Dual RAF inhibitors and tubulin inhibitors and their methods of use

Abstract

Compounds that are dual RAF inhibitors and tubulin inhibitors, and their use in the treatment of disorders such as cancer, are described herein. TIFF2026521539000118.tif48165

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 507,787, filed on 13 June 2023, and U.S. Provisional Patent Application No. 63 / 587,821, filed on 4 October 2023, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] BRAF V600X (i.e., V600E) variants of BRAF are known to be oncogenic, and several BRAF inhibitors are currently on the market to inhibit oncogenic BRAF V600E signaling in melanoma and other cancers. BRAF V600E signals as a monomer and is constitutively active, independent of upstream regulation by the RAS. Commercially available BRAF V600E inhibitors include vemurafenib, dabrafenib, and encorafenib.

[0003] With the exception of BRAF V600X variants, almost all other oncogenic forms of BRAF signaling transmit signals through the formation of homodimers (BRAF-BRAF dimers) or heterodimers (e.g., BRAF-CRAF dimers) that are refractory to BRAF V600X inhibitors such as vemurafenib, dabrafenib, and encorafenib. These dimers are formed in cancers driven by BRAF fusions, atypical BRAF mutations, or RAS mutations.

[0004] Oncogenic BRAF fusions arise from genomic rearrangements that place the 3-prime portion of the BRAF gene encoding the kinase domain behind another gene at a 5-prime position. This rearrangement results in the expression of a tumor protein exhibiting constitutive kinase activity due to the loss of the N-terminal autoinhibitory domain of BRAF. These BRAF fusions exhibit constitutive kinase activity through spontaneous dimerization, thus enabling abnormal signaling in cancer cells independently of upstream effectors or regulatory mechanisms. In addition, some 5-prime translocation rearrangement genes can contribute to the N-terminal domain, further inducing dimerization, thereby enhancing the activation of dimerization in the BRAF fusion protein kinase domain. Since the expression of these genomic rearrangements is regulated by the promoters of the 5-prime partners, overexpression of BRAF fusion transcripts due to efficient or excessive promoter activity is often present. BRAF fusions are one of the most common kinase translocations in solid tumors. Since its initial description in 2005 as an oncogene for papillary thyroid carcinoma, hundreds of tumors with the BRAF kinase domain fused to one of over 110 different 5 prime partner genes have been identified across at least 15 different tumor types. BRAF fusions have been found in papillary thyroid carcinoma, astrocytoma, melanoma, and have also been identified in drug-resistant EGFR-mutant lung cancer. BRAF fusion proteins signal via RAS-independent dimerization and are resistant to many BRAF inhibitors, such as vemurafenib and dabrafenib, which cannot inhibit either protomer of the signaling homodimer BRAF fusion. Rare CRAF fusion proteins have also been demonstrated to be tumor-driving factors. These CRAF fusion proteins signal as CRAF-CRAF homodimers.

[0005] Other so-called atypical BRAF mutations also result in spontaneous dimerization and signaling, independently of RAS controls. Like BRAF fusions, these atypical BRAF variants signal as abnormal homodimers.

[0006] RAS-mutated cancers account for approximately 26-30% of all human cancers. RAS-mutated cancers transmit signals through the RAS→RAF→MEK→ERK MAPK signaling pathway. In this signaling cascade, kinase-inactive RAF monomers (including ARAF, BRAF, and CRAF isoforms) are recruited to oncogenic RAS, and RAS induces the formation of kinase-active signaling RAF dimers. The dominant RAF heterodimer recruited to mutant RAS is the wild-type BRAF / CRAF heterodimer.

[0007] A combined siRNA screening approach identified RAF as the dominant node in RAS-mutated cancers. Its co-depletion of both BRAF and CRAF, along with depletion of the autophagy gene ATG7, resulted in the best synthetic lethal inhibition of RAS mutant signaling, and, in addition, provided the best therapeutic time window for inhibiting signaling in RAS mutant cells compared to normal RAS wild-type cells. Furthermore, inhibition of the RAF→MEK→ERK pathway in combination with autophagy inhibitors has been reported to effectively block RAS-mutated cancer growth both in vitro and in vivo.

[0008] Vertical inhibition of the RAF→MEK→ERK pathway through pan-inhibition of RAF (specifically, BRAF+CRAF) and ERK kinase activity has been shown to produce a high synergistic effect in blocking MAPK pathway signaling in KRAS-mutant pancreatic cancer cells, organoid studies, and mouse models of KRAS-mutant pancreatic cancer. Vertical inhibition of RAF (BRAF+CRAF) and MEK kinase activity has also been shown to be synergistic in KRAS-mutant tumors.

[0009] The importance of inhibiting both BRAF and CRAF isoforms, as well as the need for inhibitors that effectively bind to and inhibit both protomers of the signaling RAF dimer, has been well demonstrated. When RAF inhibitors, particularly BRAF V600X inhibitors, fail to effectively bind to and inhibit both protomers of the signaling RAF dimer in RAS-mutated cancers, they result in paradoxical pathway stimulation rather than the desired pathway inhibition. Such BRAF V600X inhibitors are contraindicated in the treatment of RAS-mutated cancers.

[0010] There is a need to identify RAF inhibitors that can inhibit multiple RAF isoforms. Specifically, there is a need to identify RAF inhibitors that can inhibit both BRAF and CRAF isoforms. In particular, there is a need to identify RAF inhibitors that can inhibit both RAF protomers present in signaling BRAF / BRAF homodimers, and both protomers in BRAF / CRAF heterodimers. Such pan-RAF inhibitors will find usefulness in the treatment of BRAF V600X-driven cancers, atypical BRAF-mutated cancers, BRAF fusion cancers, CRAF fusion cancers, and RAS-mutated cancers.

[0011] Microtubules (MTs), the major components of the cytoskeleton in eukaryotic cells, play essential roles in multiple cellular functions, including maintaining cell morphology, signal transduction, organelle transport, cell motility, cell division, and mitosis. These cytoskeletal filaments consist of α-tubulin heterodimers and β-tubulin heterodimers. Microtubule dynamics (assembly and disintegration) are essential for proper mitotic spindle function and completion of mitosis. This highly controlled process is driven by the hydrolysis of GTP on the β-tubulin subunit. Therefore, disruption of MT dynamics is useful in anticancer therapy. Disruption of MT dynamics has been demonstrated to exhibit anticancer activity in mutant RAS and mutant RAF-driven tumors.

[0012] Microtubule-targeted agents (MTAs) possess anti-angiogenic and vascular-destructive effects, in addition to other effects on cellular function. By affecting the microtubule network, MTAs inhibit endothelial cell proliferation, migration, and tubulation, leading to significant changes in endothelial cell morphology. MTAs are also valued as potential vascular-destructive agents (VDAs). VDAs are known to block blood flow primarily in solid tumors, while leaving blood vessels intact in normal tissues.

[0013] Microtubule stabilizers (MTAs) are classified into three main classes based on their α-tubulin binding site or β-tubulin binding site. MTAs that bind to taxane sites include taxanes and epothirones. These microtubule stabilizers bind to fully formed microtubules, preventing the depolymerization of tubulin subunits. In contrast, vinca alkaloids interact with the tubulin vinca domain found in tubulin dimers, inhibiting their polymerization into microtubules (microtubule destabilizers). Colchicine and colchicine-binding site inhibitors (CBSIs) interact at distinct sites on tubulin (at the interface between the α- and β-subunits of the tubulin heterodimer) and define a third class of antimitotic agents. Similar to vinca alkaloids, these agents also act as microtubule destabilizers.

[0014] Compounds that alter microtubule function have been shown to be highly active in cancer patients. Taxanes and vinca alkaloids are currently administered for a wide variety of indications, including solid tumors and hematological malignancies. Currently, there are no approved oral CBSIs as anticancer drugs.

[0015] The main challenges of MTAs currently in clinical use (particularly taxanes) include systemic toxicity, acquired drug resistance, administration methods limited to intravenous routes, insufficient solubility requiring the use of surfactants for intravenous administration with associated hypersensitivity risks, and disease recurrence when patients are treated in an advanced environment. MTAs approved for clinical use suffer from dose-limiting neurotoxicity and hematopoietic toxicity.

[0016] The common mechanism of multidrug resistance (MDR), namely ATP-binding cassette (ABC) transporter protein-mediated drug efflux, limits the effectiveness of taxanes. P-glycoprotein (P-gp, encoded by the MDR1 gene) is a key member of the ABC superfamily. P-gp prevents the intracellular accumulation of many anticancer drugs by increasing their efflux from cancer cells. Overexpression of MDR proteins, common to most solid tumors, leads to treatment failure and uncontrolled disease progression. Other resistance mechanisms include upregulation of drug efflux pumps, altered expression of multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP), or tubulin isotypes, and mutations in the β-tubulin gene.

[0017] Drug combinations involving drugs with different anticancer mechanisms are commonly used to enhance tumor response and patient survival, particularly in the treatment of patients with advanced cancer. There is a close interaction between the RAS / MAPK pathway and the microtubule-dependent MYC regulatory pathway. For example, large-scale loss-of-function siRNA screening identified TUBB3 (encoding the bIII tubulin isoform) as a vulnerability in pancreatic cancer. Gene silencing against ERK inhibition in TUBB3-sensitive KRAS-mutated pancreatic ductal adenocarcinoma (PDAC) cells suggests that pharmacological inhibition of proteins supporting MYC expression (e.g., tubulin inhibitors) may be an effective therapeutic strategy for targeting mutant KRAS-dependent PDACs. TUBB3 also has clinical significance because overexpression of this β-tubulin isoform is associated with an inadequate response to microtubule-targeted drugs such as taxanes. Positive TUBB3 expression has been most frequently observed in various brain tumors, lung cancer, renal cell carcinoma, malignant melanoma, and PDACs. Furthermore, TUBB3 expression levels were altered in many cancer cells, and abnormal TUBB3 expression was associated with enhanced chemorespiratory resistance and poor prognosis in NSCLC, ovarian cancer, gastric cancer, breast cancer, and serous adenocarcinoma of the uterus.

[0018] Tubulin disruptors have also been shown to upregulate MAPK pathway signaling, which limits their effectiveness. Dual-target agents that inhibit MAPK pathway signaling in addition to targeting tubulin may overcome this resistance reactivation mechanism of the MAPK pathway.

[0019] Dual-target agents (a single molecule that interacts with two distinct biological targets) can also offer advantages over combination therapies, particularly a reduced risk of drug-drug interactions, a more easily predictable pharmacokinetic (PK) profile, simplified drug regimens, and increased patient compliance.

[0020] Given the high resistance to current MAPK-targeted therapies, identifying agents that exhibit BRAF inhibition and tubulin disruption could overcome BRAF inhibitor resistance and significantly benefit patients with various solid tumors, including ovarian cancer, colorectal cancer, and papillary thyroid cancer. Agents that inhibit both BRAF and CRAF (so-called pan-RAF inhibitors) and also induce tubulin disruption may also benefit patients with mutated RAS cancers, providing deeper and more sustained anticancer effects. The compounds, compositions, and methods of use described herein address this need. [Overview of the project]

[0021] Compounds that are dual RAF and tubulin inhibitors, and methods of use thereof, are described herein.

[0022] In one embodiment, the present disclosure relates to a compound represented by formula IA: [ka] Or provide a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, Q is selected from the group consisting of O and NH. X 1 , X 2 and X 5 Each is independently selected from the group consisting of CH and N. X 3 and X 4 is each independently selected from the group consisting of N, CH, C=O, C-O-LE, C-LE, C-N(R 4 ), -LE, and N-LE, X 6 is selected from the group consisting of CH and N, X 7 is selected from the group consisting of CH, CF, and N, X 8 and X 10 is each independently selected from the group consisting of CH, CF, and N, X 9 is CR 5 and is selected from the group consisting of N, provided that 2 X, 3 X, 4 and X 5 are two or less of N, provided that 6 X 7 and X 8 are one or less of N, 9 X, 10 and X 3 are one or less of N, provided that 3 when X 4 is N, X 4 is C-O-LE, C-LE, C-N(R 4 ), -LE, N, or CH, 3 when X 3 is N, X 4 is N, CH, C-O-LE, C-LE, or C-N(R 3 ), -LE,<L000028>when X[[ID=7L]] 4 is C=O, X provided that 4 when X 3 is C=O, X R 1This is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the cycloalkyl or cycloalkyl substituents are independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heterocyclyl substituent is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heteroaryl substituent is independently and arbitrarily substituted with a substituent selected from the group consisting of halogens and alkyls. R 2 It is selected from the group consisting of alkyl, H, halogen, and alkoxy, R 3 It is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R 4 It is selected from the group consisting of H and alkyl, R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R 5 However, R 3 And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is selected from the group consisting of directly bonded and optionally substituted C1-C6 alkyl groups. E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

[0023] In another embodiment, a pharmaceutical composition comprising a compound described herein (e.g., a compound disclosed herein as described herein), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient is described herein.

[0024] In another embodiment, a method for treating cancer in a patient in need is described herein, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound disclosed herein as described herein), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein.

[0025] In another embodiment, the present invention describes a method for treating a patient in need of treatment for a disorder selected from the group consisting of histiocytosis, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematological cancers, hairy cell leukemia, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of the present disclosure as described herein), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition as described herein.

[0026] In another embodiment, compounds described herein (e.g., compounds disclosed herein as described herein), or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or compositions described herein, are described herein for use in therapeutic purposes.

[0027] In another embodiment, compounds described herein (e.g., compounds of the Disclosure described herein), or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or compositions described herein for use in a method of treating cancer in a patient requiring such treatment, are described herein.

[0028] In another embodiment, the compounds described herein (e.g., the compounds of this disclosure described herein), or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or compositions described herein, are described herein for use in methods of treating a patient who requires treatment for a disorder selected from the group consisting of histiocytosis, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematological cancers, hairy cell leukemia, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway. [Brief explanation of the drawing]

[0029] [Figure 1] Figure 1 is a graph showing the maximum rate of tubulin polymerization in the presence of increasing concentrations of prinablin, a known tubulin depolymerizing agent. [Figure 2] Figure 2 is a graph showing the ratio of pellets (polymerized tubulin) to supernatant (tubulin dimer) compared to a DMSO control to increase the concentration of prinablin, a known tubulin depolymerizing agent. [Modes for carrying out the invention]

[0030] Next, the features and other details of this disclosure will be described in more detail. The specific terms used in this specification, the examples, and the appended claims are summarized here. These definitions should be understood by those skilled in the art in light of the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0031] definition The definitions provided in this application are intended to clarify the terms used throughout this application.

[0032] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art of the subject matter. Where used herein and in the appended claims, unless otherwise specified, the following terms have the meanings provided for the convenience of understanding this disclosure.

[0033] If it is shown that the bond with a substituent crosses a bond connecting two atoms in the ring, then such substituents may be bonded to any atom on the ring. If substituents are enumerated without indicating the atoms to which such substituents are bonded to the rest of the compound of a given formula, then such substituents may be bonded to any atom in such substituents. A combination of substituents, substituent positions, and / or variables is acceptable only if such combination results in a stable compound.

[0034] As used herein, the singular forms "a," "an," and "the" encompass multiple references unless the context explicitly indicates otherwise.

[0035] As used herein, the term “as used herein” means the entire application.

[0036] As used herein, “deuterated” means that at least one hydrogen atom is substituted with deuterium. In any sample of a deuterated compound, some individual molecules of the compound are likely to have hydrogen instead of deuterium at the designated position. However, the percentage of molecules in deuterated compounds that have deuterium at the designated position will be much greater than that which occurs naturally. Deuterium at the deuterated position is concentrated.

[0037] As used herein, the terms “optional” or “optionally” mean that the events or circumstances described thereafter may or may not occur, and such descriptions include both cases in which the events or circumstances occur and cases in which they do not occur. For example, “optionally substituted alkyl” means that the alkyl may or may not be substituted.

[0038] Naturally, the substituents and substitution patterns on the compounds of this disclosure can be selected by those skilled in the art and result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and by the methods described below. If the substituent itself is substituted with multiple groups, it is understood that these groups may be on the same carbon or different carbons, as long as a stable structure is obtained.

[0039] As used herein, the term “optionally substituted” refers to the substitution of 1 to 6 hydrogen atoms in a given structure with a specific substituent radical, including but not limited to hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH2-Oalkyl. “Optionally substituted” preferably means the substitution of 1 to 4 hydrogen atoms in a given structure with the substituents described above. More preferably, 1 to 3 hydrogen atoms are substituted with the substituents described above. It is understood that substituents may be further substituted.

[0040] As used herein, the term “substituted” refers to a portion having substituents that substitute hydrogens on one or more carbons of a skeleton. Naturally, “substituted” or “substituted with” implies that such substitutions comply with the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by recombination, cyclization, or removal. As used herein, the term “substituted” is intended to include all permissible substituents of an organic compound. In broad embodiments, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Permissible substituents may be one or more identical or different substituents for a given organic compound. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valency of the heteroatom.

[0041] Substituents may include any substituents described herein, for example, halogens, hydroxyls, carbonyls (such as carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (such as thioesters, thioacetates, or thioformates), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, heteroaralkyls, or aromatic or heteroaromatic moieties, unless otherwise specified. Those skilled in the art will understand that, where appropriate, substituents themselves may be substituted. For example, substituents on substituted alkyl groups may include substituted and unsubstituted amino, azide, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, etc. Unless specifically stated as "unsubstituted," references to chemical parts herein are understood to include substituted variants. For example, references to "aryl" groups or parts implicitly include both substituted and unsubstituted variants.

[0042] As used herein, the term "alkyl" refers to a fully saturated linear or branched non-aromatic hydrocarbon. Typically, a linear or branched alkyl group has 1 to about 20, preferably 1 to about 10, carbon atoms, e.g., C1-C12 unless otherwise defined. 10The alkyl group may be an alkyl group or, for example, a C1-C6 alkyl group. Examples of linear and branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. Furthermore, the term “alkyl” as used throughout this specification, examples, and claims is intended to include both “unsubstituted alkyl” and “substituted alkyl,” the latter referring to an alkyl moiety having substituents that substitute hydrogens on one or more carbons of a hydrocarbon skeleton. The “alkyl” group may be optionally substituted.

[0043] When used with chemical parts such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, "C x ~C y The term "C" means a group containing x to y carbon atoms in the chain. For example, "C x ~C y The term "alkyl group" refers to a substituted or unsubstituted saturated hydrocarbon group, which includes linear and branched alkyl groups containing x to y carbon atoms in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates hydrogen when the group is at a terminal position and a bond when it is in the interior.

[0044] As used herein, the term “hydrocarbyl” refers to a group that does not have an =O substituent or an =S substituent and typically has at least one carbon-hydrogen bond and is primarily a carbon skeleton, but optionally contains a heteroatom, and is bonded via a carbon atom. Therefore, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (which is bonded via oxygen rather than carbon) are not hydrocarbyl. Examples of hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. The “hydrocarbyl” group may be optionally substituted.

[0045] As used herein, the term "alkoxy" refers to a linear or branched saturated aliphatic (alkyl) hydrocarbon radical bonded to an oxygen atom attached to the core structure. The alkoxy group preferably has 1 to 6 carbon atoms, i.e., it may be a C1 to C6 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and 3-methylbutoxy. The "alkoxy" group may be optionally substituted.

[0046] As used herein, the term “alkoxyalkyl” refers to an alkyl group (as defined above) substituted with an alkoxy group, and may be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethylene- and ethyl-O-ethylene-. The “alkoxyalkyl” group may be optionally substituted.

[0047] As used herein, the term “haloalkyl” refers to an alkyl group (as defined above) that is substituted with one or more halogens. Monohaloalkyl radicals may have, for example, chlorine, bromine, iodine, or fluorine atoms. Dihalo and polyhaloalkyl radicals may have two or more identical or different halogen atoms. Examples of haloalkyls include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, and difluoropropyl. The “haloalkyl” group may be optionally substituted.

[0048] As used herein, the term "haloalkoxy" refers to a radical in which one or more hydrogen atoms of an alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" groups include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3). The "haloalkoxy" group may be optionally substituted.

[0049] As used herein, the term “aryl” includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. The ring is preferably a 5- to 7-membered ring, and more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (fusion rings), and at least one of the rings is aromatic. For example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The term “fusion” means that the second ring is attached to or formed by having two adjacent atoms common to the first ring. The term “fusion” is equivalent to the term “condensation.” Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, phenol, aniline, or indanyl. Unless otherwise specified, all aryl groups described herein may be optionally substituted.

[0050] As used herein, the terms “polycyclyl,” “polycycle,” and “polycyclic” refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which one or more atoms are common to two or more adjacent rings. For example, the rings are “fusion rings.” Each ring of a polycycle may be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms.

[0051] As used herein, the term "acyl" means -C(=O)-R w It refers to the base of, and in the formula, R w is an optionally substituted alkyl group. Examples of "acyl" are not limited to, but include R w However, C1-C 10 Alkyl (C1-C 10 Acyl) or C1-C 6-Examples include alkyl (C1-C6 acyl). In some embodiments, each optionally substituted substituent is independently selected from the group consisting of H, OH, alkoxy, cyano, F, and amino. Additional examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3)2.

[0052] As used herein, the term "formyl" refers to the -C(=O)H group.

[0053] As used herein, the term "sulfonamide" is expressed as follows: [ka] In the formula, R x , R y , and R z In each occurrence, independently, represents hydrogen, an optionally substituted hydrocarbyl group, or R z The groups, together with the N atoms to which they are bonded, complete a heterocycle having 4 to 8 atoms in a ring structure that can be optionally substituted.

[0054] As used herein, the terms "amine" and "amino" both refer to unsubstituted and substituted amines and their salts, for example, the portion represented by the following formula: [ka] In the formula, R z R independently represents a hydrogen or optionally substituted hydrocarbyl group, or z The groups, together with the N atoms to which they are bonded, complete a heterocycle having 4 to 8 atoms in a ring structure that can be optionally substituted.

[0055] As used herein, the terms "amide" and "amido" refer to the group represented by the following formula, respectively: [ka] In the formula, R x , R y , and R z Each of these independently represents a hydrogen atom or an optionally substituted hydrocarbyl group, or R y , and R z The groups, together with the N atoms to which they are bonded, complete a heterocycle having 4 to 8 atoms in a ring structure that can be optionally substituted.

[0056] As used herein, the term "amidine" refers to the group represented by the following formula: [ka] In the formula, R x , R y , and R z Each independently represents a hydrogen atom or an optionally substituted hydrocarbyl group, or R y and R z These atoms, together with the N atoms to which they are attached, complete a heterocycle having 4 to 8 atoms in a ring structure that can be optionally substituted.

[0057] As used herein, the term "phosphine oxide" refers to a group represented by the following formula: [ka] In the formula, R z Each of these independently represents a hydrogen atom or an optionally substituted hydrocarbyl group.

[0058] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0059] As used herein, the term "amide alkyl" refers to an alkyl group substituted with an amide group.

[0060] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0061] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, and may be represented by the general formula alkyl-S-.

[0062] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0063] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

[0064] As used herein, the term “cycloalkyl” refers, alone or in combination with other terms, to a fully saturated cyclic hydrocarbon. “Cycloalkyl” includes monocyclic, bicyclic, and tricyclic rings. Typically, monocyclic cycloalkyls have 3 to about 10 carbon atoms, unless otherwise defined, and more typically 3 to 8 carbon atoms (e.g., C3-C3). 10 Cycloalkyl, or for example, C 3-It has a C6 cycloalkyl group. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The second ring of a bicyclic cycloalkyl, or the second or third ring of a tricyclic cycloalkyl, can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyls include bicyclic and tricyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "condensed cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a condensed bicyclic cycloalkyl, or the second or third ring of a condensed tricyclic cycloalkyl, can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyls can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc. Cycloalkyls may alternatively be polycyclic compounds having three or more rings. Examples of polycyclic cycloalkyls include crosslinked, condensed, and spirocyclic carbocyclils.

[0065] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

[0066] As used herein, the terms “carbocyclic” or “carbocyclic formula” include bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term “condensed carbocyclic” refers to a bicyclic carbocyclic in which each ring shares two adjacent atoms with the other ring. Each ring in a condensed carbocyclic may be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring, e.g., phenyl, may be condensed to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic formula, insofar as the valence allows. Exemplary “carbocyclic” examples include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octo-3-ene, naphthalene, and adamantane. Examples of condensed carbo-rings include decalin, 4,5-naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The "carbo-ring" may be substituted at any one or more positions where a hydrogen atom may be present.

[0067] As used herein, the term "cyano" refers to the -CN group.

[0068] As used herein, the terms "hydroxy" or "hydroxyl" refer to the -OH group.

[0069] As used herein, the terms "halo" or "halogen," alone or in combination with other terms, mean chloro, fluoro, bromo, and iodine.

[0070] As used herein, the term “heteroatom” refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0071] As used herein, the terms “heterocyclyl,” “heterocycloalkyl,” “heterocycle,” and “heterocyclic formula” refer to non-aromatic, saturated, or partially saturated ring systems, including 3- to 15 membered monocyclic, polycyclic (e.g., bicyclic, tricyclic), bridged, or fused, having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)₂, NH₃, or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclyls" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azosinyl, chromanyl, xanthenyl, and their N-oxides. The attachment of heterocycloalkyl substituents may occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups may be optionally substituted with one or more preferred groups by one or more of the aforementioned groups. Preferably, “heterocyclyl” refers to a five- or six-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranil, piperidinyl, piperazinyl, tetrahydropyranil, morpholinyl, thiomorpholinyl, 1,4-dioxanil, and their N-oxides. More preferably, “heterocyclyl” includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. All heterocyclyls are optionally substituted with one or more of the aforementioned groups.

[0072] As used herein, the term “heteroaryl” means a substituted or unsubstituted aromatic monocyclic structure, preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, wherein the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The term “heteroaryl” also means a substituted or partially aromatic ring system containing at least one heteroatom, having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), and containing 8 to 20 ring atoms, preferably 5 to 10 ring atoms, which are covalently bonded or fused, with two or more atoms common to two adjacent rings, and at least one of the rings is heteroaromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The rings may contain an N or S atom, which is optionally oxidized, or the N atom is optionally quaternized. All heteroaryl groups are optionally substituted. Any preferred ring position of the heteroaryl moiety may be covalently bonded to the defined chemical structure.Examples of heteroaryls include furanil, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranil, benzothienyl, benzotriazinyl, phthalazinyl, thiantrene, dibenzofuranil, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, alpha-carborin, i Examples include, but are not limited to, ndridinil, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, flopyridinil, purinil, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriasiazolyl, 7-azaindazolyl, 7-azaindazolyl, pyrrolopyridinil, pyrrolopyrimidinil, oxazolonepyridinil, oxazolonepyrimidinil, imidazolonpyridinil, imidazolonpyrimidinil, pyrazolopyridinil, pyrazolopyrimidinil, tetrahydronaphthilidinil, tetrahydropyridolpyriminil, dihydronaphthilidinil, naphthilidinil, oxazinanonepyridinil, oxazinanonepyrimidinil, carbazolyl, dibenzothienyl, and acridinil.

[0073] As used herein, the terms "sulfone" or "sulfonyl" refer to -S(O)2-R 6d It refers to the base, and in the formula, R 6d This represents hydrocarbil that has been optionally substituted.

[0074] When used herein, within the ring [ka] This refers to a single or double bond that, as far as the valence allows, results in the formation of a stable ring portion. In certain embodiments, the variable X in a compound of formula IA or IB. 2, X 3 , X 4 , and X 5 The ring containing the atom contains single or double bonds to form a stable aromatic ring portion, as far as the valence allows.

[0075] "Combination therapy" is a treatment that includes the administration of two or more therapeutic agents, for example, the compounds of this disclosure and MAPK pathway inhibitors, to patients who require such treatment.

[0076] The terms "disease," "disorder," and "condition" are used interchangeably in this specification.

[0077] The terms “individual,” “patient,” or “subject” are used interchangeably herein and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds described herein may be administered to mammals such as humans, but may also be administered to other mammals that require veterinary treatment, such as pets (e.g., dogs, cats, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0078] As used herein, the MAPK pathway is a signaling pathway that includes RAS → RAF → MEK → ERK.

[0079] "MAPK pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Examples of inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120, encorafenib), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., urixertinib, SCH772984, LY3214996, ERAS-007). The terms "MAPK pathway inhibitor" and "MAPK kinase inhibitor" are used interchangeably herein.

[0080] "Pharmacologically or pharmacologically acceptable" includes, where necessary, molecular entities and compositions that do not cause adverse reactions, allergic reactions, or other undesirable reactions when administered to animals or humans. For administration to humans, the formulation must meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics standards.

[0081] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refer to any solvent, dispersion medium, coating, isotonic agent, and absorption retarder, etc., that are compatible with pharmaceutically active substances. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0082] As used herein, the term “pharmaceutical composition” refers to a composition comprising at least one compound disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0083] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of any acidic or basic group that may be present in the compounds used in the composition. The compounds contained in this composition, which are inherently basic, can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, but are not limited to, salts containing pharmaceutically acceptable anions, including, non-toxic acid addition salts, i.e., malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bicarbonate tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucarons, sugars, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present composition, which are inherently acidic, can form base salts having a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present composition, including a basic or acidic moiety, can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a base salt.

[0084] The compounds of this disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term “stereoisomer” comprises all enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S” depending on the stereoconfiguration of substituents around the stereocarbon, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center. These compounds may also be designated by “(+)” and “(-)” based on their optical rotation. The compounds described herein encompass various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the symbols “(±)” in nomenclature, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center.

[0085] In this specification, the term “therapeutic dose” means the amount of the compound of the subject that elicits a biological or medical response in a tissue, system, or animal (e.g., mammal or human) as required by researchers, veterinarians, physicians, or other clinicians. The compounds described herein are administered in therapeutic doses to treat a disorder.

[0086] "To treat" includes any effect that brings about improvement in a condition, disease, disorder, etc., such as alleviation, reduction, regulation, or elimination.

[0087] This disclosure also includes isotope-labeled compounds that are identical to those enumerated herein, except that one or more atoms are substituted by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35S, 18 F, and 36 Examples include Cl. For instance, the compounds of this disclosure may have one or more H atoms substituted with deuterium.

[0088] The individual enantiomers and diastereomers of the disclosed compounds may be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or they may be prepared by the preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the enantiomer mixture to a chiral auxiliary group, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary; (2) salt formation using optically active resolving agents; (3) direct separation of the optical enantiomer mixture in a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture may also be separated into its component enantiomers by well known methods such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms an heterogeneous mixture of stereoisomers during the creation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH:Weinheim, 2009.

[0089] As used herein, the compounds of the present disclosure include compounds of formula IA, formula IB, formula IC, formula ID, formula IE, formula IF, formula IG, formula IH, or formula IJ, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof.

[0090] compound In one embodiment, the compound represented by formula IA: [ka] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof is provided herein, wherein Q is selected from the group consisting of O and NH, X 1 、X 2 及びX 5 are each independently selected from the group consisting of CH and N, X 3 及びX 4 are each independently selected from the group consisting of N, CH, C=O, C-O-LE, C-LE, C-N(R 4 )-LE, and N-LE, X 6 is selected from the group consisting of CH and N, X 7 is selected from the group consisting of CH, CF, and N, X 8 及びX 10 are each independently selected from the group consisting of CH, CF, and N, X 9 は、CR 5 及びNからなる群から選択され、 ただし、X 2 、X 3 、X 4 、及びX 5 のうちの2つ以下が、Nであることを条件とし、 ただし、X 6 及びX<00001​​​​​​​​​​​​​​​​​​​​​​This is N, CH, COLE, CLE, or CN(R 4 ) - Provided that it is LE, However, X 3 If C=O, then X 4 This is conditional on it being an NLE, However, X 4 If C=O, then X 3 This is conditional on it being an NLE, R 1 This is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the cycloalkyl or cycloalkyl substituent of a cycloalkylalkyl is independently and optionally substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heterocyclyl substituent is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heteroaryl substituent is independently and arbitrarily substituted with a substituent selected from the group consisting of halogens and alkyls. R 2 It is selected from the group consisting of alkyl, H, halogen, and alkoxy, R 3 It is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R 4 It is selected from the group consisting of H and alkyl, R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R 5 R 3And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is selected from the group consisting of directly bonded and optionally substituted C1-C6 alkyl groups. E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

[0091] In one embodiment, the compound represented by formula IB: [ka] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof is provided herein, in the formula, X 1 , X 2 and X 5 Each is independently selected from the group consisting of CH and N. X 3 and X 4 These are N, CH, C=O, COLE, CLE, and CN(R) respectively, independently. 4 Selected from the group consisting of )-LE and NLE, X 6 It is selected from the group consisting of CH and N, X 7 It is selected from the group consisting of CH, CF, and N. X 8 and X 10 Each is independently selected from the group consisting of CH, CF, and N. X 9 CR 5 Selected from the group consisting of and N, However, X 2 , X 3 , X 4 , and X 5The condition is that two or fewer of them are N, However, X 6 and X 7 The condition is that one or less of them is N, However, X 8 , X 9 , and X 10 The condition is that one or less of them is N, However, X 3 If X is N, 4 COLE, CLE, CN(R 4 )-LE, N, or CH, However, X 4 If X is N, 3 This is N, CH, COLE, CLE, or CN(R 4 ) - Provided that it is LE, However, X 3 If C=O, then X 4 This is conditional on it being an NLE, However, X 4 If C=O, then X 3 This is conditional on it being an NLE, R 1 This is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the heterocyclyl substituent is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heteroaryl substituent is independently and arbitrarily substituted with a substituent selected from the group consisting of halogens and alkyls. R 2 It is selected from the group consisting of alkyl, H, halogen, and alkoxy, R 3However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R 4 It is selected from the group consisting of H and alkyl, R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R 5 However, R 3 And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is selected from the group consisting of directly bonded and optionally substituted C1-C6 alkyl groups. E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

[0092] In one embodiment, a compound represented by formula IC: [ka] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof is provided herein, in the formula, X 4 These are N, CH, COLE, CLE, and CN(R 4 Selected from the group consisting of )-LE, X 5 It is selected from the group consisting of CH and N, X 6 It is selected from the group consisting of CH and N, X 7 It is selected from the group consisting of CH, CF, and N. X 8 and X 10Each is independently selected from the group consisting of CH, CF, and N. X 9 CR 5 Selected from the group consisting of and N, However, X 4 and X 5 The condition is that one or less of them is N, However, X 6 and X 7 The condition is that one or less of them is N, However, X 8 , X 9 , and X 10 The condition is that one or less of them is N, R 1 This is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the heterocyclyl substituent is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heteroaryl substituent is independently and arbitrarily substituted with a substituent selected from the group consisting of halogens and alkyls. R 2 It is selected from the group consisting of alkyl, H, halogen, and alkoxy, R 3 It is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R 4 It is selected from the group consisting of H and alkyl, R 5 However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R 5 However, R 3and together with the carbon atoms to which they are each attached, form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure, L is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituents are, in each occurrence, independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano.

[0093] In one embodiment, a compound represented by Formula I-D:

Chemical Formula

[0094] In some embodiments, R 3 is H.

[0095] In some embodiments, R 5 is haloalkyl, cycloalkyl, or cyano.

[0096] In one embodiment, a compound represented by Formula I-E:

Chemical formula

[0097] In one embodiment, the compound represented by formula IF: [ka] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof is provided herein, in the formula, R 1 This is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the heterocyclyl substituent is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heteroaryl substituent is independently and arbitrarily substituted with a substituent selected from the group consisting of halogens and alkyls. and R 5 The group is selected from haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl.

[0098] In some embodiments, R 1is alkyl, cycloalkyl, or H.

[0099] In some embodiments, R 5 is haloalkyl, cycloalkyl, or cyano.

[0100] In one embodiment, a compound represented by Formula I-G:

Chemical formula

[0101] In some embodiments, R 3 is haloalkyl or cycloalkyl.

[0102] In one embodiment, a compound represented by Formula I-H:

Chemical formula

[0103] In one embodiment, the compound represented by formula IJ: [ka] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof is provided herein, in the formula, X 1 , X 2 and X 5 Each is independently selected from the group consisting of CH and N. X 6 It is selected from the group consisting of CH and N, X 7 It is selected from the group consisting of CH, CF, and N. X 8 and X 10 Each is independently selected from the group consisting of CH, CF, and N. X 9 CR 5 Selected from the group consisting of and N, However, X2 biX 5 The condition is that one or less of them is N, However, X 6 and X 7 The condition is that one or less of them is N, However, X 8 , X 9 , and X 10 The condition is that one or less of them is N, R 1 This is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the heterocyclyl substituent is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. In each instance, the heteroaryl substituent is independently and arbitrarily substituted with a substituent selected from the group consisting of halogens and alkyls. R 2 It is selected from the group consisting of alkyl, H, halogen, and alkoxy, R 3 It is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R 5 However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R 5 However, R 3 And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is selected from the group consisting of directly bonded and optionally substituted C1-C6 alkyl groups. E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

[0104] X 1 In some embodiments, X 1 It is CH.

[0105] X 2 , X 3 , X 4 , X 5 In some embodiments, X 2 It is CH.

[0106] In some embodiments, X 3 It is N.

[0107] In some embodiments, X 4 These are N, CH, COLE, and CN(R 4 Selected from the group consisting of )-LE. In some embodiments, X 4 is selected from the group consisting of N and CH. In some embodiments, X 4 CO-CH(R 4 )-CH2-OH and C-NH-CH(R 4 Selected from the group consisting of )-CH2-OH.

[0108] In some embodiments, X 5 It is CH.

[0109] In some embodiments, X 2 , X 3 , X 4 , and X 5 The ring containing is [ka] Selected from the group consisting of, In the formula, s1 contains N and -C(O)NHR 1 This shows bonding to the ring substituted with X, where s2 is X 6 and X 7 This shows bonding to a ring containing [the specified element].

[0110] X 6 , X 7 In some embodiments, X 6 It is CH.

[0111] In some embodiments, X 7 It is CH.

[0112] X 8 , X 9 , X 10 In some embodiments, X 8 It is N.

[0113] In some embodiments, X 9 CR 5 That is the case.

[0114] In some embodiments, R 5 The element is selected from the group consisting of alkyl, cycloalkyl, and haloalkyl.

[0115] In some embodiments, X 10 It is CH.

[0116] R 1 In some embodiments, R 1 The alkyl substituent is selected from the group consisting of H, alkyl, (C3-C8)cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, and the alkyl substituent is independently and optionally substituted in each instance with substituents selected from the group consisting of amine, halogen, cyano, (C3-C8)cycloalkyl, and heterocyclyl. In some embodiments, R 1The alkyl substituent is selected from the group consisting of H, alkyl, (C3-C8)cycloalkyl, alkoxyalkyl, heterocyclyl, and haloalkyl, and the alkyl substituent is independently and optionally substituted in each instance with substituents selected from the group consisting of amine, halogen, and (C3-C8)cycloalkyl. In some embodiments, R 1 methyl and [ka] It is selected from the group consisting of the following.

[0117] R 2 In some embodiments, R 2 R is selected from the group consisting of alkyls and halogens. In some embodiments, R 2 The compound is selected from the group consisting of methyl and ethyl.

[0118] R 3 In some embodiments, R 3 The element is selected from the group consisting of H, alkyl, alkoxy, and haloalkyl.

[0119] In some embodiments, R 3 This is selected from the group consisting of trifluoromethyl and H.

[0120] R 4 In some embodiments, R 4 H is H.

[0121] R 5 In some embodiments, R 5 The element is selected from the group consisting of H, alkyl, alkoxy, amine, amide, haloalkyl, cycloalkyl, phosphine oxide, halogen, haloalkoxy, cyano, and cyanoalkyl.

[0122] In some embodiments, R 5 H, trifluoromethyl, isopropyl, cyclopropyl, chloro, [ka] It is selected from the group consisting of the following.

[0123] L In some embodiments, L is optionally substituted with a C1-C6 alkyl group.

[0124] L is [ka] Selected from the group consisting of, where E is bonded to the carbon specified by *. In some embodiments, L is, [ka] Selected from the group consisting of, in the formula, E is bonded to the carbon specified by *.

[0125] E In some embodiments, E is selected from the group consisting of H, methyl, and hydroxy.

[0126] In some embodiments, a compound selected from the group consisting of the following, [ka] [ka] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0127] Treatment method The compounds described herein (e.g., compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers) can act as dual RAF inhibitors and tubulin inhibitors and are therefore useful in treating diseases and disorders in patients requiring such treatment, such as cancer. Exemplary cancers include, but are not limited to, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, hematological cancers, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway. In some embodiments, the cancers described herein are BRAF V600X-driven cancers, atypical BRAF-mutated cancers, BRAF-fusion cancers, CRAF-fusion cancers, or RAS-mutated cancers. In some embodiments, the cancers have BRAF oncogenic mutations. In some embodiments, the cancer has a RAS oncogenic mutation. In some embodiments, the RAS oncogenic mutation is a RAS Q61R or Q61K mutation. In some embodiments, the cancer has an NF1 oncogenic mutation. In some embodiments, lung cancer is non-small lung cancer (NSCL). In some embodiments, colorectal cancer is colon cancer. In some embodiments, colorectal cancer is rectal cancer.

[0128] In some embodiments, compounds described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions thereof, for use in therapeutics are provided herein.

[0129] In some embodiments, compounds described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions thereof, are provided herein for use in the treatment of cancer in patients requiring such treatment. In some embodiments, the cancer is selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematological cancers, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway. In some embodiments, the cancer has a BRAF oncogenic mutation. In some embodiments, the cancer has a RAS oncogenic mutation. In some embodiments, the cancer has an NRAS oncogenic mutation. In some embodiments, the NRAS oncogenic mutation is NRAS Q61R or NRAS Q61K. In some embodiments, the cancer has a KRAS oncogenic mutation. In some embodiments, the KRAS oncogenic mutation is KRAS G12D, KRAS G12V, KRAS G12C, KRAS G12R, or KRAS G13D. In some embodiments, the cancer has an NF1 oncogenic mutation.

[0130] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions described herein, are described herein for use in methods of treating disorders selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematological cancers, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway, in patients requiring treatment of such disorders.

[0131] The compounds provided herein can be administered in doses that would provide optimal pharmacokinetic efficacy to patients (animals and humans) requiring such treatment. It will be understood that the dose required for any particular use will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the patient's age and condition, any concomitant medications or special diets subsequently followed by the patient, and other factors that a person skilled in the art would recognize, and that the appropriate dose is ultimately left to the discretion of the attending physician. To treat the clinical conditions and diseases described above, the compounds provided herein are dosage units containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles, and may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0132] Treatment can be continued for as long or as short a period as is desirable. The composition may be administered, for example, in a regimen of 1 to 4 or more times a day. A suitable treatment period may be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinitely. The treatment period may be terminated when the desired result is achieved.

[0133] Combination therapy The compounds described herein, for example, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, may be administered in combination with one or more additional therapeutic agents to treat the disorders described herein, such as cancer, as described herein. For example, a pharmaceutical composition comprising the compounds described herein, for example, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, one or more additional therapeutic agents, and pharmaceutically acceptable excipients is provided in this disclosure. In some embodiments, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, along with one additional therapeutic agent, are administered. In some embodiments, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, along with two additional therapeutic agents, are administered. In some embodiments, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, along with three additional therapeutic agents, are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, as well as additional therapeutic agents, may be formulated and administered separately.Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising, for example, a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, and IJ as one therapeutic agent, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents, such as a MAPK pathway inhibitor or chemotherapeutic agent. For example, a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, along with an additional therapeutic agent, can be administered in a single formulation. Other combinations are also included in combination therapy. Two or more drugs can be administered simultaneously in combination therapy, but they do not need to be administered at the same time. For example, the administration of the first drug (or combination of drugs) may precede the administration of the second drug (or combination of drugs) by several minutes, several hours, several days, or several weeks. Therefore, two or more drugs can be administered to each other within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks of each other. In some cases, longer intervals are also possible. In many cases, it is desirable, but not essential, for the two or more drugs used in combination therapy to be present in the patient's body at the same time.

[0134] Combination therapy may also involve administering one or more of the drugs used in combination two or more times, using different sequences of the component drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times consecutively in any combination, such as in the order XYX, XXY, YXY, YYX, XXYY.

[0135] In some embodiments, the compounds described herein are combined with other agents, including MAPK pathway inhibitors. In some embodiments, the other agents are RAS inhibitors. In some embodiments, the other agents are RAS inhibitors. In some embodiments, the other agents are oncogenic KRAS inhibitors. In some embodiments, the other agents are KRAS G12C inhibitors. In some embodiments, the other agents are RAS inhibitors. In some embodiments, the other agents are KRAS G12D inhibitors. In some embodiments, the other agents are MEK inhibitors. In some embodiments, the other agents are ERK inhibitors.

[0136] In some embodiments, the compounds described herein are combined with immunomodulators. In some embodiments, the immunomodulatory properties enhance the adaptive immune response. In some embodiments, the immunomodulatory properties enhance the activity of antigen-presenting cells. In some embodiments, the immunomodulatory properties enhance the antitumor activity of myeloid cells, including macrophages. In some embodiments, the immunomodulatory properties enhance the antitumor activity of natural killer cells. In some embodiments, the immunomodulatory properties enhance the activity of effector T cells, including cytotoxic T cells.

[0137] In some embodiments, one or more additional therapeutic agents that may be administered in combination with the compounds provided herein may be MAPK pathway inhibitors. Examples of such MAPK pathway inhibitors include MEK inhibitors, ERK inhibitors, and Ras inhibitors.

[0138] Examples of MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and their pharmaceutically acceptable salts. Examples of ERK inhibitors include, but are not limited to, urixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and their pharmaceutically acceptable salts. Examples of Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446, and their pharmaceutically acceptable salts.

[0139] In some embodiments, additional therapeutic agents may include, but are not limited to, immunomodulatory agents comprising anti-PD-1 or anti-PDL-1 therapeutic agents such as pembrolizumab, nivolumab, pizilizumab, semiprimab, atezolizumab, durvalumab, BMS-936559, or avelumab. In some embodiments, additional therapeutic agents may include, but are not limited to, anti-TIM3 (anti-HAVcr2) therapeutic agents including TSR-022 or MBG453, anti-LAG3 therapeutic agents including, but not limited to, relatrimab, LAG525, or TSR-033, anti-4-1BB (anti-CD37, anti-TNFRSF9), SGN-40, CP-870, 893, or RO7009789, but not limited to, anti-CD47 therapeutic agents including, but not limited to, Hu5F9-G4, anti-CD20 therapeutic agents, anti-CD38 therapeutic agents, STING agonists including, but not limited to, ADU-S100, MK-1454, ASA404, or amidobenzimidazole. In some embodiments, additional therapeutic agents may include anti-CTLA4 agents including ipilimumab and tremelimumab. In some embodiments, additional therapeutic agents may include, but are not limited to, other immunomodulatory agents, including, azacitidine or decitabine, epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone, as well as hypomethylating agents. In some embodiments, additional therapeutic agents may include immunotherapies, including targeted therapies, cancer vaccines, and CAR-T cell therapies.

[0140] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents include radiotherapy, antitubulins, DNA alkylating agents, DNA synthesis inhibitors, DNA insertion agents, antiestrogens, antiandrogens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CDK4 / CDK6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, PARP (poly-ADP-ribose polymerase) inhibitors, cell cycle regulatory kinase inhibitors, thalidomide, lenalidomide, and antibody-drug conjugates (ADCs).

[0141] In one embodiment, additional therapeutic agents include antitubulin agents (e.g., paclitaxel, paclitaxel protein-binding particles for injectable suspensions including but not limited to nab-paclitaxel, eribulin, docetaxel, ixabepyrone, vincristine, auristatin, or maytansinoids), vinorelbine, and DNA alkylating agents (cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide). These may be chemotherapeutic agents, including but not limited to: DNA insertion agents or DNA topoisomerase inhibitors (e.g., anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin; camptothecines such as topotecan, irinotecan, or exatecan); 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate.

[0142] In some embodiments, additional therapeutic agents may include, but are not limited to, kinase inhibitors such as erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, ripretinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, loxo292, lalotrectinib, and quizartinib.

[0143] In some embodiments, additional therapeutic agents include, but are not limited to, anti-estrogens including tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; anti-androgens including, but not limited to, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate; steroids including, but not limited to, prednisone and dexamethasone; PARP inhibitors including, but not limited to, neraparib, olaparib, thalazoparib, and rucaparib; and topoisomerases including, but not limited to, irinotecan, camptothecin, exatecan, and topotecan. The following may also be biological agents, including but not limited to topoisomerase II inhibitors, anthracyclines, etoposide, etoposide phosphate, and mitoxantrone; histone deacetylase (HDAC) inhibitors, including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; DNA methylation inhibitors, including but not limited to DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including but not limited to bortezomib and carfilzomib; and biological agents, including but not limited to trastuzumab, adtrastuzumab, pertuzumab, cetuximab, and panitumumab.

[0144] In some embodiments, additional therapeutic agents may include, but are not limited to, bevacizumab, levatinib, aflibercept, and AMG386, as anti-angiogenic agents.

[0145] In some embodiments, additional therapeutic agents may include, but are not limited to, antibody-drug conjugates (ADCs) containing a payload of DM1, DM4, MMAE, MMAF, or camptothecin, brentuximab vedotin and trastuzumab emtansine, radiotherapy, or therapeutic vaccines containing, but not limited to, cypleurol-T.

[0146] In some embodiments, additional therapeutic agents may include, but are not limited to, autophagy inhibitors, ULK inhibitors such as ULK1 inhibitors, ULK2 inhibitors, ULK1 / ULK2 inhibitors, VPS34 inhibitors, PPT1 inhibitors, or lysosomal blockers, as well as inhibitors of vesicular transport. In some embodiments, additional therapeutic agents may include DCC-3116, SAR405, SB02024, hydroxychloroquine, chloroquine, and LYS05.

[0147] In some embodiments, additional therapeutic agents may include, but are not limited to, EGFR inhibitors, cetuximab, osimertinib, and afatinib, as well as pharmaceutically acceptable salts thereof.

[0148] In some embodiments, additional therapeutic agents are selected from luteinizing hormone-releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0149] In some embodiments, additional therapeutic agents include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, and AZD 2171, Buttabulin, of atumtunab, zanolimmab, edotecarin, tetrandrin, lubitecan, tesmifene, oblimersen, tisilimmab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, sirengitide, jaimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, rucanton, LY 317615, Neurabrab, Vitespan, Rta 744, aranosine (Sdx 102), tarampanel, atrasentan, XR 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Cericlib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)-ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperazine methyl)-indolyl]-quinolone, batalanib, AG-013736, AVE-0005, [D-Ser(tBu)6, Azgly 10] Acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-Azgly-NH2 acetate (SEQ ID NO: 3) [C; 59 H 84 N 18 O 14 -(C2H4O2) x(wherein x=1~2.4)], goserelin acetate, leuprolide acetate, triptrelyn pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guerin bacillus (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrone Lu, Epirubicin, Fludarabine, Fludrocortisone, Fluoxymesterone, Flutamide, Gemcitabine, Gleevec, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, Lebamisol, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Strep Tozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-Cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine, Altretamine, Phloxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mecaptopurine, Deoxycoformycin, Calcitriol, Barrubicin, Mithramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxin, Marimasut, COL-3, Neovastat, BMS-275291, Squalamine,Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (Monoc) (Ronal antibody) and Erbitux, Cremofor-free paclitaxel, Epitilon B, BMS-247550, BMS-310705, Doroxifen, 4-hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Waltmannin, ZM336372, L-779450, PEG-filgrastim, Darbepoetin, Erythropoetin, Granulocyte colony-stimulating factor, Zolendronate, Prednisone, Cetuximab, Granulocyte-macrophage colony-stimulating factor, Histrelin, Pegylated interferon alpha-2a, Interferon alpha-2a, Pegylated interferon alpha-2b, Interferon Alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netsupitant, NK1 receptor blockers,Selected from the group consisting of palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoetin, epoetin alfa and darbepoetin alfa, ipilumumab, and mixtures thereof.

[0150] Pharmaceutical compositions and kits Another aspect of this disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, this disclosure provides pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers), formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but the most suitable mode of administration in any given case depends on the degree and severity of the condition being treated and the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral or subcutaneous administration.

[0151] Exemplary pharmaceutical compositions may be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, comprising one or more of the compounds described herein as active ingredients mixed with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. The active ingredients may be formulated with, for example, tablets, pellets, capsules, suppositories, solvents, emulsions, suspensions, and any other forms suitable for use, which are ordinary, non-toxic, and pharmaceutically acceptable carriers. The active compound of the subject is contained in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0152] To prepare solid compositions such as tablets, a primary active ingredient can be mixed with a pharmaceutical carrier, such as conventional tableting components like corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other pharmaceutical diluents, such as water, to form a solid pre-formulation composition containing a homogeneous mixture of the compounds provided herein or their non-toxic, pharmaceutically acceptable salts. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0153] For solid dosage forms for oral administration (capsules, tablets, pills, sugars, powders, granules, etc.), the composition in question is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) wetting agents, such as glycerol; (4) disintegrants. (5) Decomposing agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (6) Dissolution retarders, such as paraffin; (7) Absorption enhancers, such as quaternary ammonium compounds; (8) Wetting agents, such as acetyl alcohol and glycerol monostearate; (9) Absorbents, such as kaolin and bentonite clay; (10) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (11) Colorants. In the case of capsules, tablets, and pills, the composition may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0154] Tablets may be prepared by compression or molding with one or more adjuncts as optional. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of the subject composition moistened with an inert liquid diluent using a suitable machine. Tablets, and other solid dosage forms such as sugars, capsules, pills, and granules, may optionally be scored or prepared using coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology.

[0155] Compositions for inhalation or inhalation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solvents, suspensions, syrups, and elixirs. In addition to the compositions of the subject, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0156] The suspension may include, in addition to the subject composition, suspensions such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar, and tragacanth, as well as mixtures thereof.

[0157] Formulations for rectal or vaginal administration may be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, and may be presented as suppositories that are solid at room temperature but become liquid at body temperature, and therefore dissolve in a body cavity to release the active drug.

[0158] Dosage forms for transdermal administration of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solvents, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0159] Ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0160] Powders and sprays may, in addition to the subject composition, contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may further contain common propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0161] Alternatively, the compositions and compounds of the present disclosure may be administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellants) suspensions may be used. Ultrasonic nebulizers may be used because they minimize exposure of the drug to shear, which can lead to the degradation of the compounds contained in the compositions of the subject. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition of the subject together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular composition of the subject, but typically include nonionic surfactants (Tween, Pluronic®, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0162] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, and may include antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the recipient of the formulation, or suspending agents or thickeners.

[0163] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0164] In another embodiment, an enteric pharmaceutical formulation is provided comprising the disclosed compounds and enteric-coated materials, and pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5.

[0165] Therefore, enteric-coated materials will not dissolve until the pH reaches, for example, approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Exemplary enteric materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate acetate (PVAP), hydroxypropyl methylcellulose succinate acetate (HPMCAS), cellulose trimellitate acetate, hydroxypropyl methylcellulose succinate, cellulose succinate acetate, cellulose hexahydrophthalate acetate, cellulose propionate phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionate acetate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl methacrylate and methacrylic acid, methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal colophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit Examples include L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is either known or readily determinable in vitro. The foregoing is a list of possible materials, but those skilled in the art who are interested in this disclosure will recognize that it is not exhaustive and that there are other enteric-coated materials that serve the purposes described herein.

[0166] Advantageously, this specification provides, for example, kits for use by purchasers who require treatment for cancer. Such kits include appropriate dosage forms, such as those described above, and instructions describing how to use such dosage forms to mediate, reduce, or prevent inflammation. The instructions instruct consumers or healthcare professionals to administer the dosage forms according to dosage forms known to those skilled in the art. Such kits may, advantageously, be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively rigid material covered with a foil, preferably made of clear plastic material. During the packaging process, indentations are formed in the plastic foil. These indentations have the size and shape of the tablets or capsules to be packaged. The tablets or capsules are then placed in the indentations, and the sheet of relatively rigid material is sealed against the plastic foil with the foil side opposite to the direction in which the indentations were formed. As a result, the tablet or capsule is sealed within a recess between the plastic foil and the sheet. Preferably, the sheet is strong enough so that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess, thereby creating an opening within the sheet at the location of the recess. The tablet or capsule can then be removed through this opening.

[0167] It may be desirable to provide memory aids on the kit, for example in the form of numbers, next to the tablets or capsules, where the numbers correspond to the days of the regimen in which the designated tablets or capsules should be taken. Another example of such memory aids is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, ... etc... Week 2, Monday, Tuesday, ..." Other variations of memory aids will also be readily apparent. The "daily dose" can be a single tablet or capsule or multiple tablets or capsules taken on a given day. Furthermore, the daily dose of a first compound may consist of one tablet or capsule, and the daily dose of a second compound may consist of multiple tablets or capsules, and vice versa. Memory aids should reflect this. [Examples]

[0168] The compounds described herein can be prepared by a number of methods based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of the synthetic methods below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and work-up procedure, can be selected to be standard conditions for the reaction unless otherwise indicated. Those skilled in the field of organic synthesis will understand that functional groups present in various parts of the molecule should be compatible with the proposed reagents and reactions. Substitutions of reaction conditions and compatibility will be obvious to those skilled in the art, and therefore alternative methods are shown. The starting materials for the examples are commercially available or readily prepared by standard methods from known materials.

[0169] The following abbreviations are used in this disclosure and have the following definitions: “ADP” is adenosine diphosphate, “Ag2CO3” is silver acetate, “aq” is aqueous solution, “AT” is adenosine triphosphate, “Ar” is argon gas, “Boc” is t-butyl carbonate, “BSA” is bovine serum albumin, “B2pin2” is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), “CaCl2” is calcium chloride, “cataCXium(R)A-Pd-G2” is chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), “CDCl3” is chloroform-deuterium, “Cs2CO3” is cesium carbonate, “DCM” is dichloromethane, and “DIEA” is N,N-diisopropyl alcohol "Pyroethylamine" is "DMF" is N,N-dimethylformamide, "dppf" is 1,1'-bis(diphenylphosphin)ferrocene, "DMSO-d6" is dimethyl sulfoxide-deuterium, "DSC" is N,N'-succinimidyl carbonate, "DTT" is dithiothreitol, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" is electrospray ionization, "siRNA" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is time, "HATU" is hexafluorophosphate azabenzotriazole tetramethyluronium, "H2" is hydrogen gas, "HCl" is hydrochloric acid, "H2O" is water, "H2O2" is hydrogen peroxide, and "IC 50" is the 50% inhibitory concentration, "K2CO3" is potassium carbonate, "KOAc" is potassium acetate, "LiOH" is lithium hydroxide, "m CPBA" is meta-chloroperoxybenzoic acid, "MeCN" is acetonitrile, "MeOH" is methanol, "Mesyl" is methanesulfonyl, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is minutes, "MS" is mass spectrometry, "m / z" is mass / charge number, "NaCN" is sodium cyanide, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, "NaHCO3" is sodium bicarbonate, and "NaOEt" is sodium methoxide "Na2SO4" is sodium sulfate, "NH4Cl" is ammonium chloride, "NH4OH" is ammonium hydroxide, "NMR" is nuclear magnetic resonance, "OMs" is mesylate, "PBS" is phosphate-buffered saline, "Pd" is palladium, "Pd / C" is palladium-carbon, "rt" is room temperature, also known as ambient temperature, understood to be within the range of normal laboratory temperatures of 15-25°C, "satd." is saturated, "SFC" is supercritical fluid chromatography, "SM" is the starting material, and "S N "Ar" is a nucleophilic aromatic substitution, "T3P" is 1-propanephosphonic anhydride, "TBAF" is tetrabutylammonium fluoride, "TBDMS" is tert-butyldimethylsilyl, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, "THF" is tetrahydrofuran, "Tris" is tris(hydroxymethyl)aminomethane, and "XPhos Pd G2" is chloro(2-dicyclohexylphosphin-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

[0170] general chemistry The exemplary compounds described herein are available by general synthesis methods shown in the following schemes, intermediate preparations, and accompanying examples.

[0171] Synthesis scheme Scheme 1 [ka] Scheme 1 shows an exemplary preparation of boronate 1-4. Amine 1-1 (commercially available or synthesized by those skilled in the art) is reacted with carboxylic acid 1-5 (commercially available or synthesized by those skilled in the art) to obtain amide 1-2. Compound 1-2 after borylation yields boronate 1-4. Boration is a reaction well demonstrated by those skilled in the art (e.g., Pd(0) catalyzed reaction with B2pin2). Alternatively, boronate 1-4 can be prepared by amide coupling reaction of carboxylic acid 1-5 with 1-3 (commercially available or synthesized by Pd-catalyzed borylation from 1-1) in the presence of coupling reagents such as HATU, T3P, and EDC.

[0172] Scheme 2 [ka] Scheme 2 shows exemplary preparations of intermediates 2-4 and 2-5. Boronate 2-1(X) in the presence of a palladium catalyst. 4 The treatment of bromide 1-1 (commercially available or synthesized by a person skilled in the art) using =CH,C-alkyl (commercially available or synthesized by a person skilled in the art) (Suzuki reaction) is 2-2(X 4 =CH,C-alkyl) is obtained. Subsequent Suzuki reaction of 2-2 with boronate or boronic acid 2-6 (commercially available or synthesized by those skilled in the art) yields 2-4a(X 1A 2-1 Suzuki reaction is obtained. Alternatively, the borylation of chloride 2-2 with B2pin2 reacts with chloride (or bromide) 2-7 (commercially available or synthesized by those skilled in the art) under typical Suzuki reaction conditions to convert it to boronate 2-3, from which 2-4b(X1=N) can be obtained. In another embodiment, amide 2-5 can be prepared by (1) a 2-2 amide coupling reaction with carboxylic acid 1-5 (commercially available or synthesized by those skilled in the art), and (2) a 2-1 Suzuki reaction with bromide 1-2.

[0173] Scheme 3 [ka] Scheme 3 shows exemplary preparations of intermediates 3-6a, 3-6b, and 3-6c. 3-3 is obtained by treating 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 3-1 with bromide 1-1 in the presence of a palladium catalyst (Suzuki reaction). Compound 3-3 is reacted with boronate or boronic acid ELB(OR)2 to obtain compound 3-5c. Compound 3-5c(X 4 If 2,6-dichloro-4-iodopyridine (CLE) contains unsaturated functional groups such as double or triple bonds, hydrogenation can proceed in the presence of a Pd catalyst. Hydrogenation of 2,6-dichloro-4-iodopyridine (CLE) can proceed at high temperature in the presence of a base such as K2CO3, in an aprotic solvent such as NMP, with an alcohol EL-OH or amine ELN(R) 4 ) react with H, and each is 3-4a(X 4 =COLE) and 3-4b(X 4 =CN(R 4 )-LE) is obtained. Under Pd(0) catalytic coupling conditions, boronates 1-3 and 3-4a and 3-4b are reacted in the Suzuki reaction to obtain 3-5a and 3-5b, respectively. Finally, 3-5a, 3-5b, and 3-5c are reacted with boronate or boronic acid 2-6 under Suzuki reaction conditions to obtain 3-6a(X 4 =COLE), 3-6b(X 4 =CN(R 4 )-LE), and 3-6c(X 4Obtain =CLE).

[0174] Scheme 4 [ka] Scheme 4 shows exemplary preparations of intermediates 4-4a and 4-4b. 4-Bromo-6-chloropyridine-2-ol (4-1) reacts with alkylating reagent ELX (X=Cl, Br, I, OMs) in the presence of a base such as Ag2CO3 in an aprotic solvent such as toluene to produce a mixture of O-alkylated (4-2a) and N-alkylated (4-2b) compounds that can be separated by preferred methods such as SFC purification, crystallization, or chromatography. Each of 4-2a and 4-2b reacts with boronate 1-3 under Suzuki reaction conditions to obtain 4-3a and 4-3b, respectively. Amide coupling reactions of 4-3a and 4-3b with carboxylic acid 1-5 yield 4-4a and 4-4b, respectively. In another embodiment, Suzuki reactions of 4-2a and 4-2b with boronate 1-4 yield boronate 4-4a and 4-4b, respectively.

[0175] Scheme 5 [ka] Scheme 5 shows exemplary preparations of intermediates 5-4a and 5-4b. In the same manner as described in Scheme 4, 5-1 is prepared using alkylating reagent F3-L 3 -Reacts with X (X=Cl, Br, I, OMs) to produce a mixture of O-alkylated (5-2a) and N-alkylated (5-2b) compounds, which can be separated by preferred methods well known to those skilled in the art. The Suzuki reaction of 5-2a and 5-2b with boronate 1-3 yields boronate 5-3a and 5-3b, respectively. Finally, each of 5-3a and 5-3b after treatment with carboxylic acid 1-5 under amide coupling conditions yields 5-4a and 5-4b, respectively. In another embodiment, the Suzuki reaction of 5-2a and 5-2b with boronate 1-4 yields boronate 5-4a and 5-4b, respectively.

[0176] Scheme 6 [ka] Scheme 6 shows an exemplary preparation of intermediate 6-4. Dichloride 6-1(X 4 A C-alkyl compound (either commercially available or synthesized by those skilled in the art) is reacted with boronate or boronic acid 2-6 in the presence of a palladium catalyst (Suzuki reaction) to obtain 6-2. Subsequently, intermediate 6-4 is obtained by a palladium-catalyzed Suzuki reaction of 6-2 with bromide 1-1. Similarly, dichloride 6-1 (either commercially available or synthesized by those skilled in the art) is reacted with bromide 1-1 under Suzuki reaction conditions to obtain 6-3. Subsequently, intermediate 6-4 is obtained by a palladium-catalyzed Suzuki reaction of 6-3 with boronate or boronic acid 2-6.

[0177] Scheme 7 [ka] Scheme 7 is intermediate 7-5a(X 4 =COLE) and 7-5b(X 4 =CN(R 4 Exemplary preparations of )-LE) are shown. 4,6-dichloro-2-(methylthio)pyrimidine (7-1) is reacted with boronate or boronic acid 2-6 by the Suzuki reaction to obtain 7-2. Compound 7-2 is reacted with boronate 1-6 in the presence of a palladium catalyst (Suzuki reaction) to obtain 7-3. Compound 7-3 is oxidized using a well-supported reaction sequence: m CPBA in DCM, followed by oxidation of the resulting intermediate with a commercially available alcohol EL-OH or amine ELN(R) 4 )H is substituted to form compounds 7-4a (X4=COLE) and 7-4b (X4=CN(R 4 It can be converted to )-LE). Finally, by nitro reduction of 7-4a and 7-4b under mild reducing conditions (zinc or iron metal containing ammonium chloride), the corresponding amine 7-5a(X 4 =COLE) and 7-5b(X 4 =CN(R 4)-LE) were obtained respectively.

[0178] Scheme 8 [ka] Scheme 8 shows an exemplary preparation of intermediate 8-4. 2,6-dichloropyrazine (8-1) can be reacted with boronate or boronic acid 2-6 by a Suzuki reaction to obtain 8-2, which can then be subjected to another Suzuki reaction with boronate 1-3 to provide 8-4. Similarly, 2,6-dichloropyrazine 8-1 can be reacted with boronate 1-3 by a Suzuki reaction to obtain 8-3, which can then be subjected to another Suzuki reaction with boronate 2-6 to obtain 8-4.

[0179] Scheme 9 [ka] Scheme 9 shows exemplary preparations of intermediates 9-5 and 9-7. Compound 9-1 (2,4-dichloropyrimidine or 4-bromo-2-chloropyrimidine) is reacted with boronate 1-6 by a Suzuki reaction to obtain 9-2, which is then subjected to another Suzuki reaction with boronate or boronic acid 2-6 to obtain 9-4. Mild reduction of 9-4 (with zinc or iron metal containing ammonium chloride) yields the corresponding amine 9-5. Similarly, compound 9-1 can be reacted with boronate or boronic acid 2-6 by a Suzuki reaction to obtain 9-6, which is then subjected to another Suzuki reaction with boronate 1-3 to provide compound 9-7.

[0180] Scheme 10 [ka] Scheme 10 shows exemplary preparations of intermediates 10-4a and 10-4b. 10-2 is obtained by treating 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10-1) with chloride (or bromide) 2-7 in the presence of a palladium catalyst (Suzuki reaction). Intermediate 10-4b (X) is obtained by another Suzuki reaction of 10-2 with boronate 1-3. 1 Similarly, chloride 10-3 was reacted with boronate or boronic acid 2-6 under typical Suzuki conditions to obtain intermediate 10-4a(X 1 We obtain =CH).

[0181] Scheme 11 [ka] Scheme 11 is intermediate 11-3(X 4 Exemplary preparations of (=CH,C-alkyl) are shown. Dichloropyridine 11-1 is treated with boronate 1-3 in the presence of a palladium catalyst (Suzuki reaction) to obtain 11-2. 11-3 is obtained by treating 11-2 with carboxylic acid 1-5 under amide coupling conditions known to those skilled in the art. In another embodiment, commercially available 11-1 is reacted with boronate 1-4 by the Suzuki reaction to obtain intermediate 11-3.

[0182] Scheme 12 [ka] Scheme 12 shows exemplary preparations of intermediates 12-6a, 12-6b, and 12-6c. 1,3-dibromo-5-iodobenzene, 12-1(Y=I), is converted at high temperature in the presence of a base such as K2CO3, and in an aprotic solvent such as DMSO under the catalysis of amine ELN(R) with CuI / L-proline. 4 ) is reacted with H to obtain 12-2. Under Pd(0) catalysis, compound 12-2 is reacted with B2pin2 in the well-known boration reaction to obtain boronate 12-3, which is then reacted with chloride (or bromide) 2-7 by the Suzuki reaction to obtain intermediate 12-5a(X 4 =CN(R 4)-LE) can be obtained. In another embodiment, compound 12-1 (Y=H, alkyl) reacts with B2pin2 under Pd(0) catalyst to obtain boronate 12-4. Suzuki reaction of 12-4 with chloride (or bromide) 2-7 (1 equivalent) yields 12-5b(X) 4 =CH) and 12-5c(X 4 A C-alkyl compound is obtained. Finally, each compound 12-5a, 12-5b, and 12-5c is reacted with boronate 1-3 under the Suzuki reaction to obtain 12-6a, 12-6b, and 12-6c, respectively.

[0183] Scheme 13 [ka] Scheme 13 shows exemplary preparations of pyridazine intermediates 13-4, 13-5, and 13-6. Alternatively, treatment of 5-bromo-3-chloropyridazine 13-1 with boronate 1-3 under Suzuki reaction conditions yields 13-3. Chloride 13-3 reacts with boronate or boronic acid 2-6 to yield 13-4 by Pd(0) catalyzed Suzuki reaction. Chloride 13-3 reacts with carboxylic acid 1-5 under amide coupling conditions to yield intermediate 13-5. Alternatively, intermediate 13-5 can be prepared directly from 13-1 using boronate 1-4 by Suzuki reaction. Treatment of 5-bromo-3-chloropyridazine 13-1 with boronate or boronic acid 2-6 under Suzuki reaction conditions yields 13-2. Chloride 13-2 reacts with boronate 1-3 to yield 13-6 by Pd(0) catalyzed Suzuki reaction.

[0184] Scheme 14 [ka] Scheme 14 shows exemplary preparations of intermediates 14-6a, 14-6b, 14-6c, 14-6d, and 14-6e. Compound 14-3 can be prepared in the presence of a palladium catalyst by (1) the Suzuki reaction of 14-1 (commercially available or synthesized by those skilled in the art) with boronic acid or boronate 2-6, or (2) the Suzuki reaction of 14-2 (commercially available or synthesized by those skilled in the art) with chloride (or bromide) 2-7. Compound 14-3 (Y=H, alkyl) is reacted with boronates 1-3 by the Suzuki reaction to obtain 14-6c(X 4 =CH) and 14-6d(X 4 A compound 14-3 (Y=Cl) is obtained. In another embodiment, compound 14-3 (Y=Cl) is reacted with boronate or boronic acid ELB(OR)2 under Pd(0) catalytic coupling conditions using established literature conditions well known to those skilled in the art to obtain 14-4. A Suzuki reaction of 14-4 with boronate 1-3 under Pd(0) catalytic coupling conditions is obtained to obtain compound 14-6e. Compound 14-6e(X 4 If compound 14-3 (Y=F) contains unsaturated functional groups such as double or triple bonds, hydrogenation can proceed in the presence of a Pd catalyst. Alternatively, compound 14-3 (Y=F) can be hydrogenated in the presence of a base. N Ar reaction to produce alcohol EL-OH or amine ELN(R) 4 ) reacted with H, and each was 14-5a(X 4 =COLE) and 14-5b(X 4 =CN(R 4 )-LE) is obtained. Finally, chlorides 14-5a and 14-5b are reacted with boronate 1-3 under Suzuki reaction conditions to obtain intermediate 14-6a(X 4 =COLE) and 14-6b(X 4 =CN(R 4 You can obtain )-LE) respectively.

[0185] Scheme 15 [ka] Scheme 15 shows exemplary preparations of pyrimidine intermediates 15-3a, 15-3b, 15-3c, and 15-3d. The S of 2,4,6-trichloropyrimidine 15-1 with alcohol (EL-OH) N Ar reaction 15-2a(X 4 =COLE) and 15-2c(X 4 This yields a mixture of (=COLE), which can be separated by a preferred method (e.g., SFC purification, column chromatography, or recrystallization). Similarly, 2,4,6-trichloropyrimidine 15-1 is obtained from S N Under Ar reaction conditions, amine (ELN(R) 4 Reacting with )H), 15-2b(X 4 =CN(R 4 )-LE) and 15-2d(X 4 =CN(R 4 A mixture of )-LE) is obtained and can be separated by an appropriate method (e.g., SFC purification, column chromatography, or recrystallization). Suzuki reactions of 15-2a and 15-2b with boronate or boronic acid 2-6 yield 15-3a and 15-3b, respectively. 15-2c(X 4 The Suzuki reaction of 15-3c and 15-3e with 15-2d(X) yields a mixture of 15-3c and 15-3e that can be separated by a preferred method (e.g., SFC purification, column chromatography, or recrystallization). Similarly, the Suzuki reaction of 15-2d(X) yields a mixture of 15-3c and 15-3e that can be separated by a preferred method (e.g., SFC purification, column chromatography, or recrystallization). 4 =CN(R 4 The Suzuki reaction of )-LE) with boronate or boronic acid 2-6 yields a mixture of 15-3d and 15-3f which can be separated by a preferred method (e.g., SFC purification, column chromatography, or recrystallization).

[0186] Scheme 16 [ka] Scheme 16 shows exemplary preparations of the compounds of formula I (16-2a, 16-2b, 16-2c, and 16-2d). The compounds of formula I (16-2a and 16-2b) can be prepared by the Suzuki reaction of chloride A (6-2, 8-2, 9-6, 10-2, 13-2, 14-4, 14-5a, 14-5b, 15-3a, 15-3b, 15-3c, 15-3d, 15-3e, and 15-3f) with boronates 1-4. Similarly, chloride B (2-5, 4-4a, 4-4b, 5-4a, 5-4b, 11-3, and 13-5) can be reacted with boronates or boronic acids 2-6 (commercially available or synthesized by those skilled in the art) under Suzuki conditions to obtain the compound of formula I (16-2a). Alternatively, Pd-boration of chlorides B (2-5, 4-4a, 4-4b, 5-4a, 5-4b, 11-3, and 13-5) using B2pin2 converts them to boronate 16-1. Boronate 16-1 is reacted with chloride (or bromide) 2-7 (commercially available or synthesized by those skilled in the art) under Suzuki reaction conditions to obtain compound (16-2b) of formula I. In another embodiment, aniline C (2-4a, 2-4b, 3-6a, 3-6b, 3-6c, 6-4, 7-5a, 7-5b, 8-4, 9-5, 9-7, 10-4a, 10-4b, 12-6a, 12-6b, 12-6c, 13-4, 13-6, 14-6a, 14-6b, 14-6c, 14-6d, and 14-6e) react with carboxylic acids 1-5 or imidates 1-7 under typical coupling conditions to convert compounds of formula I (16-2a, 16-2b, 16-2c, 16-2d).

[0187] Scheme 17 [ka] Scheme 17 shows an exemplary preparation of the compound of formula I(17-2). Chloride B(2-5, 4-4a, 4-4b, 5-4a, 5-4b, 11-3, and 13-5) are reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile under Suzuki conditions to obtain 17-1a(X 1Alternatively, boronate 16-1 can be reacted with 6-chloropyrimidine-4-carbonitride under Suzuki reaction conditions to obtain 17-1b(X). 1 The nitriles (17-1a and 17-1b) are reacted with hydrogen peroxide in the presence of a small amount of alkali such as NaOH (a well-known preparative procedure) to obtain the primary amide compounds of formula I (17-2a and 17-2b, respectively).

[0188] Preparation of intermediates The following compounds were prepared using the synthesis procedures and methods described herein, as well as methods known to those skilled in the art:

[0189] Preparation of intermediate A1 Intermediate A1: N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide [ka] A mixture of 4-chloro-N-methylpicolinamide (3.5 g, 21 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.8 g, 31 mmol), and KOAc (6.0 g, 62 mmol) in 1,4-dioxane (70 mL) was purged with Ar for minutes. PdCl2 (dppf) (0.75 g, 1.03 mmol) was added, and the mixture was heated at 100°C for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The solution was filtered through a Celite pad, and the filtrate was treated with saturated NaHCO3. The mixture was extracted with DCM (3 ×). The combined organic matter was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% MeOH / DCM) to obtain N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (3.1 g, 57%) as a yellowish-brown solid. 1H NMR(400MHz,DMSO-d6):δ 8.78(d,J=5.6Hz,1H),8.66(d,J=4.7Hz,1H),8.22(s,1H),7.73(dd,J=1.2,4 .7Hz,1H),2.81(d,J=4.9Hz,3H),1.32(s,12H);MS(ESI)m / z:181.2(boronic acid, M+H + ).

[0190] The following compounds are essentially prepared by preparation method A1. [ka]

[0191] Preparation of intermediate B1 3-(2-chloropyridine-4-yl)-4-methylaniline [ka] A solution of 4-bromo-2-chloropyridine (1.7 mL, 16 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.4 g, 23 mmol) in 1,4-dioxane (70 mL) and water (8 mL) was treated with K2CO3 (5.4 g, 23 mmol). The reaction mixture was purged with nitrogen gas for 20 minutes, and then Pd(dppf)Cl2·DCM adduct (0.23 g, 0.31 mmol) was added. The reaction mixture was heated at 100 °C for a further 3.5 hours, and the mixture was cooled to room temperature. The solution was filtered through a Celite pad and washed with DCM (40 mL). The filtrate was washed with saturated NaHCO3, followed by water. The combined organic matter was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (0-100% siRNA / hexane) to obtain 3-(2-chloropyridine-4-yl)-4-methylaniline (3.4 g, 99% yield) as a light brown solid. 1H NMR (400MHz, DMSO-d6): δ8.41(d,J=5.1Hz,1H),7.42(d,J=1.4Hz,1H),7.35(dd,J=1.5,5.1Hz,1H),6.96(d,J=8 .2Hz,1H),6.56(dd,J=2.4,8.1Hz,1H),6.46(d,J=2.4Hz,1H),5.03(s,2H),2.06(s,3H);MS(ESI)m / z:219.2(M+H + ).

[0192] The following compounds are essentially prepared by preparation method B1. [ka] [ka]

[0193] Preparation of intermediate C1: 4-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)aniline [ka] A mixture of 3-(5-chloropyridine-3-yl)-4-methylaniline (B4, 1.0 g, 4.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.7 g, 6.8 mmol), and K2CO3 (1.4 g, 14 mmol) in 1,4-dioxane (12 mL) was degassed with Ar for 5 minutes. XPhos Pd G2 (0.18 g, 0.23 mmol) was added, and the mixture was heated at 100°C for 4 hours. The mixture was cooled to room temperature and then quenched with saturated NaHCO3 (aqueous solution) and phenylethylamine. The mixture was extracted with phenylethylamine (3×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)aniline (1.4 g, crude product) as a brown solid. MS(ESI)m / z:229.2 (boronic acid, M+H+).

[0194] Preparation of intermediates D1 and D2: 2-((2,6-dichloropyrimidine-4-yl)amino)ethane-1-ol (D1) and 2-((4,6-dichloropyrimidine-2-yl)amino)ethane-1-ol (D2) [ka] A solution of 2-aminoethanol (3.3 mL, 54 mmol) in THF (30 mL) was added dropwise to a solution of 2,4,6-trichloropyrimidine (3.1 mL, 27 mmol) in THF (50 mL). The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-20% siRNA / petroleum ether) to obtain 2-[(4,6-dichloropyrimidine-2-yl)amino]ethanol (D1, 2.0 g, 35%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 8.25-8.33(br m,1H),6.56(s,1H),4.83(t,J=8.0Hz,1H),3.51(m,2H),3.36(m,2H);MS(ESI)m / z:208.0(M+H + ) and 2-[(2,6-dichloropyrimidine-4-yl)amino]ethanol (D2, 2.7g, 48%) were obtained as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 8.06(t,J=5.6Hz,1H),6.85(s,1H),4.70(t,J=5.6Hz,1H),3.48(m,2H),3.30(m,2H);MS(ESI)m / z:208.0(M+H + ).

[0195] The following compounds are essentially prepared by the same method as the preparation of intermediates D1 and D2. [ka]

[0196] Preparation of intermediate E1: 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyridine-4-yl)-4-methylaniline [ka] A solution of 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (0.42 g, 2.4 mmol) in DMF (5.0 mL) was slowly treated with NaH (0.15 g, 3.8 mmol, 60% in mineral oil) under an ice bath, and the reaction mixture was stirred under the same conditions for 30 minutes. A solution of 3-(2-chloro-6-fluoropyridine-4-yl)-4-methylaniline (B8, 0.45 g, 1.9 mmol) in DMF (1 mL) was added to the reaction mixture, and the reaction mixture was heated at 40°C for 2 hours. The reaction mixture was quenched with water (20 mL) under an ice bath. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5-10% Âxane) to obtain 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyridine-4-yl)-4-methylaniline (0.47 g, yield 62%). MS(ESI)m / z:393.2(M+H + ).

[0197] The following compounds are essentially prepared by the method for preparing intermediate E1. [ka]

[0198] Preparation of intermediate E3: (R)-2-((4-(5-amino-2-methylphenyl)-6-chloropyridine-2-yl)amino)propan-1-ol [ka] A solution of (R)-2-((6-chloro-4-iodopyridine-2-yl)amino)propan-1-ol (D3, 2.7 g, 8.6 mmol) in a mixture of 1,4-dioxane (40 mL) / water (5 mL) was mixed with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.1 g, 9.1 mmol) treated with K2CO3 (3.6 g, 26 mmol), and the reaction mixture was then degassed under Ar for 3 minutes. PdCl2 (dppf) (0.63 g, 0.86 mmol) was added, and the reaction mixture was then heated overnight at 90°C. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-100% MeOH / DCM) to obtain (R)-2-((4-(5-amino-2-methylphenyl)-6-chloropyridine-2-yl)amino)propan-1-ol (2.3g, 86%) as a brown oily substance. 1 H NMR(400MHz,DMSO-d6):δ6.91(d,J=8.0Hz,1H),6.75(d,J=7.9Hz,1H),6.50(dd,J=2.4,8.2Hz,1H),6.40(d,J=2.4Hz,1H),6.35(d,J=0.8Hz,1H ),6.31(d,J=0.8Hz,1H),4.96(s,2H),4.71(t,J=5.6Hz,1H),3.88(m,1H),3.46(m,1H),3.29(m,1H),2.05(s,3H),1.12(d,J=6.6Hz,3H):292.1

[0199] The following compounds are essentially prepared by preparation method intermediate E3. [ka]

[0200] Preparation of intermediate F1: 4-(5-amino-2-methylphenyl)-N-methyl-[2,4'-bipyridine]-2'-carboxamide [ka] A mixture of 3-(2-chloropyridine-4-yl)-4-methylaniline (B1, 2.5 g, 11 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (A1, 4.5 g, 17 mmol), and K2CO3 (4.7 g, 34 mmol) in a mixture of 1,4-dioxane (80 mL) and water (9 mL) was purged with Ar for 10 minutes. Pd(dppf)Cl2·DCM adduct (0.93 g, 1.1 mmol) was added, and then the reaction mixture was sealed and heated to 100°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO3 (aqueous solution). The mixture was extracted with DMC (3×), the combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The black oily substance was purified by silica gel column chromatography (0-80% siRNA / hexane) to obtain 4-(5-amino-2-methylphenyl)-N-methyl-[2,4'-bipyridine]-2'-carboxamide (2.3 g, 64%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ8.83(q,J=5.5Hz,1H),8.78(d,J=5.0Hz,1H),8.74(m,2H),8.30(dd,J=1.8,5.1Hz,1H),8.07(s,1H),7.45(dd,J=1 .5,5.0Hz,1H),6.99(d,J=8.1Hz,1H),6.58(dd,J=2.4,8.1Hz,1H),6.56(d,J=2.4Hz,1H),5.03(s,2H),2.85(d,J=4.8Hz,3H),2.11(s,3H).

[0201] The following compounds are essentially prepared by preparation method F1. [ka] [ka]

[0202] Preparation of intermediate G1: 3-chloro-5-cyclopropylpyridazine [ka] A suspension of 5-bromo-3-chloropyridazine (10 g, 52 mmol), cyclopropylboronic acid (4.4 g, 52 mmol), and Na2CO3 (16 g, 155 mmol) in a mixture of 1,4-dioxane (100 mL) and H2O (20 mL) was purged with N2 for 3 minutes. Pd(dppf)Cl2 (3.0 g, 4.1 mmol) was added, and the mixture was then heated at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted with siRNA (4×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-50% siRNA / petroleum ether) to obtain 3-chloro-5-cyclopropylpyridazine (4.1 g, yield 51%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 9.08(d,J=2.0Hz,1H),7.59(d,J=1.9Hz,1H),2.01(m,1H),1.15-1.21(m,2H),0.98-1.04(m,2H). MS(ESI)m / z:155.1(M+H+)。

[0203] Preparation of intermediate G2: 3-chloro-5-(1-ethoxyvinyl)pyridazine [ka] A 2 L round-bottom flask equipped with a stirring bar was packed with 5-bromo-3-chloropyridazine (40 g, 208 mmol), tributyl(1-ethoxyvinyl) stannan (70 mL, 208 mmol), and TEA (87 mL, 620 mmol) in DMF (500 mL) and purged with N2 for 3 minutes. Pd(PPh3)2Cl2 (7.3 g, 10 mmol) was added, and the mixture was then heated at 90°C for 3 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature and quenched at 0°C with saturated NH4Cl (100 mL) and saturated KF (1 L). The mixture was stirred at room temperature for 0.5 hours and then extracted with RINKAN (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-100% siRNA / petroleum ether) to obtain 3-chloro-5-(1-ethoxyvinyl)pyridazine (30 g, 79%) as a yellow solid. 1 H NMR(400MHz,メタノール-d4)δ 9.41(d,J=1.6Hz,1H),7.95(d,J=1.8Hz,1H),5.29(d,J=3.8Hz,1H),4.76(d,J=3.9Hz,1H),4.03(q,J=7.0Hz,2H),1.47(t,J=7.0Hz,3H).

[0204] Preparation of intermediate H1: 5-cyclopropylpyridazine-3-carboxylate methyl [ka] A solution of 3-chloro-5-cyclopropylpyridazine (4.0 g, 26 mmol) in MeOH (40 mL) was treated with DIEA (9.0 mL, 52 mmol). The suspension was purged with CO for 3 minutes, then purged with Pd(dppf)Cl2 (1.9 g, 2.6 mmol). The mixture was heated at 80°C for 3 hours under CO (50 Psi). The reaction mixture was cooled to room temperature, diluted with water, and extracted with siRNA (4×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% siRNA / petroleum ether) to obtain methyl 5-cyclopropylpyridazine-3-carboxylate (3.1 g, 67%) as a brown oil. 1 H NMR(400MHz,DMSO-d6):δ 9.23(d,J=2.3Hz,1H),7.83(d,J=2.3Hz,1H),3.94(s,3H),2.10(m,1H),1.13-1.25(m,2H),0.95-1.06(m,2H);MS(ESI)m / z:179.1(M+H + ).

[0205] The following compounds are essentially prepared by preparation method H1. [ka]

[0206] Preparation of intermediate H6: Methyl 5-(trifluoromethyl)pyridazine-3-carboimoidate [ka] A solution of methyl 5-(trifluoromethyl)pyridazine-3-carboxylate (1.5 g, 7.3 mmol) in 7.0 M NH3 / MeOH (10 mL) was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain 5-(trifluoromethyl)pyridazine-3-carboxamide (1.2 g, 73%) as a yellow solid. 1H NMR(400MHz,DMSO-d6):δ 9.89(s,1H),8.81(s,1H),8.47(s,1H),8.20(s,1H). MS(ESI)m / z:191.9(M+H + ).

[0207] A solution of 5-(trifluoromethyl)pyridazine-3-carboxamide (1.2 g, 6.3 mmol) in toluene (15 mL) was mixed with POCl3 (3.7 mL, 39 mmol) at room temperature. The reaction mixture was heated at 100 °C for 1 hour and then cooled to room temperature. The mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-10% siRNA / petroleum ether) to obtain 5-(trifluoromethyl)pyridazine-3-carbonitrile (0.8 g, 59%) as a pale yellow oil. 1 H NMR(400MHz,CDCl3):δ 9.57(d,J=1.8Hz,1H),8.02(d,J=1.6Hz,1H);MS(ESI)m / z:173.9(M+H + ).

[0208] A solution of 5-(trifluoromethyl)pyridazine-3-carbonitride (0.2 g, 1.2 mmol) in MeOH (1 mL) was mixed with NaOMe (0.46 g, 2.31 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with water and extracted with RINKAN (2×). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 5-(trifluoromethyl)pyridazine-3-carboimoid (H6, 0.2 g, 84%) as a pale yellow solid. 1 H NMR:(400MHz,CDCl3):δ 9.65(s,1H),9.43(d,J=1.8Hz,1H),8.11(d,J=1.8Hz,1H),4.03(s,3H);MS(ESI)m / z:206.0(M+H + ).

[0209] The following compounds are essentially prepared by preparation method H6. [ka]

[0210] Preparation of intermediate H8: 5-(1,1-difluoroethyl)pyridazine-3-carboxylate methyl [ka] A solution of methyl 5-acetylpyridazine-3-carboxylate (H3, 30g, 166 mmol) in DCM (300 mL) was stirred at 0°C. DAST (66 mL, 500 mmol) was added dropwise at 0°C and the mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 10 hours. Water (300 mL) was added, and the solution was then extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-100% Âxy / petroleum ether) to obtain methyl 5-(1,1-difluoroethyl)pyridazine-3-carboxylate (H8, 11g, 33%) as a white solid. 1 H NMR(400MHz,MeOD):δ 9.48(d,J=2.2Hz,1H),8.30(d,J=2.0Hz,1H),3.99(s,3H),1.95(t,J=18.9Hz,3H).

[0211] Preparation of intermediate H9: 5-(2-cyanopropan-2-yl)methyl nicotinate [ka] A mixture of methyl 5-bromopyridine-3-carboxylate (4.0 g, 18 mmol), 2-trimethylsilylacetonitrile (3.6 mL, 26 mmol), and difluorozinc (2.3 g, 22 mmol) in NMP (80 mL) was purged with N2 for 3 minutes. Xanthophos Pd G4 (1.8 g, 1.8 mmol) was added, and the mixture was then heated at 130 °C for 3 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (40 mL) and extracted with HCl (3×). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% HCl / petroleum ether) to obtain methyl 5-(cyanomethyl)nicotinate (1.7 g, 52%) as a pink solid. 1 H NMR(400MHz,DMSO-d6):δ 9.05(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),8.31(t,J=2.2Hz,1H),4.23(s,2H),3.92(s,3H);MS(ESI)m / z:177.3(M+H + ).

[0212] A solution of methyl 5-(cyanomethyl)nicotinate (1.0 g, 5.7 mmol) in THF (10 mL) was mixed with NaH (1.4 g, 34 mmol, 60% in mineral oil) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere, then MeI (2.1 mL, 34 mmol) was added at 0°C, and the mixture was continuously stirred at 0°C for 1 hour under an N2 atmosphere. The reaction mixture was quenched with water and extracted with RINKAN (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% RINKAN / petroleum ether) to obtain methyl 5-(2-cyanopropan-2-yl)nicotinate (H9, 0.15 g, 13%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 9.08(d,J=2.0Hz,1H),9.04(d,J=2.4Hz,1H),8.37(t,J=2.2Hz,1H),3.93(s,3H),1.79(s,6H);MS(ESI)m / z:205.0(M+H+ ).

[0213] Preparation of intermediate I1: 5-cyclopropylpyridazine-3-carboxylic acid [ka] A solution of methyl 5-cyclopropylpyridazine-3-carboxylic acid (H1, 2.9 g, 16 mmol) in a mixture of THF (15 mL) and water (15 mL) was treated with LiOH·H2O (1.4 g, 32 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was acidified with 1.0 N HCl to approximately pH 3, and the resulting precipitate was collected by filtration to obtain 5-cyclopropylpyridazine-3-carboxylic acid (1.4 g, 52%) as a brown solid. 1 ¹H NMR (400MHz, DMSO-d6): δ 9.22 (d, J=2.4Hz, 1H), 7.82 (d, J=2.4Hz, 1H), 2.10 (m, 1H), 1.13-1.25 (m, 2H), 0.97-1.06 (m, 2H), acid protons are missing; MS (ESI) m / z: 165.1 (M+H + ).

[0214] The following compounds are essentially prepared by preparation method I1. [ka]

[0215] Preparation of intermediate J1: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide [ka] A solution of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (I4, 6.35 g, 33 mmol), HATU (13.8 g, 36 mmol), and DIEA (17 mL, 99 mmol) in DMF (66 mL) was stirred at 0°C for 15 minutes. 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.71 g, 33 mmol) was added, and the reaction mixture was then warmed to room temperature and stirred overnight at room temperature. The reaction mixture was quenched with water, and the resulting solid was collected by filtration.

[0216] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (12 g, 87%) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 11.14(s,1H),9.92(s,1H),8.55(d,J=2.3Hz,1H),8.20(d,J=2.5Hz,1H),7.85(dd,J=2.4,8. 2Hz,1H),7.19(d,J=8.3Hz,1H),2.44(s,3H),1.30(d,J=1.4Hz,12H);MS(ESI)m / z:408.2(M+H + ).

[0217] The following compounds are essentially prepared by preparation method intermediate J1. [ka]

[0218] Preparation of intermediate J7: 5-cyano-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridazine-3-carboxamide [ka] A solution of N3-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridazine-3,5-dicarboxamide (J6, 16.5 g, 43 mmol) in THF (200 mL) was treated with methoxycarbonyl-(triethylammonio)sulfonyl azanide (51.4 g, 216 mmol). The mixture was stirred at 20°C for 1 hour, and the resulting precipitate was collected by filtration to obtain 5-cyano-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridazine-3-carboxamide (5.0 g, 31%) as a yellow solid. The mother liquor was concentrated under reduced pressure, and the resulting residue was ground with water (50 mL). The solid was filtered to obtain a second batch of 5-cyano-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridazine-3-carboxamide (4.2 g, 25%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 11.13(s,1H),9.86(d,J=1.8Hz,1H),8.78(d,J=1.8Hz,1H),8.21(d,J=2.2Hz,1H),7.85(dd, J=2.2,8.2Hz,1H),7.20(d,J=8.2Hz,1H),2.45(s,3H),1.32(s,12H);MS(ESI)m / z:365.1(M+H + ).

[0219] Preparation of intermediate K1: N-(3-(2-chloropyridine-4-yl)-4-methylphenyl)-6-(difluoromethyl)nicotinamide [ka] A solution of 6-(difluoromethyl)nicotinic acid (0.40 g, 2.3 mmol) in DMF (6 mL) was treated with HATU (0.87 g, 2.3 mmol) and DIEA (0.6 mL, 3.4 mmol). The mixture was stirred at room temperature for 10 minutes. A solution of 3-(2-chloropyridine-4-yl)-4-methylaniline (B1, 0.25 g, 1.1 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice water and stirred for 90 minutes. The yellow solid was filtered and dried under high vacuum. The yellow solid was purified by silica gel column chromatography (0-50% siRNA / hexane) to obtain N-(3-(2-chloropyridine-4-yl)-4-methylphenyl)-6-(difluoromethyl)nicotinamide (0.30 g, yield 70%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 10.63(s,1H),9.19(s,1H),8.48-8.51(m,2H),7.89(d,J=8.1Hz,1H),7.77(d,J=8.3Hz,1H),7.74(s,1H),7.56(s ,1H),7.48(d,J=5.1Hz,1H),7.38(d,J=8.3Hz,1H),7.04(t,J=56.0Hz,1H),2.26(s,3H);MS(ESI)m / z:374.2(M+H + ).

[0220] The following compounds are essentially prepared by the method for preparing intermediate K1. [ka]

[0221] Preparation of intermediate K2: N-[3-[6-chloro-2-(2-hydroxyethylamino)pyrimidine-4-yl]-4-methylphenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide [ka] A mixture of 2-[(4,6-dichloropyrimidine-2-yl)amino]ethanol (D2, 0.20 g, 0.96 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide (J1, 0.39 g, 0.96 mmol) in 1,4-dioxane (3 mL) was treated with 2.0 M Na2CO3 (1.5 mL, 3 equivalents). The mixture was purged with N2 for 3 minutes, and then Pd(dppf)Cl2 (0.070 g, 0.1 equivalents) was added. The reaction mixture was heated at 90°C for 2 hours under an N2 atmosphere. The reaction mixture was diluted with water and extracted with ELISA (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-65% ethylethanol / petroleum ether) to obtain N-[3-[6-chloro-2-(2-hydroxyethylamino)pyrimidine-4-yl]-4-methylphenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide (0.20 g, 46%) as a brown solid. MS(ESI)m / z:452.9(M+H + ).

[0222] The following compounds are essentially prepared by the method for preparing intermediate K2. [ka] [ka] [ka]

[0223] Preparation of intermediate K16: N-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyridine-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide [ka] A solution of 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (K10, 3.5 g, 20 mmol) in 1,4-dioxane (30 mmol) was added to NaH (1.2 g, 25 mmol). The mixture was stirred at room temperature for 1 hour, and then N-(3-(2,6-dichloropyridine-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (5.0 g, 12 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then heated at 70 °C for 1 hour. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was treated with water and then extracted with DCM (3×). The combined organic extracts were filtered through a short silica gel column. The filtrate was concentrated to obtain N-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyridine-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (K16, 5.1g, 77%) as an orange liquid. MS(ESI)m / z:567.2(M+H + ).

[0224] Preparation of Example 1: N-(3-(2'-cyano-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide [ka] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.53 g, 2.3 mmol) and N-(3-(2-chloropyridine-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (K8, 0.9 g, 2.3 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.6 mL) was treated with K2CO3 (0.79 g, 5.7 mmol). The mixture was purged with Ar for 5 minutes, and then PdCl2(dppf)·DCM adduct (0.19 g, 0.23 mmol) was added. The reaction mixture was purged again with Ar for 5 minutes. The reaction mixture was then sealed and heated to 90°C for 2 hours. The reaction mixture was filtered through a Celite pad and washed with ELISA (200 mL) and 10% ELISA / MeOH (200 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% ELISA / hexane) to obtain N-(3-(2'-cyano-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (1, 1.0 g, 95%) as a brown solid. MS m / z: 393.0 (M+H + ).

[0225] The following compounds are essentially prepared by the preparation method of Example 1. [ka] [ka] [ka] [ka] [ka] [ka]

[0226] Preparation of Example 2: N,6-dimethyl-4-(2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamide)phenyl)-[2,4'-bipyridine]-2'-carboxamide [ka] A mixture of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (0.14 g, 0.75 mmol), 4-(5-amino-2-methylphenyl)-N,6-dimethyl-[2,4'-bipyridine]-2'-carboxamide (F3, 0.25 g, 0.75 mmol), pyridine (0.18 mL), and EDC (0.23 g, 1.50 mmol) in DMF (4 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into water, the resulting solid was filtered, and washed with water. The solid was purified by silica gel column chromatography (0-100% HCl / hexane) to obtain N,6-dimethyl-4-(2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamide)phenyl)-[2,4'-bipyridine]-2'-carboxamide (0.26 g, 67%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 11.32(s,1H),9.95(d,J=2.2Hz,1H),8.83(q,J=4.8Hz,1H),8.75(d,J=1.8Hz,1H),8.73(d,J=5.1Hz,1H),8.57(d,J=2.3Hz,1H) ,8.30(dd,J=1.8,5.2Hz,1H),7.93-8.01(m,3H),7.43(s,1H),7.38(m,1H),2.85(d,J=4.8Hz,3H),2.66(s,3H),2.31(s,3H);MS m / z:507.2(M+H + ).

[0227] The following compounds are essentially prepared by the preparation method of Example 2. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0228] Preparation of Example 3: 4-(2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamide)phenyl)-[2,4'-bipyridine]-2'-carboxamide [ka] A mixture of N-(3-(2'-cyano-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (1, 0.29 g, 0.64 mmol) and K2CO3 (0.13 g, 0.96 mmol) in DMSO (3 mL) was stirred at room temperature. H2O2 (1-2 drops, 30% in water) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ELISA (300 mL) and cooled to 0°C in an ice bath. Sodium thiosulfate solution (10% water) was slowly added, and the mixture was stirred at 0°C for 1 hour. The resulting white solid was filtered, washed with water, and dried under high vacuum. The crude product was purified using silica gel column chromatography (0-100% ELISA / hexane). Since the product contained impurities, the product was suspended in MeCN and sonicated. The solid was filtered, washed with MeCN, and dried. The product was shown with a purity of 81%. The product was suspended in MeOH (5 mL) and sonicated. The solid was filtered, washed with MeOH, and dried to obtain 4-(2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamide)phenyl)-[2,4'-bipyridine]-2'-carboxamide (3, 0.15 g, 49%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 11.35(s,1H),9.95(d,J=2.3Hz,1H),8.84(d,J=5.0Hz,1H),8.78(d,J=1. 8Hz,1H),8.75(d,J=5.1Hz,1H),8.57(d,J=2.3Hz,1H),8.33(dd,J=1.9,5. 1Hz,1H),8.20(d,J=2.6Hz,2H),7.99(m,2H),7.74(m,1H),7.57(dd,J=1. 6,4.9Hz,1H),7.40(d,J=9.0Hz,1H),2.31(s,3H);MS(ESI)m / z:461.0(M+H + ).

[0229] The following compounds are essentially prepared by the preparation method of Example 3. [ka]

[0230] Preparation of Example 52: N 3 -(3-(6-(2-hydroxyethoxy)-2'-(methylcarbamoyl)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)pyridazine-3,5-dicarboboxamide [ka] A solution of 5-cyano-N-[3-[2-(2-hydroxyethoxy)-6-[2-(methylcarbamoyl)-4-pyridyl]-4-pyridyl]-4-methylphenyl]pyridazine-3-carboxamide (49 mg, 180 mg, crude) in a mixture of THF (2 mL) and H2O (0.4 mL) was treated with NaOH (22 mg, 3 equivalents). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (3 mL) and extracted with ELISA (3×). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by preparative HPLC (20-50% H2O (10 mM NH4HCO3) / CH3CN) and N 3 -[3-[2-(2-hydroxyethoxy)-6-[2-(methylcarbamoyl)-4-pyridyl]-4-pyridyl]-4-methylphenyl]pyridazine-3,5-dicarboxamide (16 mg, 16%) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 11.23(s,1H),9.75(d,J=2.0Hz,1H),8.84(q,J=4.4Hz,1H),8.74(d,J=5.2Hz,1H),8.71(d,J=1.2Hz,1H),8.67(br s,1H),8.65(d,J=2.4Hz,1H),8.31(dd,J=1.6,5.2Hz,1H),8.10(s,1H),7.96-8.00(m,2H),7.81(d,J=0.8Hz,1H),7.39(m,1H),6.96(s,1H),4.92(t,J=5.6Hz,1H),4.50(t,J=4.8Hz,2H),3.83(q,J=5.4Hz,2H),2.85(d,J=4.8Hz,3H),2.32(s,3H);MS m / z:528.2(M+H + ).

[0231] B-Raf biochemical assay The activity of B-Raf kinase (SEQ ID NO: 1) was spectroscopically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using 0.13 nM B-Raf (Sigma), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 30.1 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100). B-Raf inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorption at 340 nm was continuously monitored for 6 hours at 30°C using a multimode microplate reader (BioTek). The reaction rate was calculated using a time frame of 4-5 hours. The reaction rate at each concentration of the compound was converted to an inhibition percentage using a control (i.e., a reaction without the test compound and a reaction with a known inhibitor), and the IC50 value was calculated by fitting a 4-parameter sigmoid curve to the data using Prism (GraphPad software). B-Raf protein sequence with N-terminal GST tag, residues 416-766 (SEQ ID NO: 1) LQKSPGPQRERKSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTV KIGDFGLATVKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMMECLKKKRDERPLFPQILASIELLARSLPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYAFPVH

[0232] Assay of C-Raf The activity of C-Raf kinase (SEQ ID NO: 2) was spectroscopically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using 0.43 nM C-Raf (Sigma), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 30.1 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100). C-Raf inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorption at 340 nm was continuously monitored for 6 hours at 30°C using a multimode microplate reader (BioTek). The reaction rate was calculated using a time frame of 4-5 hours. The reaction rate at each concentration of the compound was converted to an inhibition percentage using a control (i.e., a reaction without the test compound and a reaction with a known inhibitor), and the IC50 value was calculated by fitting a 4-parameter sigmoid curve to the data using Prism (GraphPad software). C-Raf residue at terminal 306; Y340D, Y341D (SEQ ID NO: 2) with N-terminal GST tag QPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSDDWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF [Table 1]

[0233] In Table 1, "++++" indicates ICs with a impedance of 100 nM or less. 50 This refers to ICs with a impedance of over 100nM and 500nM or less. 50 This refers to ICs with a impedance of over 500nM and less than or equal to 1000nM. 50 This refers to ICs with a impedance of over 1000nM and less than or equal to 10000nM. 50 It refers to.

[0234] MiaPaca-2 Cell Proliferation Assay Miapaca-2 cells (catalog number CRL-1420) were obtained from the American Type Culture Collect (ATTC, Manassas, Virginia). Briefly, the cells were grown in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, California), 2.5% New Zealand-origin horse serum, and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. The cells were expanded to a density of 70–95%, at which point they were subcultured or harvested for assay use. For assays completed in 96-well plates, serial dilutions of the test compound were distributed in triple 96-well black clear-bottom plates. 3000 cells per well were added to 200 μL of full growth medium in the 96-well plates. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 67–72 hours. At the end of incubation, 40 μL of 440 mM Lezazlin (Sigma, St. Louis, Missouri) solution in PBS was added to each well of the plate, and the plates were incubated for a further 5–6 hours at 37°C, 5% CO2, and 95% humidity. For the 384-well assay, eight 3-fold serial dilutions of the compound were arranged in columns in a 384-well black, clear-bottomed tissue culture plate using a Beckman Coulter Echo 650. Similarly, eight 3-fold serial dilutions of cobimetinib were arranged in rows in a 384-well black, clear-bottomed plate containing the compound. The DMSO concentration was constant at 0.4% across all wells. 750 cells per well were added to 50 μL of full growth medium in each 384-well plate. Incubate the plate at 37°C, 5% CO2, and 95% humidity for 67–72 hours. At the end of incubation, add 10 μL of 440 mM Lezazlin (Sigma, St. Louis, Missouri) solution in PBS to each well of the plate, and incubate the plate for a further 4–6 hours at 37°C, 5% CO2, and 95% humidity. Read the plate on a Synergy2 or equivalent reader (Biotek, Winooski, Vermont) using 540 nm excitation and 600 nm emission.We used Prism software (Graphpad, San Diego, California) to analyze the data and for IC. 50 Calculate the value.

[0235] HCT-116 Cell Proliferation Assay HCT-116 cells (catalog number CCL-247) were obtained from the American Type Culture Collect (ATCC, Manassas, Virginia). Briefly, the cells were grown in McCoy's 5A supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, California) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. The cells were expanded to a density of 70–95%, at which point they were subcultured or harvested for assay use. Serial dilutions of the test compound were dispensed three times into 384-well black clear-bottom plates. 375 cells per well were added in 50 μL of complete growth medium in the 384-well plates. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 67–72 hours. At the end of incubation, 40 μL of 440 mM Lezazlin (Sigma, St. Louis, Missouri) solution in PBS was added to each well of the plate, and the plate was incubated for a further 4-5 hours at 37°C, 5% CO2, and 95% humidity. The plate was read using a Synergy2 or equivalent reader (Biotek, Winooski, Vermont) with excitation at 540 nm and emission at 600 nm. The data was analyzed using Prism software (Graphpad, San Diego, California) to determine IC 50 Calculate the value.

[0236] HPAF-II Cell Proliferation Assay HPAF-II cells (catalog number CRL-1997) were obtained from the American Type Culture Collect (ATCC, Manassas, Virginia). Briefly, the cells were grown in minimal essential medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, California) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. The cells were expanded to a density of 70–95%, at which point they were subcultured or harvested for assay use. Serial dilutions of the test compound were dispensed three times into 384-well black clear-bottom plates. 750 cells per well were added in 50 μL of complete growth medium in the 384-well plates. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 115–120 hours. At the end of incubation, 40 μL of 440 mM Lezazlin (Sigma, St. Louis, Missouri) solution in PBS was added to each well of the plate, and the plate was incubated for a further 18–24 hours at 37°C, 5% CO2, and 95% humidity. The plate was read using a Synergy2 or equivalent reader (Biotek, Winooski, Vermont) with excitation at 540 nm and emission at 600 nm. The data was analyzed using Prism software (Graphpad, San Diego, California) to determine IC 50 Calculate the value.

[0237] Pa16c Cell Proliferation Assay Pa16c cells were obtained from Dr. Channing Der of the University of North Carolina at Chapel Hill. Briefly, cells were grown in Dulbecco's Modified Eagle Medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, California) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded to a density of 70–95%, at which point they were subcultured or harvested for assay use. Serial dilutions of the test compound were dispensed three times into 384-well black clear-bottom plates. 750 cells per well were added in 50 μL of complete growth medium in the 384-well plates. Plates were incubated at 37°C, 5% CO2, and 95% humidity for 67–72 hours. At the end of incubation, 40 μL of 440 mM Lezazlin (Sigma, St. Louis, Missouri) solution in PBS was added to each well of the plate, and the plate was incubated for a further 18–24 hours at 37°C, 5% CO2, and 95% humidity. The plate was read using a Synergy2 or equivalent reader (Biotek, Winooski, Vermont) with excitation at 540 nm and emission at 600 nm. The data was analyzed using Prism software (Graphpad, San Diego, California) to determine IC 50 Calculate the value. [Table 2-1] [Table 2-2]

[0238] In Table 2, "++++" indicates ICs with a impedance of 100 nM or less. 50 This refers to ICs with a impedance of over 100nM and 500nM or less. 50 This refers to ICs with a impedance of over 500nM and less than or equal to 1000nM. 50 This refers to ICs with a impedance of over 1000nM and less than or equal to 10000nM. 50 It refers to.

[0239] Biochemical tubular phosphopolymerization assay Porcine brain tubulin (T240) and tubulin polymerization assay kit (BK011P) are purchased from Cytoskeleton, Inc. (Denver, Colorado). Briefly, serial dilutions of the test compound are dispensed three times into a 384-well black plate. 25 μL of the assay mixture containing buffer, glycerol, GTP, and porcine brain tubulin from the assay kit is added to each well of the 384-well plate. The plate is briefly centrifuged and then read using a Synergy Neo2 or equivalent reader (BioteK, Winooski, Vermont) at 37°C for 1 hour at 2-minute intervals, using 335 nm excitation and 450 nm emission, to generate kinetic data and the maximum polymerization rate from 0 to 1 hour. Data are analyzed using Prism software (Graphpad, San Diego, California) for IC50. 50 Calculate the value.

[0240] Figure 1 shows the maximum rate of tubulin polymerization in the presence of increasing concentrations of the tubulin depolymerizer, prinablin. In this recombinant biochemical tubulin assay, prinablin yielded a 2.7 mM IC50. 50 This inhibits tubulin polymerization.

[0241] Cellular tubular phosphopolymerization assay HCT-116 cells (catalog number CCL-247) were obtained from the American Type Culture Collect (ATCC, Manassas, Virginia). Briefly, the cells were grown in McCoy's 5A supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, California) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. The cells were grown until they reached a density of 70–95%, at which point they were subcultured or harvested for assay use. 450,000 cells were added per well in 1500 μL of complete growth medium in a tissue culture-treated 12-well plate. The plate was incubated at 37°C, 5% CO2, and 95% humidity for 18–24 hours. At the end of incubation, 2000 μL of base culture medium was added to each well, followed by serial dilution of the compound. The plate is incubated for an additional 1 hour at 37°C, 5% CO2, and 95% humidity. Lysates are prepared by adding 100 μL of lysates supplemented with GTP (BST06, Cytoskeleton Inc.), ATP (BSA04, Cytoskeleton Inc.), and protease inhibitor cocktail stock (PIC02, Cytoskeleton Inc.) and microtubule stabilizing buffer 1 (LMS01, Cytoskeleton Inc., Denver, Colorado). Cells are scraped from the wells using a rubber cell scraper and collected in a clean 96-well plate. The lysates are centrifuged at 1000 × g, 37°C for 10 minutes, and the supernatant fraction is added to an additional 96-well plate. The remaining pellet fraction is reconstituted in 100 μL of LMS01 buffer and sonicated for 10 minutes. The pellet and supernatant fractions are probed for α-tubulin via Western blotting using the Jess System or an equivalent (Bio-techne, Minneapolis, Minnesota). The data is analyzed using Prism software (Graphpad, San Diego, California) for IC 50 Calculate the value.

[0242] Figure 2 shows the ratio of the pellet (polymerized tubulin) to the supernatant (tubulin dimer) compared to a DMSO control to increase the concentration of the tubulin depolymerizer prinablin. In this cell tubulin assay, prinablin increased the IC50 to 5 nM. 50 This inhibits tubulin polymerization.

[0243] The compounds disclosed herein exhibit an unexpected dual mechanism of action by 1) inhibiting BRAF and CRAF MAP kinases and 2) inhibiting tubulin polymerization. While such dual inhibition can be achieved by combining several anticancer agents, the compounds disclosed herein provide such dual inhibition within the same pharmacophore. This unexpected dual mechanism of action enables potent monotherapy inhibition of mutant RAS cancer cell lines, which could not be achieved with previously reported BRAF / CRAF inhibitors.

[0244] Typical examples are shown in Table 3. These examples, as shown in Table 3, involve biochemical ICs. 50 These examples inhibit BRAF and CRAF at specific values. These examples also inhibit tubulin polymerization in tubulin biochemical assays. In cell assays, these examples demonstrate potent monotherapy antiproliferative activity in MiaPaca-2 mutant KRAS pancreatic cancer cell lines, HCT-116 mutant KRAS colorectal cancer cell lines, and HPAF-II mutant KRAS pancreatic cancer cell lines. For comparison, Table 4 contains representative compounds of those disclosed in PCT / US2022 / 081242.

[0245] Table 5 shows other chemical classes of reported BRAF and / or CRAF inhibitors. These compounds inhibit BRAF and / or CRAF, but none of them potently inhibit tubulin polymerization. The compounds in Table 5 showed weaker antiproliferative activity in MiaPaca-2 mutant KRAS pancreatic cancer cell lines, weaker antiproliferative activity in HCT-116 mutant KRAS colorectal cancer cell lines, and weaker antiproliferative activity in HPAF-II mutant KRAS pancreatic cancer cell lines. [Table 3] Table 3 shows data for BRAF, CRAF, and MiaPaca-2. HCT-116, HPAF-II, and tubulin cell assays are included. "++++" indicates IC50 or less than 100 nM. 50 This refers to ICs with a impedance of over 100nM and 500nM or less. 50 This refers to an IC with a impedance of over 500nM and under 1000nM. 50 This refers to ICs with a impedance greater than 1000nM and less than or equal to 10000nM. 50 This refers to the tubulin biochemical assay, where "****" indicates an IC of 3 mM or less. 50 This refers to ICs with a impedance greater than 3mM and less than or equal to 20mM. 50 This refers to ICs with a impedance of over 20mM and 100mM or less. 50 This refers to ICs with a minimum impedance of 100mM. 50 It refers to. [Table 4] Table 4 shows data for BRAF, CRAF, and MiaPaca-2. HCT-116, HPAF-II, and tubulin cell assays; "++++" indicates IC100nM or less. 50 This refers to ICs with a impedance of over 100nM and 500nM or less. 50 This refers to an IC with a impedance of over 500nM and under 1000nM. 50 This refers to ICs with a impedance greater than 1000nM and less than or equal to 10000nM. 50 This refers to the tubulin biochemical assay, where "****" indicates an IC of 3 mM or less. 50 This refers to ICs with a impedance greater than 3mM and less than or equal to 20mM. 50 This refers to ICs with a impedance of over 20mM and 100mM or less. 50 This refers to ICs with a minimum impedance of 100mM. 50 It refers to. [Table 5] Table 5 shows data for BRAF, CRAF, and MiaPaca-2. HCT-116, HPAF-II, and tubulin cell assays are included. "++++" indicates IC50 below 100 nM. 50 This refers to ICs with a impedance of over 100nM and 500nM or less. 50 This refers to an IC with a impedance of over 500nM and under 1000nM. 50 This refers to ICs with a impedance greater than 1000nM and less than or equal to 10000nM. 50 This refers to the tubulin biochemical assay, where "****" indicates an IC of 3 mM or less. 50 This refers to ICs with a impedance greater than 3mM and less than or equal to 20mM. 50 This refers to ICs with a impedance of over 20mM and 100mM or less. 50 This refers to ICs with a minimum impedance of 100mM. 50 It refers to.

[0246] Equal portions While specific embodiments have been discussed, the above specification is illustrative and not limiting. Many variations of the embodiments will become apparent to those skilled in the art when examining this specification. The full scope of what is disclosed should be determined by referring to the claims, in addition to the full scope of their equivalents, and in addition to this specification, to such variations.

[0247] Unless otherwise indicated, all numbers representing quantities of components, reaction conditions, etc., used herein and in the claims should be understood in all cases to be modified by the term "approximately." Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained.

Claims

1. Compound represented by formula I-A: 【Chemistry 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, Q is selected from the group consisting of O and NH. X １ , X ２ and X ５ However, each is independently selected from the group consisting of CH and N, X ３ and X ４ However, each is independent of N, CH, C=O, C-O-L-E, C-L-E, C-N(R ４ Selected from the group consisting of )-L-E and N-L-E, X ６ However, selected from the group consisting of CH and N, X ７ However, selected from the group consisting of CH, CF, and N, X ８ and X １０ are each independently selected from the group consisting of CH, CF, and N, X ９ However, CR ５ Selected from the group consisting of and N, However, X ２ , X ３ , X ４ , and X ５ The condition is that two or fewer of them are N, However, X ６ and X ７ The condition is that one or less of them is N, However, X ８ , X ９ , and X １０ The condition is that one or less of them is N, However, X ３ If X is N, ４ are C-O-L-E, C-L-E, C-N(R ４ ) - Provided that it is L-E, N, or CH, However, X ４ If X is N, ３ is N, CH, C-O-L-E, C-L-E, or C-N(R ４ ) - L - E condition, However, X ３ If C = O, then X ４ This is conditional on it being N-L-E, However, X ４ If C = O, then X ３ This is conditional on it being N-L-E, R １ This is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. In each instance, the cycloalkyl or cycloalkyl substituent of the cycloalkylalkyl is independently and arbitrarily substituted with substituents selected from the group consisting of halogens and alkyls. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. R ２ However, it is selected from the group consisting of alkyl, H, halogen, and alkoxy, R ３ However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R ４ However, selected from the group consisting of H and alkyl, R ５ However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R ５ However, R ３ And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is directly bonded and C is optionally substituted. １ -C ６ Selected from the group consisting of alkyl groups, A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

2. Compound represented by formula I-B: 【Chemistry 2】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X １ , X ２ and X ５ However, each is independently selected from the group consisting of CH and N, X ３ and X ４ However, each is independent of N, CH, C=O, C-O-L-E, C-L-E, C-N(R ４ Selected from the group consisting of )-L-E and N-L-E, X ６ However, selected from the group consisting of CH and N, X ７ However, selected from the group consisting of CH, CF, and N, X ８ and X １０ However, each is independently selected from the group consisting of CH, CF, and N. X ９ However, CR ５ Selected from the group consisting of and N, However, X ２ , X ３ , X ４ , and X ５ The condition is that two or fewer of them are N, However, X ６ and X ７ The condition is that one or less of them is N, However, X ８ , X ９ , and X １０ The condition is that one or less of them is N, However, X ３ If X is N, ４ are C-O-L-E, C-L-E, C-N(R ４ ) - Provided that it is L-E, N, or CH, However, X ４ If X is N, ３ is N, CH, C-O-L-E, C-L-E, or C-N(R ４ ) - L - E condition, However, X ３ If C = O, then X ４ This is conditional on it being N-L-E, However, X ４ If C = O, then X ３ This is conditional on it being N-L-E, R １ However, it is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. R ２ However, it is selected from the group consisting of alkyl, H, halogen, and alkoxy, R ３ However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R ４ However, selected from the group consisting of H and alkyl, R ５ However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R ５ However, R ３ And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is directly bonded and C is optionally substituted. １ -C ６ Selected from the group consisting of alkyl groups, A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

3. Compounds represented by formula I-C: 【Transformation 3】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X ４ However, N, CH, C-O-L-E, C-L-E, and C-N (R ４ Selected from the group consisting of )-L-E, X ５ However, selected from the group consisting of CH and N, X ６ However, selected from the group consisting of CH and N, X ７ However, selected from the group consisting of CH, CF, and N, X ８ and X １０ However, each is independently selected from the group consisting of CH, CF, and N. X ９ However, CR ５ Selected from the group consisting of and N, However, X ４ and X ５ are subject to the condition that one or less of them is N However, X ６ and X ７ The condition is that one or less of them is N, However, X ８ , X ９ , and X １０ The condition is that one or less of them is N, R １ is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. R ２ However, it is selected from the group consisting of alkyl, H, halogen, and alkoxy, R ３ However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R ４ However, selected from the group consisting of H and alkyl, R ５ However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R ５ However, R ３ And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is directly bonded and C is optionally substituted. １ -C ６ Selected from the group consisting of alkyl groups, A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

4. Compounds represented by formula I-D: 【Chemistry 4】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X ８ and X １０ However, each is independently selected from the group consisting of CH, CF, and N. X ９ However, CR ５ Selected from the group consisting of and N, However, X ８ , X ９ , and X １０ The condition is that one or less of them is N, R １ This is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. R ２ However, it is selected from the group consisting of alkyl, H, halogen, and alkoxy, R ３ However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R ５ However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R ５ R ３ Compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, which, together with the carbon atoms to which they are each bonded, form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure.

5. R ３ The compound according to claim 4, wherein H is present.

6. R ５ The compound according to claim 4, wherein the compound is a haloalkyl, cycloalkyl, or cyano.

7. Compounds represented by formula (I-E): 【Transformation 5】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X ８ It is selected from the group consisting of CH, CF, and N. R １ This is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl. The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. and R ５ A compound selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

8. Compounds represented by formula (I-F): 【Transformation 6】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, R １ However, it is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. and R ５ A compound selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

9. R １ The compound according to claim 8, wherein the compound is alkyl, cycloalkyl, or H.

10. R ５ The compound according to claim 8, wherein the compound is a haloalkyl, cycloalkyl, or cyano.

11. Compounds represented by formula (I-G): 【Transformation 7】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, R １ However, it is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. and R ３ A compound selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

12. R ３ The compound according to claim 11, wherein the compound is a haloalkyl or cycloalkyl.

13. Compounds represented by formula (I-H): 【Transformation 8】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X １ , X ２ and X ５ However, each is independently selected from the group consisting of CH and N, X ６ It is selected from the group consisting of CH and N, X ７ However, selected from the group consisting of CH, CF, and N, X ８ and X １０ However, each is independently selected from the group consisting of CH, CF, and N. X ９ However, CR ５ Selected from the group consisting of and N, However, X ２ biX ５ The condition is that one or less of them is N, However, X ６ and X ７ The condition is that one or less of them is N, However, X ８ , X ９ , and X １０ The condition is that one or less of them is N, R １ However, it is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. R ２ However, it is selected from the group consisting of alkyl, H, halogen, and alkoxy, R ３ However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R ４ However, selected from the group consisting of H and alkyl, R ５ However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R ５ However, R ３ And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is directly bonded and C is optionally substituted. １ -C ６ Selected from the group consisting of alkyl groups, A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

14. Compound represented by formula (I-J): 【Chemistry 9】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X １ , X ２ and X ５ However, each is independently selected from the group consisting of CH and N, X ６ However, selected from the group consisting of CH and N, X ７ However, selected from the group consisting of CH, CF, and N, X ８ and X １０ However, each is independently selected from the group consisting of CH, CF, and N. X ９ However, CR ５ Selected from the group consisting of and N, However, X ２ biX ５ The condition is that one or less of them is N, However, X ６ and X ７ The condition is that one or less of them is N, However, X ８ , X ９ , and X １０ The condition is that one or less of them is N, R １ However, it is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, The alkyl substituents are independently and optionally substituted in each instance with substituents selected from the group consisting of amines, halogens, cyanos, cycloalkyls, and heterocyclines. The heterocyclyl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. The heteroaryl substituent is independently and optionally substituted in each instance with a substituent selected from the group consisting of halogens and alkyls. R ２ However, it is selected from the group consisting of alkyl, H, halogen, and alkoxy, R ３ However, it is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amine. R ５ However, it is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or R ５ However, R ３ And together with the carbon atoms to which they are each bonded, they form a cycloalkyl or heterocyclyl ring having 4 to 6 atoms in the ring structure. L is directly bonded and C is optionally substituted. １ -C ６ Selected from the group consisting of alkyl groups, A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, and the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amine, hydroxy, oxo, and cyano in each occurrence.

15. X １ The compound according to any one of claims 1 to 2 and 13 to 14, wherein the compound is CH.

16. X ２ The compound according to any one of claims 1 to 2 and 13 to 15, wherein the compound is CH.

17. X ３ The compound according to any one of claims 1 to 2 and 15 to 16, wherein N is present.

18. X ４ However, N, CH, C-O-L-E, and C-N (R ４ A compound according to any one of claims 1 to 3 and 15 to 17, selected from the group consisting of )-L-E.

19. X ４ However, the compound according to any one of claims 1 to 3 and 15 to 18, selected from the group consisting of N and CH.

20. X ４ However, C-O-CH(R ４ ) - CH ２ -OH and C-NH-CH(R ４ ) - CH ２ A compound according to any one of claims 1 to 3 and 15 to 18, selected from the group consisting of -OH.

21. X ５ The compound according to any one of claims 1 to 3 and 13 to 20, wherein the compound is CH.

22. X ２ , X ３ , X ４ , and X ５ A ring containing is selected from the group consisting of the following: 【Chemistry 10】 In the formula, s1 contains N and -C(O)NHR １ This shows bonding to the ring substituted with X ６ and X ７ The compound according to claim 1 or 2, which exhibits bonding to a ring containing a ring.

23. X ６ The compound according to any one of claims 1 to 3 and 13 to 22, wherein the compound is CH.

24. X ７ The compound according to any one of claims 1 to 3 and 13 to 23, wherein the compound is CH.

25. X ８ The compound according to any one of claims 1 to 7 and 13 to 24, wherein N is present.

26. X ９ However, CR ５ The compound according to any one of claims 1 to 6 and 13 to 25.

27. R ５ The compound according to any one of claims 1 to 10 and 13 to 26, selected from the group consisting of alkyl, cycloalkyl, and haloalkyl.

28. X １０ The compound according to any one of claims 1 to 6 and 13 to 27, wherein the compound is CH.

29. R １ The compound according to any one of claims 1 to 28, wherein the alkyl substituent is selected from the group consisting of H, alkyl, (C3-C8) cycloalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, and haloalkyl, and the alkyl substituent is independently and optionally substituted in each occurrence with a substituent selected from the group consisting of amine, halogen, cyano, (C3-C8) cycloalkyl, and heterocyclyl.

30. R １ The compound according to any one of claims 1 to 29, wherein the alkyl substituent is selected from the group consisting of H, alkyl, (C3-C8)cycloalkyl, alkoxyalkyl, heterocyclyl, and haloalkyl, and the alkyl substituent is independently and optionally substituted in each occurrence with a substituent selected from the group consisting of amine, halogen, and (C3-C8)cycloalkyl.

31. R １ However, methyl and 【Chemistry 11】 A compound according to any one of claims 1 to 30, selected from the group consisting of the following.

32. R ２ The compound according to any one of claims 1 to 6 and 13 to 31, selected from the group consisting of alkyl and halogen.

33. R ２ The compound according to any one of claims 1 to 6 and 13 to 32, selected from the group consisting of methyl and ethyl.

34. R ３ The compound according to any one of claims 1 to 6 and 11 to 33, selected from the group consisting of H, alkyl, alkoxy, and haloalkyl.

35. R ３ The compound according to any one of claims 1 to 6 and 11 to 34, selected from the group consisting of trifluoromethyl and H.

36. R ４ The compound according to any one of claims 1 to 3 and 15 to 35, wherein H is present.

37. R ５ The compound according to any one of claims 1 to 10 and 13 to 36, wherein the compound is selected from the group consisting of H, alkyl, alkoxy, amine, amide, haloalkyl, cycloalkyl, phosphine oxide, halogen, haloalkoxy, cyano, and cyanoalkyl.

38. R ５ However, H, trifluoromethyl, isopropyl, cyclopropyl, chloro, 【Chemistry 12】 A compound according to any one of claims 1 to 10 and 13 to 37, selected from the group consisting of the following.

39. L is C1-C ６ The compound according to any one of claims 1 to 3 and 13 to 38, which is optionally substituted with an alkyl group.

40. L, 【Chemistry 13】 A compound according to any one of claims 1 to 3 and 13 to 39, selected from the group consisting of, wherein E is bonded to the carbon specified by * in the formula.

41. L, 【Chemistry 14】 A compound according to any one of claims 1 to 3 and 13 to 40, selected from the group consisting of, wherein E is bonded to the carbon specified by * in the formula.

42. The compound according to any one of claims 1 to 3 and 13 to 41, wherein E is selected from the group consisting of H, methyl, and hydroxy.

43. Compounds selected from the following group: 【Chemistry 15-1】 【Chemistry 15-2】 Furthermore, pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

45. A method for treating cancer in a patient requiring cancer treatment, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition according to claim 43.

46. The method according to claim 45, wherein the cancer is selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, hematological cancer, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

47. The method according to claim 45 or 46, wherein the cancer has a BRAF oncogenic mutation.

48. The method according to any one of claims 45 to 47, wherein the cancer has an RAS oncogenic mutation.

49. The method according to any one of claims 45 to 48, wherein the cancer has an NRAS oncogenic mutation.

50. The method according to claim 49, wherein the NRAS oncogenic mutation is an NRAS Q61R or NRAS Q61K mutation.

51. The method according to any one of claims 45 to 50, wherein the cancer has a KRAS oncogenic mutation.

52. The method according to claim 51, wherein the KRAS oncogenic mutation is KRAS G12D, KRAS G12V, KRAS G12C, KRAS G12R, or KRAS G13D.

53. The method according to any one of claims 45 to 52, wherein the cancer has an NF1 oncogenic mutation.

54. A method for treating a patient in need of treatment for a disorder selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, hematological cancer, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition according to claim 44.

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