. 96/41807 and 5,256,790, phosphorus-containing rapamycin derivatives (e.g., WO 05016252), and 4H-1-benzopyran-4-one derivatives (e.g., US Provisional Patent Application No. 60/528,340).

MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. The 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.

SHP inhibitors include, but are not limited to, SHP099.

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

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.

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

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

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).

Exemplary anti-PD-1 antibodies and methods of using them 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 therapeutic 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).

In some embodiments, the one or more additional therapeutic agents include an anti-PD-1 antibody.

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 certain 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.

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.

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.

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.

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.

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.

Exemplary anti-PD-1 antibody sequences are provided in Table 2.

GITR agonists include, but are not limited to, those described, for example, in U.S. Patent No. 6,111,090 box. GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in, for example, U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent 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. Examples of such antibodies include the anti-GITR antibodies described in 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.

Compounds of the Disclosure In some aspects, the disclosure provides a compound of formula (0):
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 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH;
^W1 is N or CR ^W1 ;
R ^W1 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
^W2 is N or CR ^W2 ;
R ^W2 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogens;
^W3 is N or CR ^W3 ;
R ^W3 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
^W4 is N or CR ^W4 ;
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, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein the 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, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^1a ;
each R ^1a is 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- to 10-membered heteroaryl;
^R2 is H, halogen, cyano, oxo, OH, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, or _C1 - _C6 alkoxy;
^R3 is H, halogen, cyano, oxo, OH, _C1 - _C6 alkyl, _{C2 - C6} alkenyl, C2- _C6 alkynyl, or _C1 - _C6 alkoxy, or ^R1 and ^R3 together with the atoms therebetween form a 4-12 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 a bond to A;
R ^X1 is independently H, S(=O) ₂ R ^X1a , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl _, wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C ₂ -C6 alkynyl, C _{1 -C6 alkoxy, C 3 -C 12 cycloalkyl} , 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^X1a ;
each R ^X1a is independently halogen, C ₁ -C ₆ alkyl, or 3-12 membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl or 3-12 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 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 -(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 substituted with one or more R ^A ;
Each R ^A is independently halogen, cyano, oxo, OH, OR ^A1 , NH ₂ , NHR ^A1 , N(R ^A1 ) ₂ , (═N)R ^A1 , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered _heteroaryl , wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C ₁ -C6 alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ;
Each R ^A1 is independently halogen, cyano, oxo, OH, OR ^A2 , NH ₂ , NHR ^A2 , N(R ^A2 ) ₂ , C(═O)R ^A2 , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C 2 -C6 _alkynyl , C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C ₁ -C6 alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to ₁₂ -membered heterocycloalkyl, _{C 6} -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A2 ;
each R ^A2 is 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 alkynyl;
wherein R ^A3 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl.

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

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

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

For 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, where applicable, be selected from the groups described herein; 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 , ^RA3, can be combined, where applicable, with any group described herein for one or more of the remainder of the variables X, ^RX , ^W1 , ^RW1 , ^W2 , ^RW2 , ^W3 _, ^RW3 , ^W4 , ^RW4 , RA1, ^R1a , ^{R2, R3, X1, RX1, RX1a , A , RA , RA1 , RA2} , ^RA3 .

Variables X and ^R
In some embodiments, X is CR ^{3 X} or N. In some embodiments, X is N. In some embodiments, X is CR ^{3 X.} In some embodiments, X is CH. In some embodiments, X is C(CN). In some embodiments, X is CF.

In some embodiments, R 1 ^X is H, halogen, cyano, oxo, OH, _{C 1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, or C 1 _-C6 alkoxy, wherein the C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, or C _{1 -C6} alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH. In some embodiments, each R 1 ^X is H, halogen, cyano, oxo, or OH. In some embodiments, R 1 ^X is H. In some embodiments, R 1 ^{X is halogen. In some embodiments, R 1 X is} fluorine. In some embodiments, R 1 ^X is chlorine. In some embodiments, R 1 ^X is bromine. In some embodiments, R ^{1 X} is iodine. In some embodiments, R 1 ^X is cyano. In some embodiments, R ^X is 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 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH. In some embodiments, R ^X is C ₁ -C ₆ alkoxy optionally substituted with one or more OH. In some embodiments, R ^X is C ₁ alkoxy optionally substituted with one or more OH. In some embodiments, R ^X is C ₂ alkoxy optionally substituted with one or more OH. In some embodiments, R ^X is C 3 alkoxy optionally substituted _with one or more OH. In some embodiments, R ^X is C ₄ alkoxy optionally substituted with one or more OH. In some embodiments, R 1 ^X is a C ₅ alkoxy optionally substituted with one or more OH. In some embodiments, R 1 ^X is a C ₆ alkoxy optionally substituted with one or more OH.

Variables ^W1 , R ^W1 , ^W2 , R ^W2 , ^W3 , R ^W3 , ^W4 , 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.

In some embodiments, R ^W1 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl. In some embodiments, R ^W1 is H or halogen. In some embodiments, R ^W1 is H. In some embodiments, R ^W1 is halogen. In some embodiments, R ^W1 is fluorine. In some embodiments, R ^W1 is chlorine. In some embodiments, R ^W1 is bromine. In some embodiments, R ^W1 is iodine. In some embodiments, R ^W1 is C ₁ -C ₆ alkyl, _{C 2} -C ₆ alkenyl, or C _{2 -C 6} alkynyl. In some embodiments, R ^W1 is ^{C 1 alkyl. In some embodiments, R W1} _is ^C ₂ alkyl. In some embodiments, R ^W1 is _C3 alkyl. In some embodiments, R ^W1 is _C4 alkyl. In some embodiments, R ^W1 is _C5 alkyl. In some embodiments, R ^W1 is _C6 alkyl. In some embodiments, R ^W1 is _CH3 .

In some embodiments, ^W2 is N or CR ^W2 . In some embodiments, W2 is N. ^In some embodiments, ^W2 is CR ^W2 . In some embodiments, ^W2 is CH. In some embodiments, ^W2 is C(CH ₃ ).

In some embodiments, R ^W2 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein the C ₁ -C ₆ alkyl, C _{2 -C 6 alkenyl, or C 2 -C 6 alkynyl is} optionally substituted with one or more halogens.

In some embodiments, R ^W2 is H or halogen. In some embodiments, R ^W2 is H. In some embodiments, R ^W2 is 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 C _{1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the C 1 -C 6} ^alkyl _{, C 2 -C 6 alkenyl} , or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogens. In some embodiments, R ^W2 is C _{1 -C 6} alkyl, C ₂ -C ₆ alkenyl, _or C ₂ -C ₆ alkynyl. In some embodiments, R ^W2 is C ₁ -C ₆ alkyl. In some embodiments, R ^W2 is C ₁ alkyl. In some embodiments, R ^W2 is C ₂ alkyl. In some embodiments, R ^W2 is C ₃ alkyl. In some embodiments, R ^W2 is C ₄ alkyl. In some embodiments, R ^W2 is C ₅ alkyl. In some embodiments, R ^W2 is C ₆ alkyl. In some embodiments, R ^W2 is CH ₃ .

In some embodiments, ^W3 is N or CR ^W3 . In some embodiments, ^W3 is N. In some embodiments, ^W3 is CR ^W3 . In some embodiments, ^W3 is CH.

In some embodiments, R ^W3 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl. In some embodiments, R ^W3 is H or halogen. In some embodiments, R ^W3 is H. In some embodiments, R ^W3 is halogen. In some embodiments, R ^W3 is fluorine. In some embodiments, R ^W3 is chlorine. In some embodiments, R ^W3 is bromine. In some embodiments, R ^W3 is iodine. In some embodiments, R ^W3 is C ₁ -C ₆ alkyl, _{C 2} -C ₆ alkenyl, or C _{2 -C 6} alkynyl. In some embodiments, R ^W3 is ^{C 1 alkyl. In some embodiments, R W3} _is ^C ₂ alkyl. In some embodiments, R ^W3 is a _C3 alkyl. In some embodiments, R ^W3 is a _C4 alkyl. In some embodiments, R ^W3 is a _C5 alkyl. In some embodiments, R ^W3 is a _C6 alkyl.

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.

In some embodiments, 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). In some embodiments, R ^W4 is H or halogen. In some embodiments, R ^W4 is H. In some embodiments, R ^W4 is halogen. In some embodiments, R ^W4 is fluorine. In some embodiments, R ^W4 is chlorine. In some embodiments, R ^W4 is bromine. In some embodiments, R ^W4 is iodine.

In some embodiments, R ^W4 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or S(C ₁ -C ₆ alkyl).

In some embodiments, R ^W4 is C ₁ -C ₆ alkyl. In some embodiments, R ^W4 is C ₁ alkyl. In some embodiments, R ^W4 is C ₂ alkyl. In some embodiments, R ^W4 is C ₃ alkyl. In some embodiments, R ^W4 is C ₄ alkyl. In some embodiments, R ^W4 is C ₅ alkyl. In some embodiments, R ^W4 is C ₆ alkyl. In some embodiments, W ¹ is CR ^W1 , W ² is CR ^W2 , W ³ is CR ^W3 , and W ⁴ is CR ^W4 .

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

Variables R ¹ , R ^1a , R ² , R ³
In some embodiments, 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 ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^1a . In some embodiments, R ¹ is H. In some embodiments, R ¹ is C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is substituted with one or more R ^1a . In some embodiments, R ¹ is C ₁ -C ₆ alkyl. In some embodiments, R ¹ is C ₁ alkyl. In some embodiments, R ¹ is C ₂ alkyl. In some embodiments, R ¹ is C ₃ alkyl. In some embodiments, R ¹ is C ₄ alkyl. In some embodiments, R ¹ is C ₅ alkyl. In some embodiments, R ¹ is C ₆ alkyl. In some embodiments, R ¹ is CH _3. In some embodiments, R ¹ is CH ₂ CH ₃ .

In some embodiments, each R ^1a is 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 ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl. In some embodiments, R ^1a is halogen, cyano, oxo, OH, or NH _2. In some embodiments, R ^1a is cyano. In some embodiments, R ^1a is 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 ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl.

In some embodiments, R ² is H, cyano, oxo, OH, C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, or C _{1 -C6} alkoxy. In some embodiments, R ² is H, cyano, oxo, or OH. In some embodiments, R ² is H. In some embodiments, R ² is cyano. In some embodiments, R ² is OH. In some embodiments, R ² is C _{1 -C6} alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, or C _{1 -C6} alkoxy. In some embodiments _, R ² is H, halogen, cyano _, oxo, OH, C _{1 -C6} alkyl, C _{2 -C6 alkenyl} , C _{2 -C6 alkynyl} , or C _{1 -C6} alkoxy.

In some embodiments, 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 alkoxy.

In some embodiments, R ¹ and R ³ together with the atoms between them form a 4-12 membered heterocycloalkyl optionally substituted with one or more oxo.

Variables ^X1 , 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) ₂ NR ^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) ₂ NR ^X1 -*, or -NR ^X1 S(=O) ₂ -*, where * indicates a bond to A. In some embodiments, is -NR ^X1 -*, where * indicates a bond to A. In some embodiments, is -NH-*, where * indicates a bond to A. In some embodiments, X ¹ is —C(═O)NR ^X1 —* or —NR ^X1 C(═O)—*, where * indicates a bond to A. In some embodiments, X ¹ is —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 is —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 is —NR ^X1 C(═NH)—*, where * indicates a bond to A. In some embodiments, X ¹ is —NHC(═NH)—*, where * indicates the bond to A.

In some embodiments, R ^X1 is H, S(═O) ₂ R ^X1a , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C8 cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C _{10 aryl} , or 5-10 membered heteroaryl, wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C _{3 -C8} cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^X1a . In some embodiments, R ^X1 is H. In some embodiments, R ^X1 is S(=O) ₂ R ^X1a . In some embodiments, R ^X1 is C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C 1 _-C6 alkoxy, C _{3 -C8} cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein C _{1 -C6} alkyl, C ₂ -C6 alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C _{3 -C8 cycloalkyl} , 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10 _- membered heteroaryl is optionally substituted with one or more R ^X1a . In some embodiments, R ^X1 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl. In some embodiments, R ^X1 is C ₁ -C ₆ alkyl. In some embodiments, R ^X1 is CH ₃ .

In some embodiments, R ^X1a is halogen, C ₁ -C ₆ alkyl, or 3-8 membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more halogens. In some embodiments, R ^X1a is halogen. In some embodiments, R ^X1a is C ₁ -C ₆ alkyl optionally substituted with one or more halogens. In some embodiments, R ^X1a is 3-8 membered heterocycloalkyl optionally substituted with one or more halogens.

In some embodiments, A is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, -(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl), -(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), or -(C ₁ -C ₆ alkyl)-(5- to 10-membered heteroaryl), wherein C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, -(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -(C ₁ -C In some embodiments, A is C 1 -C 6 alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C 3 -C 8 cycloalkyl, _3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^A. In some embodiments, A is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^A. In some embodiments, A is C ₃ -C ₈ cycloalkyl, a 3-8 membered heterocycloalkyl, a C ₆ -C ₁₀ aryl, or a 5-10 membered heteroaryl, wherein the C 3 -C ₈ cycloalkyl, the 3-8 membered heterocycloalkyl, the C ₆ -C ₁₀ aryl, or the 5-10 membered heteroaryl is optionally substituted with one or more R ^A. In some embodiments, A is C _{3 -C 8} cycloalkyl, or a 3-8 membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or the 3-8 membered heterocycloalkyl is optionally substituted with one or more R ^A. In some embodiments, A is a 3-8 membered heterocycloalkyl. In some embodiments, A is tetrahydropyranyl. In some embodiments, A is piperidinyl. 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 one or more R ^A. In some embodiments, A is C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein the C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^A. In some embodiments, A is C ₆ -C ₁₀ aryl optionally substituted with one or more R ^A. In some embodiments, A is C ₆ -C ₁₀ aryl. In some embodiments, A is phenyl. In some embodiments, A is phenyl optionally substituted with one or more R ^A. In some embodiments, A is 5-10 membered heteroaryl optionally substituted with one or more R ^A. In some embodiments, A is 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 pyridyl optionally substituted with one or more R ³ As. In some embodiments, A is triazolyl optionally substituted with one or more R ⁴ As. In some embodiments, A is pyrazolyl optionally substituted with one or more R ⁵ As. 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 A. In some} embodiments, A is 4,5,6,7-tetrahydrobenzo[d]isoxazolyl optionally substituted with one or more R ^A. In some embodiments, A is —(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), —(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl), —(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), or —(C ₁ -C ₆ alkyl)-(5- to 10-membered heteroaryl), wherein —(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), —(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl), —(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), or —(C ₁ -C ₆ alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R ^A. In some embodiments, A is -(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl), or -(C ₁ -C ₆ alkyl)-(5- to 10-membered heteroaryl), wherein -(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl), or -(C ₁ -C ₆ alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R ^A. In some embodiments, A is -(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl) optionally substituted with one or more R ^A. In some embodiments, A is -(C ₁ -C ₆ alkyl)-(3- to 8-membered heterocycloalkyl). In some embodiments, A is -(C ₁ alkyl)-(tetrahydropyranyl). In some embodiments, A is -(C ₁ alkyl)-(piperidinyl). In some embodiments, A is -( _C1 alkyl)-(tetrahydropyranyl) optionally substituted with one or more R ^A. In some embodiments, A is -( _C1 alkyl)-(piperidinyl) optionally substituted with one or more R ^A. In some embodiments, A is -( _C1 - _C6 alkyl)-(5-10 membered heteroaryl) optionally substituted with one or more R ^A. In some embodiments, A is -( _C1 - _C6 alkyl)-(5-10 membered heteroaryl). In some embodiments, A is -( _C1 alkyl)-(triazolyl). In some embodiments, A is -( _C2 alkyl)-(triazolyl). In some embodiments, A is -( _C1 alkyl)-(triazolyl) optionally substituted with one or more R ^A. In some embodiments, A is -( _C2 alkyl)-(triazolyl) optionally substituted with one or more R ^A.

In some embodiments, X ¹ is -C(=O)NH-*, where * indicates a bond to A, where A is phenyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=O)-*, where * indicates a bond to A, where A is phenyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=NH)-*, where * indicates a bond to A, where A is phenyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -C(=O)NH-*, where * indicates a bond to A, where A is pyridyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=O)-*, where * indicates a bond to A, where A is pyridyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=NH)-*, where * indicates a bond to A and A is pyridyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -C(=O)NH-*, where * indicates a bond to A and A is triazolyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=O)-*, where * indicates a bond to A and A is triazolyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=NH)-*, where * indicates a bond to A and A is triazolyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is —C(═O)NH-*, where * indicates a bond to A, where A is tetrahydropyranyl optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is —NHC(═O)-*, where * indicates a bond to A, where A is tetrahydropyranyl optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is —NHC(═NH)-*, where * indicates a bond to A, where A is tetrahydropyranyl optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is —C(═O)NH-*, where * indicates a bond to A, where A is piperidinyl optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is -NHC(=O)-*, where * indicates a bond to A and A is piperidinyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=NH)-*, where * indicates a bond to A and A is piperidinyl optionally substituted with one or more R ^A. In some embodiments, X ¹ is -C(=O)NH-*, where * indicates a bond to A and A is -(C ₁ alkyl)-(tetrahydropyranyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=O)-*, where * indicates a bond to A and A is -(C ₁ alkyl)-(tetrahydropyranyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is -NHC(=NH)-*, where * indicates a bond to A and A is -(C1 alkyl)-(tetrahydropyranyl) optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is -C(=O)NH-*, where * indicates a bond to A and A is -( _{C1 alkyl} )-(piperidinyl) optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is -NHC(=O)-*, where * indicates a bond to A and A is -( _C1 alkyl)-(piperidinyl) optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is -NHC(=NH)-*, where * indicates a bond to A and A is -( _C1 alkyl)-(piperidinyl) optionally substituted with one or more R 3 ^A. In some embodiments, X ¹ is —C(═O)NH-*, where * indicates a bond to A and A is a —(C ₁ alkyl)-(triazolyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is —C(═O)NH-*, where * indicates a bond to A and A is a —(C ₂ alkyl)-(triazolyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is —NHC(═O)-*, where * indicates a bond to A and A is a —(C ₁ alkyl)-(triazolyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is —NHC(═O)-*, where * indicates a bond to A and A is a —(C ₂ alkyl)-(triazolyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is —NHC(═NH)-*, where * indicates a bond to A and A is a —(C ₁ alkyl)-(triazolyl) optionally substituted with one or more R ^A. In some embodiments, X ¹ is —NHC(═NH)-*, where * indicates a bond to A and A is a —(C ₂ alkyl)-(triazolyl) optionally substituted with one or more R ^A.

In some embodiments, R ^A is halogen, cyano, oxo, OH, OR ^A1 , NH ₂ , NHR ^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 ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally selected from the group consisting of one or more R ^A1 . In some embodiments, R ^A is halogen, cyano, oxo, OH, OR ^A1 , NH ₂ , NHR ^A1 , N(R ^A1 ) ₂ , or (═N)R ^A1 . In some embodiments, R ^A is halogen. In some embodiments, R ^A is fluorine. In some embodiments, R ^{A is chlorine. In some embodiments, R A is} bromine. In some embodiments, R ^A is iodine. In some embodiments, R ^A is cyano. In some embodiments, R ^A is OH. In some embodiments, R ^A is OR ^A1 . In some embodiments, R ^A is O(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^A2 . In some embodiments, R ^A is NHR ^A1 . In some embodiments, R ^A is N(R ^A1 ) ₂ . In some embodiments, R ^A is N(CH ₃ ) _2. In some embodiments, R ^A is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C 6 alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C _{2 -C 6 alkenyl} , C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C _{3 -C 8} cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^A1 . In some embodiments, R ^A is C ₁ -C ₆ alkyl. In some embodiments, R ^A is a _C1 alkyl. In some embodiments, R ^A is a _C2 alkyl. In some embodiments, R ^A is a _C3 alkyl. In some embodiments, R ^A is a _C4 alkyl. In some embodiments, R ^A is a _C5 alkyl. In some embodiments, R ^A is a _C6 alkyl. In some embodiments, R ^A is a _C1 - _C6 alkyl optionally substituted with one or more R ^A1 . In some embodiments, R A is a _C1 alkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a _C2 alkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a _C3 alkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a _C4 ^{alkyl optionally substituted with one or more R A1. In some embodiments, R A is a} _C5 alkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is _C6 alkyl optionally substituted with 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 _C1 alkyl optionally substituted with one or more halogens. In some embodiments, R ^A is _C3 alkyl optionally substituted with one or more halogens. In some embodiments, ^{R A} is _CH3 . In some embodiments, R ^A is _CF3 .

In some embodiments, R ^A is C(CH ₃ ) ₂ CN. In some embodiments, R ^A is C ₁ -C ₆ alkoxy. In some embodiments, R ^A is C ₁ alkoxy. In some embodiments, R ^A is C ₂ alkoxy. In some embodiments, R ^A is C ₃ alkoxy. In some embodiments, R ^A is C ₄ alkoxy. In some embodiments, R ^A is C ₅ alkoxy. In some embodiments, R ^A is C ₆ alkoxy. In some embodiments, R ^A is C ₁ -C ₆ alkoxy optionally substituted with one or more R ^A1 . In some embodiments, R ^A is C ₁ alkoxy optionally substituted with one or more R ^A1 . In some embodiments, R ^A is C ₂ alkoxy optionally substituted with one or more R ^A1 . In some embodiments, R ^A is C ₃ alkoxy optionally substituted with one or more R ^A1 . In some embodiments, R ^A is _C4 alkoxy optionally substituted with one or more R ^A1 . In some embodiments, R ^A is _C5 alkoxy optionally substituted with one or more R A1. In some embodiments, R A is _C6 alkoxy optionally substituted with one or more R ^A1 . In some embodiments, R ^A is _C3 - _C8 cycloalkyl. In some embodiments, R ^A is _C3 cycloalkyl ^. In some embodiments, R ^A is _C4 cycloalkyl. In some embodiments, R ^A is _C5 cycloalkyl ^{. In some embodiments, R A is C6 cycloalkyl. In some embodiments, R A is} _C7 ^cycloalkyl _. In some embodiments, R ^A is _C8 cycloalkyl.

In some embodiments, R ^A is a C ₃ -C ₈ cycloalkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a C ₃ cycloalkyl optionally substituted with one or more R ^A1 . In some embodiments, R A is a C ₄ cycloalkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a C ₅ cycloalkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a C ₆ cycloalkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is a C ₇ cycloalkyl optionally substituted with one or more R ^A1 . In some embodiments, R ^A is ^a C ₈ cycloalkyl optionally substituted with one or more R ^A1 .

In some embodiments, R ^A1 is halogen, cyano, oxo, OH, OR ^A2 , NH ₂ , NHR ^A2 , N(R ^A2 ) ₂ , C(═O)R ^A2 , C _{1 -C6} alkyl, C 2 _-C6 alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C8 cycloalkyl, _3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 _{membered heteroaryl, wherein C 1 -C6 alkyl} , C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C _{3 -C8} cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally selected from the group consisting of one or more R ^A2 . In some embodiments, R ^A1 is halogen, cyano, oxo, OH, OR ^A2 , NH ₂ , NHR ^A2 , N(R ^A2 ) ₂ , or C(═O)R ^A2 . In some embodiments, R ^A1 is halogen. In some embodiments, R ^A1 is fluorine. In some embodiments, R ^A1 is chlorine. In some embodiments, R ^A1 is bromine. In some embodiments, R ^A1 is iodine. In some embodiments, R ^A1 is cyano. In some embodiments, R A1 is oxo. In some embodiments, R ^{A1 is OH. In some embodiments, R A1 is OR A2. In some embodiments, R A1 is NH 2} _. In some embodiments, R ^A1 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein C ₁ -C _{6 alkyl, C 2 -C 6 alkenyl ,} C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A2 . In some embodiments, R ^A1 is C ₁ -C ₆ alkyl. In some embodiments, R ^A1 is C ₁ alkyl. In some embodiments, R ^A1 is a _C2 alkyl. In some embodiments, R ^A1 is a _C3 alkyl. In some embodiments, R ^A1 is a _C4 alkyl. In some embodiments, R ^A1 is a _C5 alkyl. In some embodiments, R ^A1 is a C6 alkyl. In some embodiments, R ^A1 is a _C1 - _C6 alkyl optionally substituted with one or more R ^{A2. In some embodiments, R A1 is a C1 alkyl optionally substituted with one or more R A2 . In some embodiments, R A1 is a C2 alkyl optionally substituted with one or more R A2. In some embodiments, R A1} _is ^{a C3} _{alkyl optionally} ^{substituted with} _one or more R ^A2 . In some embodiments, R ^{A1 is a C4 alkyl optionally substituted with one or more R A2. In some embodiments, R A1} _is ^{a C5} _alkyl optionally substituted with one or more R ^A2 . In some embodiments, R ^A1 is _C6 alkyl optionally substituted with one or more R ^A2 .

In some embodiments, R ^A is C ₁ -C ₆ alkyl and R ^A1 is halogen. In some embodiments, R ^A is C ₁ alkyl and R ^A1 is fluorine. In some embodiments, R ^A is C ₁ -C ₆ alkyl and R ^A1 is cyano. In some embodiments, R ^A is C ₁ alkyl and R ^A1 is cyano.

In some embodiments, R ^A2 is 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 alkynyl. In some embodiments, R ^A2 is halogen, cyano, OH, NH ₂ , N(R ^A3 ) ₂ , or C(═O)R ^A3 . In some embodiments, R ^A2 is halogen. In some embodiments, R ^A2 is fluorine. In some embodiments, R ^A2 is chlorine. In some embodiments, R ^A2 is bromine. In some embodiments, R ^A2 is iodine. In some embodiments, R ^A2 is OH. In some embodiments, R ^A2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl. In some embodiments, R ^A2 is C ₁ -C ₆ alkyl. In some embodiments, R ^A2 is C ₁ alkyl. In some embodiments, R ^A2 is C ₂ alkyl. In some embodiments, R ^A2 is C ₃ alkyl. In some embodiments, R ^A2 is C ₄ alkyl. In some embodiments, R ^A2 is C ₅ alkyl. In some embodiments, R ^A2 is C ₆ alkyl.

In some embodiments, R ^A3 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl.

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

In some embodiments, the compound is a compound of the following formula (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), or (It):
or a pharmaceutically acceptable salt or stereoisomer thereof.

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

In some embodiments, the compound is a compound of the following formula (I-ai), (I-bi), (I-ci), (I-di), or (If-i):
or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound of the following formula (I-gi), (I-hi), (I-ii), (I-ji), (I-ki), (I-li), (I-mi), (I-ni), (I-o-i), (I-pi), (I-qi), (I-ri), (I-si), or (I-t-i):
or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound of the following formula (I-ui), (I-vi), (I-wi), or (I-xi):
or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound of the following formula (I-a-ii), (I-b-ii), (I-c-ii), (I-d-ii), (I-e-ii), (I-f-ii), (I-g-ii), (I-h-ii), (I-i-ii), (I-j-ii), (I-k-ii), (I-l-ii), (I-m-ii), (I-n-ii), (I-o-ii), or (I-p-ii):
or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound of the following formula (I-q-ii), (I-r-ii), (I-s-ii), (I-t-ii), (I-u-ii), (I-v-ii), (I-w-ii), (I-x-ii), (I-y-ii), (I-z-ii), (I-aa-ii), (I-bb-ii), (I-cc-ii), or (I-dd-ii):
or a pharmaceutically acceptable salt or stereoisomer thereof.

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):
or a pharmaceutically acceptable salt or stereoisomer thereof.

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

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

In some embodiments, the compound is selected from the compounds set forth in Table I.

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.

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.

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.

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, and pharmaceutically acceptable salts and stereoisomers thereof.

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, and pharmaceutically acceptable salts thereof.

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.

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

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

In some embodiments, the compound is Compound No. 1.

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

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

In some embodiments, the compound is compound number 2.

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

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

In some embodiments, the compound is compound number 3.

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

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

In some embodiments, the compound is compound number 4.

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

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

In some embodiments, the compound is compound number 5.

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

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

In some embodiments, the compound is compound number 6.

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

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

In some embodiments, the compound is compound number 7.

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

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

In some embodiments, the compound is compound number 8.

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

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

In some embodiments, the compound is compound number 9.

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

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

In some embodiments, the compound is compound number 10.

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

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

In some embodiments, the compound is compound number 11.

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

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

In some embodiments, the compound is compound number 12.

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

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

In some embodiments, the compound is compound number 14.

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

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

In some embodiments, the compound is compound number 15.

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

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

In some embodiments, the compound is compound number 16.

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

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

In some embodiments, the compound is compound number 17.

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

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

In some embodiments, the compound is compound number 18.

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

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

In some embodiments, the compound is compound number 19.

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

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

In some embodiments, the compound is compound number 20.

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

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

In some embodiments, the compound is compound number 21.

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

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

In some embodiments, the compound is compound number 22.

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

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

In some embodiments, the compound is compound number 23.

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

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

In some embodiments, the compound is compound number 24.

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

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

In some embodiments, the compound is compound number 25.

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

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

In some embodiments, the compound is compound number 26.

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

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

In some embodiments, the compound is compound number 27.

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

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

In some embodiments, the compound is compound number 29.

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

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

In some embodiments, the compound is compound number 30.

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

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

In some embodiments, the compound is compound number 31.

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

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

In some embodiments, the compound is compound number 32.

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

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

In some embodiments, the compound is compound number 33.

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

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

In some embodiments, the compound is compound number 34.

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

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

In some embodiments, the compound is compound number 35.

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

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

In some embodiments, the compound is compound number 37.

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

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

In some embodiments, the compound is compound number 38.

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

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

In some embodiments, the compound is compound number 39.

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

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

In some embodiments, the compound is compound number 40.

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

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

In some embodiments, the compound is compound number 41.

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

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

In some embodiments, the compound is compound number 42.

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

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

In some embodiments, the compound is compound number 43.

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

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

In some embodiments, the compound is compound number 44.

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

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

In some embodiments, the compound is compound number 49.

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

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

In some embodiments, the compound is compound number 52.

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

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

In some embodiments, the compound is compound number 53.

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

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

In some embodiments, the compound is compound number 55.

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

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

In some embodiments, the compound is compound number 56.

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

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

In some embodiments, the compound is compound number 57.

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

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

In some embodiments, the compound is compound number 58.

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

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

In some embodiments, the compound is compound number 59.

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

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

In some embodiments, the compound is compound number 60.

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

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

In some embodiments, the compound is compound number 62.

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

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

In some embodiments, the compound is compound number 63.

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

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

In some embodiments, the compound is compound number 65.

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

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

In some embodiments, the compound is compound number 66.

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

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

In some embodiments, the compound is compound number 68.

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

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

In some embodiments, the compound is compound number 71.

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

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

In some embodiments, the compound is compound number 75.

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

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

In some embodiments, the compound is compound number 77.

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

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

In some embodiments, the compound is compound number 78.

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

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

In some embodiments, the compound is compound number 79.

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

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

In some embodiments, the compound is compound number 153.

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

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

In some embodiments, the compound is compound number 154.

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

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

In some embodiments, the compound is compound number 173.

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

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

In some embodiments, the compound is compound number 174.

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

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

In some embodiments, the compound is compound number 175.

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

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

In some embodiments, the compound is compound number 176.

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

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

In some embodiments, the compound is compound number 191.

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

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

In some embodiments, the compound is compound number 193.

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

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

In some embodiments, the compound is compound number 194.

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

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

In some embodiments, the compound is compound number 200.

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

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

In some embodiments, the compound is compound number 201.

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

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

In some embodiments, the compound is compound number 202.

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

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

In some embodiments, the compound is compound number 203.

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

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

In some embodiments, the compound is compound number 204.

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

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

In some embodiments, the compound is compound number 206.

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

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

In some embodiments, the compound is compound number 214.

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

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

In some embodiments, the compound is compound number 215.

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

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

In some embodiments, the compound is compound number 217.

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

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

In some embodiments, the compound is compound number 218.

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

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

In some embodiments, the compound is compound number 220.

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

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

In some embodiments, the compound is compound number 221.

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

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

In some embodiments, the compound is compound number 222.

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

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

In some embodiments, the compound is compound number 223.

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

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

In some embodiments, the compound is compound number 225.

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

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

In some embodiments, the compound is compound number 226.

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

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

In some embodiments, the compound is compound number 227.

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

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

In some embodiments, the compound is compound number 229.

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

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

In some embodiments, the compound is compound number 230.

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

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

In some embodiments, the compound is compound number 231.

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

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

In some embodiments, the compound is compound number 233.

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

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

In some embodiments, the compound is compound number 234.

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

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

In some embodiments, the compound is compound number 235.

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

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

In some embodiments, the compound is compound number 236.

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

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

In some embodiments, the compound is compound number 237.

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

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

In some embodiments, the compound is compound number 238.

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

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

In some embodiments, the compound is compound number 242.

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

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

In some embodiments, the compound is compound number 243.

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

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

In some embodiments, the compound is compound number 245.

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

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

In some embodiments, the compound is compound number 247.

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

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

In some embodiments, the compound is compound number 248.

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

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

In some embodiments, the compound is compound number 249.

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

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

In some embodiments, the compound is compound number 252.

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

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

In some embodiments, the compound is compound number 253.

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

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

In some embodiments, the compound is compound number 255.

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

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

In some embodiments, the compound is compound number 256.

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

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

In some embodiments, the compound is compound number 257.

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

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

In some embodiments, the compound is compound number 258.

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

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

In some embodiments, the compound is compound number 259.

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

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

In some embodiments, the compound is compound number 260.

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

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

In some embodiments, the compound is compound number 261.

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

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

In some embodiments, the compound is compound number 262.

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

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

In some embodiments, the compound is compound number 263.

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

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

In some embodiments, the compound is compound number 264.

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

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

In some embodiments, the compound is compound number 265.

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

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

In some embodiments, the compound is compound number 266.

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

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

In some embodiments, the compound is compound number 267.

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

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

In some embodiments, the compound is compound number 271.

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

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

In some embodiments, the compound is compound number 272.

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

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

In some embodiments, the compound is compound number 274.

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

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

In some embodiments, the compound is compound number 275.

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

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

In some embodiments, the compound is compound number 276.

Compounds of the present disclosure containing the aforementioned deuterium atom, or pharmaceutically acceptable salts thereof, are within the scope of the present disclosure. Furthermore, substitution with deuterium (i.e., ^2H ) may provide certain therapeutic benefits resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

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.

Suitable pharmaceutically acceptable salts of compounds of the present disclosure include, 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 include 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.

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.

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."

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

As used herein, the term "chiral isomer" means a compound that has at least one chiral center. Compounds that have 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).

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.

It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. Where 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.

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

As used herein, an "atropisomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. In an atropisomer, rotation is restricted by its presence, preventing 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.

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.

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

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."

The compounds of the present disclosure may have one or more asymmetric centers; 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 racemic 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 a racemate. 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 isomers, diastereoisomers, and geometric isomers, and mixtures thereof, that possess anti-tumor activity.

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

Compounds of any formula described herein are understood to include the compound itself, as well as salts and solvates thereof, if applicable. Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on a 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).

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.

It is understood that compounds of the present disclosure, such as salts of the 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.

As used herein, "solvate" refers to a solvent addition form that contains 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. A hydrate is formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as H ₂ O.

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.

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

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 physicochemically 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.

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 hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the present disclosure encompasses all such solvated forms that possess antitumor activity.

It should also be understood that certain compounds of the present disclosure may exhibit polymorphism, and that the present disclosure encompasses all such forms, or mixtures thereof, that possess antitumor activity. It is generally known that crystalline materials can be analyzed using conventional techniques, such as powder X-ray diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and/or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

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 (shown below), imine/enamine, amide/iminoalcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/acinitro.

Compounds of the present disclosure that contain an amine functional group may also form N-oxides. References herein to compounds disclosed herein that contain an amine functional group also include the N-oxide. When a compound contains multiple amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. 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, Jerry March, 4th Edition, Wiley Interscience, pages 147-150. More specifically, the N-oxide can be prepared by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

The compounds of the present disclosure may be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present disclosure. Prodrugs may be used to alter the physical and/or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs may be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents on the sulfonylurea group in a compound of any one of the formulas disclosed herein.

The present disclosure therefore 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. Therefore, 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., compounds of the present disclosure may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure are based on reasonable medical judgment that they are free of undesired pharmacological activity and are free of excessive toxicity and are suitable for administration to the human or animal body. Various forms of prodrugs are described, for example, in 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, Krogsgaard-Larsen and H. Bundgaard (ed.), Chapter 5 "Design and Application of Pro-drugs", H. By Bundgaard p. 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. , Chem. Pharm. Bull. , 32, 692 (1984), g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14, and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of 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 produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C ₁ -C ₁₀ alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and C ₁ -C ₁₀ alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C ₁ -C _alkyl ) ₂ carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C ₁ -C ₄ alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure having a carboxy group are, for example, in vivo cleavable amides thereof, for example amides formed with amines such as ammonia, C _1-4 alkylamines such as methylamine, (C ₁ -C ₄ alkyl) ₂ amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C ₁ -C ₄ alkoxy-C ₂ -C ₄ alkylamines such as 2-methoxyethylamine, phenyl-C ₁ -C ₄ alkylamines such as benzylamine, and amino acids such as glycine or its esters.

Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure 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, those formed with C ₁ -C ₁₀ alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C ₁ -C ₄ alkyl)piperazin-1-ylmethyl.

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 following 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 a precursor compound (prodrug).

Synthetic Methods In some aspects, the present disclosure provides methods for preparing the compounds disclosed herein.

In some aspects, the present disclosure provides a method for preparing a compound, comprising one or more steps described herein.

In some aspects, the present disclosure provides compounds obtainable by, obtained by, or obtained directly by the methods for preparing compounds described herein.

In some aspects, the present disclosure provides intermediates suitable for use in the methods for preparing the compounds described herein.

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.

In the description of synthetic methods provided herein, and in any referenced synthetic methods used to prepare starting materials, it should be understood that all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures, can be selected by one of ordinary skill in the art.

One skilled in the art of organic synthesis understands that the functional groups present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

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. The 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, such as "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 the skilled chemist that is appropriate for the removal of the protecting group in question, and such methods will be selected to provide for the removal of the protecting group while minimizing interference with groups elsewhere in the molecule. Thus, where reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the group during some of the reactions described herein.

For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, e.g., alkanoyl groups such as 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 with the choice of protecting group. Thus, for example, an acyl group, such as an alkanoyl or alkoxycarbonyl group or an aroyl group, can be removed, for example, 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, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation over a catalyst, for example, palladium on carbon, or by treatment with a Lewis acid, for example, boron tris(trifluoroacetic acid). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, for example, dimethylaminopropylamine, or hydrazine.

Suitable protecting groups for hydroxy groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups, e.g., benzoyl, or arylmethyl groups, e.g., benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or aroyl group may be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium, sodium, or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed by hydrogenation over a catalyst, e.g., palladium on carbon.

Suitable protecting groups for carboxy groups are, for example, esterifying groups, such as methyl or ethyl groups, which can be removed by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups, which can be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or benzyl groups, which can be removed by hydrogenation over a catalyst such as palladium on carbon.

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 following additional steps: (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.

The compounds resulting from this disclosure can be isolated and purified using techniques well known in the art.

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. These solvents include hexanes; 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.

The reaction temperature is preferably between about -100°C and 300°C, depending on the reaction step and conditions used.

Reaction times generally range from just a few minutes to several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times can be readily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperatures described above, suitable reaction times generally range from 10 minutes to 48 hours.

Furthermore, by utilizing the procedures described herein in conjunction with procedures in the art, additional compounds of the present disclosure can be readily prepared. Those of ordinary skill 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.

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 to 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, for example, in P. G. M. Wuts, T. W. This is described in more detail in Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

General routes for making the compounds of the present application are depicted in Schemes IX.

Biological Assays Once compounds designed, selected, and/or optimized by the methods described above 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.

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 conducting 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.

Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

In some embodiments, the biological assay may include retroviral production.

In some embodiments, the fusion mutant (e.g., BRAF-KIAA1549) may be subcloned into a retroviral expression vector (e.g., pMXs-IRES-Blasticidin). In this case, the retrovirus may be produced by transfecting cells (e.g., HEK293T) with a retroviral plasmid (e.g., a retroviral BRAF mutant expression vector).

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.

In some embodiments, the biological assay may involve the production of a fusion-stable cell line (e.g., a BRAF-KIAA1549 fusion-stable cell line).

In some embodiments, cells (e.g., BaF3) may be transduced with 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, fusion-stable cell lines may undergo cell banking and sequence confirmation (e.g., Sanger sequencing).

In some embodiments, the biological assay is an assay for cell proliferation.

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 compounds 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 compounds of the present disclosure, and inhibition of cell proliferation may be determined by luminescence quantitation (e.g., intracellular ATP content using CellTiterGlo) according to the manufacturer's protocol. In some embodiments, to determine _IC50 values, vehicle-treated cells were normalized to live cells and analyzed using software (e.g., CDD Vault (Collaborative Drug Discovery, Burlingame, CA)) using an algorithm (e.g., the Levenberg-Marquardt algorithm; Levenberg, K., 1994; Marquardt, D., 1963).

Pharmaceutical Compositions In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient.

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.

As used herein, the term "composition" is intended to encompass a product containing specified components in specified amounts, and any product resulting directly or indirectly from combining specified components in specified amounts.

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

The formulations of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity/suspending agents, buffers, and pH adjusters, and mixtures thereof.

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.

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, edetate tetrasodium, and mixtures thereof.

Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure). The tonicity agent 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.

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 methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, 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.

To adjust the formulation to an acceptable pH (typically in the pH range of 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, with sodium hydroxide and/or hydrochloric acid being preferred. 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 may not be necessary to use both an acid and a base; adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

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.

The formulation may further comprise a humectant. Suitable classes of humectants 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.

Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be mixed with excipients and used in the form of tablets, troches, or capsules. Oral compositions may also be prepared using a flowable carrier for use as a mouthwash, where the compound in the flowable carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically acceptable binders and/or adjuvants may be included as part of the composition. Tablets, pills, capsules, troches and the like may 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 disintegrant such as alginic acid, Primogel, or cornstarch; 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.

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.

The compositions of the present 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).

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.

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.

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):
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 alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH;
^W1 is N or CR ^W1 ;
R ^W1 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
^W2 is N or CR ^W2 ;
R ^W2 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogens;
^W3 is N or CR ^W3 ;
R ^W3 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
^W4 is N or CR ^W4 ;
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, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein the 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, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^1a ;
each R ^1a is 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- to 10-membered heteroaryl;
^R2 is H, halogen, cyano, oxo, OH, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, or _C1 - _C6 alkoxy;
^R3 is H, halogen, cyano, oxo, OH, _C1 - _C6 alkyl, _{C2 - C6} alkenyl, C2- _C6 alkynyl, or _C1 - _C6 alkoxy, or ^R1 and ^R3 together with the atoms therebetween form a 4-12 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 -*, wherein * represents a bond to A;
R ^X1 is independently H, S(=O) ₂ R ^X1a , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl _, wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C ₂ -C6 alkynyl, C _{1 -C6 alkoxy, C 3 -C 12 cycloalkyl} , 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^X1a ;
each R ^X1a is independently halogen, C ₁ -C ₆ alkyl, or 3-12 membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl or 3-12 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 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 -(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 substituted with one or more R ^A ;
Each R ^A is independently halogen, cyano, oxo, OH, OR ^A1 , NH ₂ , NHR ^A1 , N(R ^A1 ) ₂ , (═N)R ^A1 , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered _heteroaryl , wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C ₁ -C6 alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ;
Each R ^A1 is independently halogen, cyano, oxo, OH, OR ^A2 , NH ₂ , NHR ^A2 , N(R ^A2 ) ₂ , C(═O)R ^A2 , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C 2 -C6 _alkynyl , C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C ₁ -C6 alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to ₁₂ -membered heterocycloalkyl, _{C 6} -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A2 ;
each R ^A2 is 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 alkynyl;
The method wherein R ^A3 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Exemplary embodiment number 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.

Exemplary embodiment number 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.

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.

Exemplary embodiment number 18.
The method, compound, combination, or use of 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.

Exemplary embodiment number 19.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 18, wherein the cancer is characterized by at least one oncogenic mutation in the NRAS gene.

Exemplary embodiment number 20.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 19, wherein the cancer is characterized by at least one oncogenic variant of N-Ras.

Exemplary embodiment number 21.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 20, wherein the subject has at least one oncogenic mutation in the NRAS gene.

Exemplary embodiment number 22.
The method, compound, combination, or use of any one of exemplary embodiments 1-21, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of N-Ras.

Exemplary embodiment number 23.
23. The method, compound, combination, or use of any one of exemplary embodiments 1 to 22, wherein the cancer is characterized by at least one oncogenic mutation in the NF1 gene.

Exemplary embodiment number 24.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 23, wherein the cancer is characterized by at least one oncogenic variant of NF1.

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.

Exemplary embodiment number 26.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 25, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of NF1.

Exemplary embodiment number 27.
27. The method, compound, combination, or use of 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.

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, 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 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.

Exemplary embodiment number 29.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 28, wherein the cancer is a hematological cancer.

Exemplary embodiment number 30.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 29, wherein the cancer is a solid cancer.

Exemplary embodiment number 31.
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.

Exemplary embodiment number 32.
32. The method, compound, combination, or use of 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.

Exemplary embodiment number 33.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 32, wherein the cancer is glioma.

Exemplary embodiment number 34.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 33, wherein the cancer is low-grade glioma.

Exemplary embodiment number 35.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 34, wherein the cancer is glioblastoma.

Exemplary embodiment number 36.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 35, wherein the cancer is insensitive or resistant to treatment with one or more inhibitors of the MAPK pathway.

Exemplary embodiment number 37.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 36, wherein the cancer is insensitive or resistant to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

Exemplary embodiment number 38.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 37, wherein the subject has an adverse reaction to treatment with one or more inhibitors of the MAPK pathway.

Exemplary embodiment number 39.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 38, wherein the subject has an adverse reaction to treatment with a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

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.

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.

Exemplary embodiment number 42.
The method, compound, combination, or use according to any one of exemplary embodiments 1-41, wherein the BRAF inhibitor is vemurafenib, dabrafenib, or encorafenib.

Exemplary embodiment number 43.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 42, wherein the MEK inhibitor is trametinib, cobimetinib, or binimetinib.

Exemplary embodiment number 44.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 43, wherein the compound is administered to the subject by oral or parenteral administration.

Exemplary embodiment number 45.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 44, wherein a pharmaceutical composition comprising the compound is administered to the subject.

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).

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.

Exemplary embodiment number 48.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 47, wherein the compound and the one or more inhibitors of the MAPK pathway are administered simultaneously.

Exemplary embodiment number 49.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 48, wherein the compound and the one or more inhibitors of the MAPK pathway are administered sequentially.

Exemplary embodiment number 50.
50. The method, compound, combination, or use according to any one of exemplary embodiments 1 to 49, wherein the compound and the one or more inhibitors of the MAPK pathway are administered in close temporal proximity.

Exemplary embodiment number 51.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 50, wherein the compound and the one or more inhibitors of the MAPK pathway are administered in alternation.

Exemplary embodiment number 52.
The method, compound, combination, or use according to any one of exemplary embodiments 1 to 51, wherein the compound and the one or more inhibitors of the MAPK pathway are administered by the same route of administration.

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.

Exemplary embodiment number 54.
The method, compound, combination, or use of any one of exemplary embodiments 1 to 53, wherein the MEK inhibitor is binimetinib.

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 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±5 0 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±4 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 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 6 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 8 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±10 0 mg, about 1000±90 mg, about 1000±80 mg, about 1000±70 mg, about 1000±60 mg, about 1000±50 mg, about 1000±40 mg, about 1000±30 mg, about 1000±20 mg, or about 1000±10 mg (e.g., about 1000 mg); or about 1200±600 mg, about 1200±500 mg, about 1200±400 mg, about A dose of 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) may be administered daily. and binimetinib is administered at 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 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 g); about 75±40 mg, about 75±30 mg, about 75±20 mg, about 75±10 mg, about 75±9 mg, about 75±8 mg, about 75±7 mg, about 75±6 mg, about 75±5 mg, about 75±4 mg, about 75±3 mg, about 75±2 mg, or about 75±1 mg (e.g., about 75 mg); or about 90±50 mg, about 90±40 mg, about 90±30 mg, about 90± 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 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).

Definitions Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

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.

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.

While not intended to be limiting by this description, various options for variables are described herein, and the present disclosure is intended to encompass feasible embodiments having combinations of options. The present disclosure may be construed to exclude infeasible embodiments caused by a particular combination of options.

It should be understood, of course, that compounds of the present disclosure may be depicted in neutral, cationic (e.g., carrying one or more positive charges), or anionic (e.g., carrying one or more negative charges) forms, all of which are intended to be within the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in anionic form, it should be understood that such depiction also refers to various neutral, cationic, and anionic forms of the compound. As another example, when a compound of the present disclosure is depicted in anionic form, it should be understood that such depiction also refers to various salts (e.g., sodium salts) of the anionic form of the compound.

"Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to treat such disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

As used herein, "alkyl,""C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ alkyl," or "C ₁ -C ₆ alkyl" is intended to include "C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ straight-chain (linear) saturated aliphatic hydrocarbon groups, and C ₃ , C ₄ , C ₅ or C ₆ branched-chain saturated aliphatic hydrocarbon groups. For example, C ₁ -C ₆ alkyl includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C It is intended to include alkyl groups having from 1 to _{6 carbon atoms. Examples of alkyl include, but are not limited to, moieties having from 1 to 6} carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms (e.g., C _{1 -C 6} for straight chain, C _{3 -C 6} for branched chain), and in other embodiments, a straight chain or branched chain alkyl has four or fewer carbon atoms.

As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched-chain alkenyl groups. In certain embodiments, a straight-chain or branched-chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., _C2 - _C6 for straight chain, _C3 - _C6 for branched chain). The term " _C2 - _C6 " includes alkenyl groups containing two to six carbon atoms. The term " _C3 - _C6 " includes alkenyl groups containing three to six carbon atoms.

As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., erynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, a straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term "C ₂ -C ₆ " includes alkynyl groups containing two to six carbon atoms. The term "C ₃ -C ₆ " includes alkynyl groups containing three to six carbon atoms. As used herein, a " _C2 - _C6 alkenylene linker" or " _C2 - _C6 alkynylene linker" is intended to include a _C2 , _C3 , _C4 , _C5 , or _C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a _C2 - _C6 alkenylene linker is intended to include a _C2 , _C3 , _C4 , _C5 , or _C6 alkenylene linker group.

As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties bearing one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., _C3 - _C12 , _C3 - _C10 , or _C3 - _C8 ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. For polycyclic cycloalkyls, only one of the rings in the cycloalkyl need be non-aromatic.

As used herein, the term "heterocycloalkyl," unless otherwise specified, refers to a saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms, e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-o- azepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5' -furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 6,7, Examples include 8,9-tetrahydro-5H-imidazo[1,2-a]azepinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, and 2-oxa-azaspiro[3.4]octan-6-yl. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl need be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

As used herein, the term "aryl" includes groups having aromatic character, including "conjugated," or polycyclic ring systems having one or more aromatic rings, and no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, the aryl is phenyl.

As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heteroaromatic ring composed of carbon atoms and one or more heteroatoms independently selected from the group consisting of, for example, nitrogen, oxygen, and sulfur, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other defined substituent). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O, and S(O) _p , where p=1 or 2). Note that the total number of S and O atoms in the heteroaromatic ring is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

The terms "aryl" and "heteroaryl" further include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, and indolizine.

In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may have at one or more ring positions (e.g., a ring carbon or a heteroatom, e.g., N) a substituent such as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl The aryl and heteroaryl groups may be substituted with aryl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylic acid, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with non-aromatic, alicyclic, or heterocyclic rings to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl, such as benzo[d][1,3]dioxol-5-yl).

As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a group selected from a specified group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., ═O), two hydrogen atoms on the atom are replaced. Keto substituents do not occur in aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

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

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

As used herein, the term "hydroxy" or "hydroxyl" includes groups with an --OH or ^--O.sub.2-- .

As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl group having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be optionally substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

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

It should be understood that the present disclosure provides methods for synthesizing compounds of any of the formulas described herein. The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to those shown in the following schemes and examples.

Throughout the description, when a composition is described as having, including, or comprising particular ingredients, it should be understood that the composition is also contemplated as consisting essentially of or consisting of the recited ingredients. Similarly, when a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of or consists of the recited process steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

It should be understood that the synthetic processes of the present disclosure can tolerate a wide range of functional groups and, therefore, can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the completion of the overall process, in certain instances, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

It will be understood that the compounds of the present disclosure can be made in a variety of ways using commercially available starting materials, compounds known in the literature, or readily made intermediates by employing standard synthetic methods and procedures that are known to those skilled in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. See, for example, but not limited to, any one or more sources, Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^5th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., and others. , Protective Groups in Organic Synthesis, ^3rd edition, John Wiley & Sons: New York, 1999; L. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. , Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and widely recognized references on organic synthesis known to those skilled in the art and are incorporated herein by reference.

Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be changed during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these protecting groups can be found in Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, ^3rd edition, John Wiley & Sons: New York, 1999.

Unless otherwise specified, any reference to a method of treatment should be understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating or preventing such diseases. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

As used herein, the term "subject" includes human and non-human mammals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

As used herein, the term "subject in need thereof" refers to a subject who has a disease or is at high risk of developing a disease. A subject in need thereof may be a subject who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject who is at high risk of developing such a disease or disorder compared to the population at large (i.e., a subject who is more likely to develop such a disorder compared to the population at large). A subject in need thereof may be refractory or resistant to a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof has undergone all known effective therapies for a disease or disorder disclosed herein to no avail. In some embodiments, a subject in need thereof has undergone at least one prior therapy.

As used herein, the term "treating" or "treat" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" may also include the treatment of cells in vitro or in an animal model. It should be recognized that references to "treating" or "treatment" include the alleviation of symptoms of established diseases. Thus, "treating" or "treatment" of a condition, disorder, or disease includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or disease in a person who may be afflicted with or predisposed to the condition, disorder, or disease, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or disease; (2) inhibiting the condition, disorder, or disease, i.e., arresting, reducing, or delaying the onset of the disease, or its recurrence (in the case of maintenance treatment), or the development of at least one clinical or subclinical symptom thereof; and (3) palliating or attenuating the disease, i.e., regressing the condition, disorder, or disease, or regressing at least one clinical or subclinical symptom thereof.

As used herein, the terms "preventing," "prevent," or "protect from" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

As used herein, the term "proximal in time" refers to administration of one therapeutic agent (a compound of the present disclosure) within a period of time before or after administration of another therapeutic agent (one or more inhibitors of the MAPK pathway) such that the therapeutic effects of one therapeutic agent overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, the therapeutic effects of one therapeutic agent completely overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, "proximal in time" refers to administration of one therapeutic agent within a period of time before or after administration of another therapeutic agent such that there is a synergistic effect between the two therapeutic agents. "Proximal in time" can vary depending on various factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition being treated or ameliorated; the therapeutic outcome being achieved; the dose, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "proximate in time" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may be administered in close temporal proximity to a single administration of another therapeutic agent. In some embodiments, the temporal proximity may vary during a treatment cycle or dosing regimen.

It is understood that the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may prevent or may be used to prevent the associated disease, condition, or disorder, or may be used to identify suitable candidates for such purposes.

All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, one skilled in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure.

In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. However, it will be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

Those skilled in the art will understand that for detailed descriptions of known techniques or equivalent techniques described herein, they can refer to general reference texts, including Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual ( ^3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al. , Current Protocols in Immunology, John Wiley & Sons, N. Y. ; Enna et al. , Current Protocols in Pharmacology, John Wiley & Sons, N. Y. ;Fingl et al. , The Pharmaceutical Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co. , Easton, PA, ^18th edition (1990). These texts may, of course, also be referred to when making or using aspects of the present disclosure.

It is understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or salt thereof) in a unit dose of the composition is an effective amount and will vary according to the particular treatment involved. Those skilled in the art will recognize that routine variations in dosage may be necessary depending on the age and condition of the patient. Dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any required preservatives, buffers, or propellants.

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

"Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise harmful and is useful in preparing pharmaceutical compositions, and includes excipients that are applicable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both single and multiple excipients.

It should be understood that pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous use may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparabens; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetates, citrates, or phosphates, and an agent for adjusting tonicity such as sodium chloride or dextrose. pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many of the well-known methods currently used for chemotherapy treatment. For example, the compounds of the present disclosure may be injected into the bloodstream or a body cavity, or taken orally, or applied through the skin using a patch. The dosage selected should be sufficient to provide effective treatment, but not so high as to cause unacceptable side effects. The patient's condition (e.g., a disease or disorder disclosed herein) and health status should preferably be closely monitored during treatment and for an appropriate period after treatment.

As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorate, or prevent a specified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

It should be understood that for any compound, the therapeutically effective amount can be initially estimated either in cell culture assays, for example, of tumor cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED50 (the dose therapeutically effective in 50% of the population) and _LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio _LD50 / _ED50 . Pharmaceutical compositions exhibiting large therapeutic indices are preferred. Dosages can vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be taken into consideration include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, concomitant formulations, reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

Pharmaceutical compositions containing the active compounds of the present disclosure can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and/or adjuvants that facilitate processing of the active compound into pharmaceutically usable preparations. Of course, the appropriate formulation will depend upon the chosen route of administration.

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

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

Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be mixed with excipients and used in the form of tablets, troches, or capsules. Oral compositions may also be prepared using a flowable carrier for use as a mouthwash, where the compound in the flowable carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically acceptable binders and/or adjuvants may be included as part of the composition. Tablets, pills, capsules, troches and the like may 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 disintegrant such as alginic acid, Primogel, or cornstarch; 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.

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

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

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

Formulating oral or parenteral compositions in dosage unit form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent on the unique characteristics of the active compound(s) and the particular therapeutic effect to be achieved.

In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors that will affect the selected dosage. Generally, the dose should be sufficient to slow, and preferably cause regression of, the symptoms of a disease or disorder disclosed herein, and preferably complete regression of the disease or disorder. Dosages may range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred embodiments, dosages may range from about 1 mg/kg per day to about 1000 mg/kg per day. In certain embodiments, the dose ranges from about 0.1 mg/day to about 50 g/day, about 0.1 mg/day to about 25 g/day, about 0.1 mg/day to about 10 g/day, about 0.1 mg/day to about 3 g/day, or about 0.1 mg/day to about 1 g/day, in single, divided, or continuous doses (this dose can be adjusted depending on the patient's weight (kg), body surface area (m ² ), and age (years)). An effective amount of a pharmaceutical agent is that amount that produces an objectively discernible improvement as determined by a clinician or other professional observer. Improved survival and growth indicate regression. As used herein, the term "effective dosage" refers to that amount of an active compound that produces a desired biological effect in a subject or cell.

As used herein, the term "daily dose" refers to the total dose of a drug administered in one day. Such total amount can be administered in a single dose per day (e.g., once daily) or can be administered in two or more divided doses per day (e.g., twice daily).

It should be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

It should be understood that because the compounds of the present disclosure are capable of further forming salts, all of these forms are also intended to be within the scope of the claimed disclosure.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound has been modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such common non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobion, Included are salts obtained from inorganic and organic acids selected from laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, and arginine.

In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonia salt, arginine salt, or lysine salt.

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

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

The compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of particular routes of administration.

Dosage regimens using the present compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, the particular compound or salt thereof being used, etc. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, arrest, or arrest the progress of the condition.

The formulation and administration techniques of the disclosed compounds of the present disclosure are described in Remington: the Science and Practice of Pharmacy, ^19th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein and their pharmaceutically acceptable salts are combined with pharmaceutically acceptable carriers or diluents and used in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compound will be included in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, one skilled in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure.

In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. However, it will be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference. Citation of publications and patent documents does not constitute an admission that any is pertinent prior art, nor any admission as to the contents or date. While the invention has been described by way of description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the above description and the following examples are intended to be illustrative and not limiting of the scope of the claims that follow.

Example 1. Biological Activity of Exemplary Compounds Retrovirus Production: BRAF-KIAA1549 fusion mutants were subcloned into pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, CA). Retrovirus was produced by transfecting HEK 293T cells with the retroviral BRAF mutant expression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs), the pCMV-Gag-Pol vector, and the pCMV-VSV-G-Envelope vector. Briefly, HEK 293T cells were seeded into poly-D-lysine-coated 6-well plates (2.5 x ¹⁰ cells per well) and incubated overnight. The following day, retroviral plasmids (1 μg of BRAF KIAA fusion mutant, 0.32 μg of pCMV-Gag-Pol, and 0.165 μg of pCMV-VSV-G) were mixed in 300 μL of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 minutes and then added to Optimem containing the transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. The mixture was then added dropwise to HEK 293T cells. The following day, the medium was replaced with fresh culture medium, and retroviruses were harvested at 24 hours.

Generation of BRAF-KIAA1549 fusion stable cell lines: BaF3 cells were seeded (4 x 10 cells/well) in 80 μL of RPMI/10% FBS supplemented with 8 μg/mL polybrene and 0.01 ng/mL mouse IL-3 in a V-bottom 96-well plate (COSTAR ^#3894 ). Cells were transduced with 20 μL of BRAF-KIAA1549 fusion virus supernatant by centrifugation at 1000 rpm for 30 minutes. The cells were placed in a 37°C incubator overnight. The next day, 100 μL of RPMI/10% FBS and 0.01 ng/mL mouse IL-3 were added. After 24 hours, 100 μL of cells were transferred to a 24-well plate containing 900 μL of RPMI/10% FBS and 15 μg/mL blasticidin. Over a two-week period, the contents of the 24-well plate were sampled and cell viability was assessed using CellTiterGlo (Promega). Cells with a viability greater than 1x beyond the day of seeding were expanded into T25 flasks for cell banking and Sanger sequencing confirmation.

Cell proliferation assay: BaF3 BRAF-KIAA1549 fusion cells were resuspended at 1.5 ^{x 10} cells/mL in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine, and dispensed in duplicate (7 x ¹⁰ cells/well) into 384-well plates. To determine the effect of compounds on cell proliferation, BaF3 BRAF-KIAA1549 fusion cells were incubated for 96 hours in the presence of vehicle control (DMSO) or various concentrations of compounds. Inhibition of cell proliferation was determined by luminescent quantification of intracellular ATP content (Perkin Elmer Envision) using CellTiterGlo (Promega) according to the protocol provided by the manufacturer. To determine IC ₅₀ values, vehicle-treated cells were normalized as viable cells and analyzed using CDD Vault, Collaborative Drug Discovery, Burlingame, CA (the Levenberg-Marquardt algorithm; Levenberg, K., 1994 ; Marquardt, D., 1963 ).

Table A assigns each compound a code for potency in the BaF3 BRAF-KIAA1549 fusion cell proliferation assay: A, B, C, or D. According to the code, A represents an _IC50 value of <20 nM, B represents an _IC50 value of ≥20 nM and <100 nM, C represents an _IC50 value of ≥100 nM and <500 nM, and D represents an _IC50 value of ≥500 nM.

Example 2. Nonclinical Studies of Compounds of the Disclosure The pharmacological activity of compounds of the disclosure was studied both in vitro and in various in vivo animal models. Results from in vitro cell-based assays showed that the compound potently inhibited cell proliferation of a wide range of oncogenic BRAF- or NRAS-expressing cell lines, sparing wild-type BRAF (greater than 18-fold selectivity) and NRAS (8-43-fold selectivity) and avoiding paradoxical activation. The compound inhibited cell proliferation of the BRAF V600E (Class I) cell line, which is resistant to combinations of BRAF and MEK inhibitors (dabrafenib and trametinib, and encorafenib and binimetinib). Exposure in plasma, tumor, and brain increased with increasing dose. Increased tumor exposure to the compound correlated with increased inhibition of cellular ERK phosphorylation, suggesting on-target activity.

The antitumor activity of compounds of the present disclosure was investigated in mice bearing tumor models driven by BRAF class I, II, and III mutations, as well as KRAS G12D and G12V mutations (Table B). Antitumor activity was demonstrated in subcutaneous tumor models representing all three classes of BRAF mutations, as well as KRAS mutations.

Cancer cell lines endogenously carrying BRAF mutations or patient-derived tumors with KRAS mutations were implanted subcutaneously into the flanks of nude mice. When tumor volumes reached approximately 200 ^mm (170-270 ^mm depending on the model), animals were randomly assigned to vehicle/control or test substance groups. Mice were then administered vehicle/control or test substance once or twice daily for 14, 21, or 28 days. Tumor volumes were measured two to three times weekly throughout the study period.

Tumor growth inhibition (TGI) values are calculated using the following formula:
TGI (%) = [1-(D _t -D ₀ )/(C _t -C ₀ )]x100

_Dt = median tumor volume of the compound-treated group at time t. _D0 = median tumor volume of the compound-treated group at time 0. _Ct = median tumor volume of the control (vehicle) group at time t. _C0 = median tumor volume of the compound-treated group at time 0.

Please understand that the values presented in Table B are approximate and subject to experimental and instrumental variations.

Example 3. Clinical Trials of Compounds of the Disclosure This is a first-in-human, Phase 1, multicenter, open-label, dose-escalation and expansion study designed to evaluate safety and tolerability, determine RP2D, and assess preliminary antitumor activity in patients with advanced/metastatic NSCLC with BRAF class I and II alterations or KRAS non-G12C mutations, advanced/metastatic melanoma with BRAF class I mutations or NRAS mutations, histiocytic neoplasms with BRAF or NRAS mutations, and other select tumors with class I, II, and III mutations ( FIG. 1 ). The study will be conducted in two parts.

Part 1: The dose escalation portion of the study will employ a Bayesian optimal interval design (BOIN) dose escalation design, including two single-patient accelerated titration dose levels. Patients will be included who have advanced/metastatic tumors or neoplasms with BRAF, KRAS non-G12, or NRAS mutations who have progressed, resisted, or intolerant to prior standard-of-care systemic therapy.

Part 2: The dose-expansion portion of the study includes four disease-specific cohorts:
Cohort 1: Patients with recurrent advanced/metastatic NSCLC with BRAF class II alterations, including fusions, or KRAS non-G12C mutations.
Cohort 2: Patients with recurrent and intolerant histiocytic neoplasms harboring BRAF or NRAS mutations.
Cohort 3: Patients with recurrent advanced/metastatic NSCLC or melanoma harboring a BRAF V600E (Class I) mutation.
Cohort 4: Patients with recurrent, advanced/metastatic melanoma harboring NRAS mutations.

Monotherapy Dose Escalation The dose escalation portion of this study involves an accelerated single-patient dose escalation. The dose-limiting toxicity (DLT) observation period is defined as from the first dose on Day 1 of Cycle 1 (C1D1) to the end of the first cycle (28-day cycle duration).

Dose Escalation Cohort:
- Melanoma with BRAF (class I, II, or III) or NRAS mutations - NSCLC with BRAF (class I, II, or III) or KRAS non-G12C mutations
histiocytic neoplasms with BRAF (class I, II, or III) or NRAS mutations; thyroid carcinomas with BRAF (class I, II, or III) mutations; colorectal carcinomas with BRAF (class II or III) mutations.
Other solid tumors with BRAF class I mutations after prior treatment with a BRAF/MEK inhibitor

The selection of the RP2D will occur after a sufficient number of patients have enrolled, completed PK and safety assessments during dose escalation, and the data have been reviewed for safety. Once the RP2D is determined, the dose expansion portion of the study will begin in additional patients with selected neoplasms, with or without brain metastases, based on known BRAF, KRAS non-G12C, or NRAS alterations to further evaluate safety, tolerability, and preliminary evidence of antitumor activity. If the RP2D has not been established at the end of dose escalation, an expansion cohort may be opened to obtain additional PK, safety, and tolerability data to support further dose optimization, including the investigation of several dose levels, to support exposure-response analysis and define the RP2D.
Dose expansion

Patients will be enrolled and treated in each disease-specific expansion cohort (Cohorts 1, 2, 3, and 4). Enrollment for each dose expansion cohort may be extended if it is determined that additional safety, PK, and early efficacy data (if available) are needed to support further dose optimization. Additional cohorts may be added based on new data obtained from the dose escalation portion of the study. Safety data will be continuously reviewed across all expansion cohorts. Significant safety findings may lead to early halting of any expansion cohort and will be considered when deciding to initiate a new disease-specific expansion cohort.

Dose expansion cohort:
Cohort 1: Recurrent NSCLC with BRAF class II alterations or KRAS non-G12C mutations, without transformation to small cell lung cancer and with radiographically confirmed progressive disease
Cohort 2: Recurrent and intolerant histiocytic neoplasms with BRAF or NRAS alterations with radiographically confirmed progressive disease.
Cohort 3: BRAF class I mutated recurrent NSCLC (without small cell lung cancer transformation) or melanoma with radiographically confirmed progressive disease.
Cohort 4: Recurrent melanoma with NRAS mutations and confirmed active disease by radiographic evaluation.

Combination therapy with a MEK inhibitor is being investigated. A pilot food effect substudy will be conducted to assess the effect of food on PK.

Example 4. Testing of compounds of the present disclosure in combination with binimetinib.
The antitumor activity of compounds of the present disclosure in combination with binimetinib was investigated in mice bearing a KRAS G12D NSCLC patient-derived xenograft (PDX) model. Nu/Nu mice implanted with KRAS G12D patient-derived NSCLC tumors were randomly assigned to a control or treatment group when the overall mean tumor volume reached 172 ^mm3 . Mice were administered vehicle twice daily at approximately 12-hour intervals, binimetinib twice daily at approximately 12-hour intervals, and a compound of the present disclosure or a combination thereof once daily by oral gavage for 50 days. No significant weight loss was observed in any group. See Figure 2 for representative results of this study.

The antitumor activity of compounds of the present disclosure in combination with binimetinib was also investigated in mice bearing a melanoma cell line harboring the BRAF V600E mutation. BALB/c nude mice implanted with A375-Luc melanoma cells were randomly assigned to control or treatment groups when the overall mean tumor volume reached ²²⁴ mm3. Mice were administered vehicle twice daily at approximately 12-hour intervals, binimetinib twice daily at approximately 12-hour intervals, and a compound of the present disclosure or a combination thereof once daily by oral gavage for 35 days. No significant weight loss was observed in any group. See Figure 3 for representative results of this study.

Equivalents Details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, suitable methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms "a,""an," and "the" include plural referents unless the context clearly dictates otherwise. 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. All patents and publications cited herein are incorporated by reference.

The foregoing description has been presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed, other than as defined by the appended claims.

Claims (36)

1. A method of treating or preventing cancer in a subject, comprising administering to a subject a compound according to formula (0):
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 said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxy is optionally substituted with one or more halogen, cyano, oxo, or OH;
^W1 is N or CR ^W1 ;
R ^W1 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
^W2 is N or CR ^W2 ;
R ^W2 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more halogens;
^W3 is N or CR ^W3 ;
R ^W3 is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
^W4 is N or CR ^W4 ;
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, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein said 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, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with _one or more R ^1a ;
each R ^1a is 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- to 10-membered heteroaryl;
^R2 is H, halogen, cyano, oxo, OH, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, or _C1 - _C6 alkoxy;
^R3 is H, halogen, cyano, oxo, OH, _C1 - _C6 alkyl, _{C2 - C6} alkenyl, C2- _C6 alkynyl, or _C1 - _C6 alkoxy, or ^R1 and ^R3 together with the atoms therebetween form a 4-12 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 a bond to A;
R ^X1 is independently H, S(=O) ₂ R ^X1a , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein said C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R ^X1a ;
each R ^X1a is independently halogen, C ₁ -C ₆ alkyl, or 3- to 12-membered heterocycloalkyl, wherein said C ₁ -C ₆ 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 said 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 -(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 substituted with one or more R ^A ;
Each R ^A is independently halogen, cyano, oxo, OH, OR ^A1 , NH ₂ , NHR ^A1 , N(R ^A1 ) ₂ , (═N)R ^A1 , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered _heteroaryl , wherein said C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C ₁ -C6 alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ;
Each R ^A1 is independently halogen, cyano, oxo, OH, OR ^A2 , NH ₂ , NHR ^A2 , N(R ^A2 ) ₂ , C(═O)R ^A2 , C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C _{1 -C6} alkoxy, C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein said C _{1 -C6} alkyl, C _{2 -C6} alkenyl, C _{2 -C6} alkynyl, C ₁ -C6 alkoxy, C ₃ -C _{12 cycloalkyl} , 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A2 ;
each R ^A2 is 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 alkynyl;
The method wherein R ^A3 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl. A compound of formula (0), its isomer, or a pharmaceutically acceptable salt thereof for treating or preventing cancer in a subject. Use of a compound of formula (0), its isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a 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. A method for 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. 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. 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. The method, compound, combination, or use of any one of claims 1 to 7, wherein the subject is a human. 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, 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. 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 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. The method, compound, combination, or use of any one of claims 1 to 10, wherein the cancer is a blood cancer. The method, compound, combination, or use of any one of claims 1 to 11, wherein the cancer is a solid cancer. 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, kidney cancer, colorectal cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, soft tissue sarcoma, CNS and brain cancer, or thyroid cancer. 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 site, non-melanoma skin cancer, prostate cancer, gastric cancer, non-Hodgkin's lymphoma, papillary thyroid cancer, or glioblastoma. The method, compound, combination, or use of any one of claims 1 to 14, wherein the cancer is glioma. The method, compound, combination, or use of any one of claims 1 to 15, wherein the cancer is glioblastoma. The method, compound, combination, or use of any one of claims 1 to 16, wherein the cancer is lung cancer. The method, compound, combination, or use of any one of claims 1 to 17, wherein the cancer is non-small cell lung cancer (NSCLC). The method, compound, combination, or use of any one of claims 1 to 18, wherein the compound is administered to the subject by oral or parenteral administration. The method, compound, combination, or use of any one of claims 1 to 19, wherein a pharmaceutical composition containing the compound is administered to the subject. 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). 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. 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. 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. 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. 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. 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. 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. 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. the one or more additional therapeutic agents comprise one or more MET inhibitors;
30. The method, compound, combination or use of any one of claims 1 to 29, optionally wherein said one or more MET inhibitors comprise crizotinib, capmatinib, tepotinib, savolitinib, cabozantinib, glesatinib, foretinib, merestinib, tivantinib, SAR125844, onartuzumab, telisotuzumab, or JNJ-61186372. 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. 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. 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. 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. 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. 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.