Dual raf and tubulin inhibitors and methods of use thereof

Abstract

Described herein are compounds of Formula I-A that are dual RAF and tubulin inhibitors and their use in treating disorders such as cancer. Formula I-A

Description

Cross-reference

[0001] This application claims priority to U.S. Provisional Application US63 / 614,180, filed December 22, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] The BRAF V600X (V600E) mutation is known to be oncogenic, and several commercially available BRAF inhibitors are currently available to inhibit the signal transduction of oncogenic BRAF V600E in melanoma and other cancers. BRAF V600E acts as a monomeric signal transduction agent and possesses constitutive activity independent of upstream RAS controls. Commercially available BRAF V600E inhibitors include vemurafenib, dabrafenib, and encorafenib.

[0003] Aside from the BRAF V600X mutant, almost all other oncogenic forms of BRAF transmit signaling through the formation of homodimers (BRAF-BRAF dimers) or heterodimers (e.g., BRAF-CRAF dimers), making them difficult to treat with BRAF V600X inhibitors (such as vemurafenib, dabrafenib, and encofenib). These dimers form in cancers driven by BRAF fusions, atypical BRAF mutations, or RAS-mutant cancers.

[0004] Oncogenic BRAF fusions originate from genomic rearrangements that place the 3' portion of a BRAF gene encoding the kinase domain after the 5' position of another gene. The result of this rearrangement is the expression of oncogenes that exhibit constitutive kinase activity due to the loss of the N-terminal autorepressive domain of BRAF. These BRAF fusions exhibit constitutive kinase activity through spontaneous dimerization and thus enable aberrant signal transduction in cancer cells, independent of upstream effectors or regulatory mechanisms. Furthermore, some 5' translocation rearrangements further induce dimerization of the N-terminal domain, thereby enhancing the activated dimerization of the BRAF fusion protein kinase domain. Since the expression of these genomic rearrangements is controlled by the promoter of the 5' covariant, overexpression of BRAF fusion transcripts is often due to highly efficient or excessive promoter activity. BRAF fusions are the most common kinase translocations in solid tumors. Since first described as an oncogene for papillary thyroid carcinoma in 2005, hundreds of tumors across at least 15 different tumor types have identified fusions of the BRAF kinase domain with one of more than 110 different 5' covariant genes. BRAF fusion proteins have been found in papillary thyroid carcinoma, astrocytoma, and melanoma, and have also been identified in drug-resistant EGFR-mutant lung cancer. BRAF fusion proteins transmit signaling via dimerization in a RAS-independent manner and are resistant to many BRAF inhibitors such as vemurafenib and dabrafenib, which cannot inhibit the two protomers of the homodimerized BRAF fusion protein. Rare CRAF fusion proteins have also been shown to be tumor drivers. These CRAF fusion proteins act as CRAF-CRAF homodimer signaling agents.

[0005] Other so-called atypical BRAF mutations also lead to spontaneous dimerization and RAS-independent signal transduction. Like BRAF fusions, these atypical BRAF mutants act as aberrant homodimers to transmit signals.

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

[0007] Combinatorial siRNA screening identified RAF as a dominant node in RAS-mutant cancers, and the co-depletion of BRAF and CRAF, along with the depletion of the autophagy gene ATG7, provided the optimal synthetic lethal inhibition of RAS-mutant signal transduction, and also offered the optimal therapeutic window for inhibiting signal transduction in both RAS-mutant cells and normal RAS wild-type cells. Furthermore, it has been reported that the combination of inhibition of the RAF→MEK→ERK pathway and autophagy inhibitors effectively blocked the in vitro and in vivo growth of RAS-mutant cancers.

[0008] Vertical inhibition of the RAF→MEK→ERK pathway by pan-inhibiting RAF (especially BRAF + CRAF) and ERK kinase activity showed an unconventional, highly synergistic effect in blocking MAPK pathway signaling in KRAS-mutant pancreatic cancer cells, organoid studies, and a mouse model of KRAS-mutant pancreatic cancer. Vertical inhibition of RAF (BRAF + CRAF) and MEK kinase activity also showed a synergistic effect in KRAS-mutant tumors.

[0009] The importance of inhibiting BRAF and CRAF isoforms, and the requirement for inhibitors to successfully bind to and inhibit both protomers of the RAF signaling dimer, has been well-established. RAF inhibitors, particularly BRAF V600X inhibitors, have failed to successfully bind to and inhibit both protomers of the RAF signaling dimer in RAS-mutant cancers, resulting in paradoxical pathway stimulation rather than desired pathway inhibition. Such BRAF V600X inhibitors are contraindicated for the treatment of RAS-mutant cancers.

[0010] There is a need to identify RAF inhibitors that can inhibit multiple RAF isoforms. In particular, there is a need to identify RAF inhibitors that can inhibit both BRAF and CRAF isoforms. Specifically, there is a need to identify RAF inhibitors that can inhibit the RAF protons present in the BRAF / BRAF homodimer and both protons in the BRAF / CRAF heterodimer. Such pan-RAF inhibitors have shown efficacy in treating BRAFV600X-driven cancers, atypical BRAF-mutant cancers, BRAF fusion cancers, CRAF fusion cancers, and RAS-mutant cancers.

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

[0012] Microtubule-targeting agents (MTAs), in addition to their effects on cell function, also possess anti-angiogenic and anti-vascular disrupting properties. By influencing the microtubule network, MTAs inhibit endothelial cell proliferation, migration, and tube formation, and induce significant changes in endothelial cell morphology. MTAs have also been evaluated as potential vascular disruptors (VDAs). VDAs are known to primarily block blood flow in solid tumors, while maintaining the integrity of blood vessels in normal tissues.

[0013] MTAs are classified into three main categories based on their α- or β-tubulin binding sites. MTAs that bind to taxane sites include taxanes and epothilone. These microtubule stabilizers bind to fully formed microtubules and prevent the depolymerization of tubulin subunits. In contrast, vinca alkaloids interact with the vinca domain of tubulin found in tubulin dimers and inhibit its polymerization into microtubules (microtubule destabilizers). Colchicine and colchicine binding site inhibitors (CBSIs) interact at different 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 patients with cancer. Taxanes and vinca alkaloids are currently used for a variety of indications, including solid tumors and hematologic malignancies. No oral CBSIs are currently approved as anticancer agents.

[0015] The main challenges currently faced by MTAs (specifically, taxanes) used clinically include: systemic toxicity, acquired resistance, limited intravenous administration, poor water solubility requiring the use of surfactants for intravenous administration, associated risks of hypersensitivity reactions, and disease relapse when treating patients in advanced settings. MTAs approved for clinical use also have dose-limiting neurotoxicity and hematopoietic toxicity.

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

[0017] Combinations of drugs involving agents with different anticancer mechanisms are often used to enhance tumor response and patient survival, particularly in the treatment of advanced cancer. There is a close interaction between the RAS / MAPK pathway and the microtubule-dependent MYC regulatory pathway. For example, large-scale screening with loss-of-function siRNAs identified TUBB3 (encoding a βIII-tubulin isoform) as the optimal vulnerability in pancreatic cancer. Genetic silencing of TUBB3 sensitizes KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells to ERK inhibition, suggesting that pharmacological inhibition of proteins supporting MYC expression (e.g., tubulin inhibitors) may be an effective therapeutic strategy targeting mutant KRAS-dependent PDAC. TUBB3 also has clinical relevance because overexpression of this β-tubulin isoform is associated with adverse responses to microtubule-targeting drugs such as taxanes. Strong TUBB3 expression is most commonly found in various brain tumors, lung cancer, renal cell carcinoma, malignant melanoma, and PDAC. In addition, the expression level of TUBB3 is altered in many cancer cells, and abnormal expression of TUBB3 is associated with enhanced chemoresistance and poor prognosis in NSCLC, ovarian cancer, gastric cancer, breast cancer, and serous uterine cancer.

[0018] Tubulin disruptors have been shown to upregulate MAPK pathway signaling, thus limiting their effectiveness. Dual targets, besides targeting tubulin, that inhibit MAPK pathway signaling would overcome the resistance mechanism to MAPK pathway reactivation.

[0019] Dual-targeting agents (single molecules that interact with two different biological targets) can also offer advantages over combination therapies, specifically lower risk of drug-drug interactions, more predictable pharmacokinetic (PK) profiles, simplified dosing regimens, and increased patient compliance.

[0020] In the context of high resistance to current MAPK targeted therapies, identifying agents exhibiting BRAF inhibition and tubulin disruption has the potential to overcome BRAF inhibitor resistance and significantly benefit patients with various solid tumors, including ovarian cancer, colorectal cancer, and papillary thyroid carcinoma. Agents that inhibit BRAF and CRAF, which also cause tubulin disruption (so-called pan-RAF inhibitors), will also potentially benefit patients with mutant RAS cancers, providing deeper and more durable anticancer efficacy. The compounds, compositions, and methods of use described herein are aimed at addressing this need. Invention Overview This article describes compounds that act as dual RAF and tubulin inhibitors and their methods of use.

[0022] In one embodiment, this disclosure provides a compound represented by formula IA: Formula IA, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 )-LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 5 and X 6 Each is independently selected from: CH, CF, and N; X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; its constraint is X 1 X 2 X 3 and X 4 No more than two of them are N; the constraint is X. 5 and X 6 No more than one of them is N; the constraint is X. 7 X 8 and X 9 No more than one of them is N; the constraint is that when X 2 When X is N, 3 It can be CQLE, CLE, N, or CH; its constraint is that when X 3 When X is N, 2 For N, CH or CN(R) 4 )-LE;R 1Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyl, alkyl, cycloalkyl, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3-7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN, and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; L selected from: direct bond and optionally substituted C1-C6 alkyl; E selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituents are independently selected from: alkyl, halogen, amine, hydroxyl, and cyano each time they appear; and m is 0, 1, 2, 3, or 4, subject to the condition that when X 2 When X is N, 8 For CR 5 And X 7 and X 9 For CH, R 5 Not N(CH3)2; when X 2 When X is N, 1 X 3 and X 4 For CH, X 7 X 8 and X 9 One of them is N and X 7 X 8 and X 9 The other two are CH and R. 2 Not H; and when X 7 and X 9 When it is CH, X 8 For CR 5 R 2 For H, R 5 For CF3, X 2 Let N be the number of elements, and X be the number of elements. 1 and X 4 For CH, X 3 Not for , or .

[0023] In another embodiment, a pharmaceutical composition is described herein comprising the compounds described herein ( example like(such as the compounds of the present invention described herein) or their pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, and pharmaceutically acceptable carriers or excipients.

[0024] In another embodiment, this document describes a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example (such as the compounds of the present invention described herein) or their pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, or the compositions described herein.

[0025] In another embodiment, this document describes a method for treating a patient with a condition selected from: histiocytic hyperplasia, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, hematogenous cancer, hairy cell leukemia, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway. The method comprises administering to the patient a therapeutically effective amount of the compound described herein (e.g., the compound of the present invention as described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein. Attached Figure Description

[0026] Figure 1 This shows the maximum rate of tubulin polymerization in the presence of increased concentrations of the known tubulin depolymerizing agent plinabulin.

[0027] Figure 2 This shows the ratio of pellets (polymerized tubulin) to supernatant (tubulin dimers) to DMSO control at increasing concentrations of the known tubulin depolymerizing agent punabulin. Invention Details Features and other details of this disclosure will now be described more precisely. Specific terms used in this specification, embodiments, and appended claims are collectively brought together herein. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0029] definition The definitions set forth in this application are intended to clarify the terminology used throughout this application.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains. Unless otherwise stated, the following terms have the meanings assigned to facilitate understanding of the invention as used in the specification and appended claims.

[0031] When a bond to a substituent is shown to cross the bonds of two atoms in the linking ring, such a substituent may bond to any atom in that ring. If the listed substituents do not indicate that such substituents are bonded to atoms in the remainder of the compound specified, such substituents may bond via any atom of such substituents. Such combinations are permitted only if the combination of substituents, substituent positions, and / or variables produces a stable compound.

[0032] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” cover a plural referent.

[0033] As used herein, the term "this document" refers to the entire application.

[0034] As used herein, “deuteration” refers to the substitution of at least one hydrogen atom with deuterium. In any sample of a deuterated compound, some discrete molecules of the compound may have hydrogen instead of deuterium at a specified position. However, the percentage of molecules in a deuterated compound having deuterium at a specified position will be much greater than in naturally occurring compounds. Deuterium is enriched at the deuteration site.

[0035] As used herein, the terms "optional" or "optionally" mean that an event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not. For example, "optionally substituted alkyl" means both the possibility that the alkyl group may be substituted and the possibility that the alkyl group is not substituted.

[0036] It should be understood that those skilled in the art can select the substituents and substitution modes of the compounds disclosed herein to produce chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods set forth below. If a substituent is itself replaced by more than one group, it should be understood that these multiple groups may be on the same carbon or different carbons, as long as a stable structure is produced.

[0037] As used herein, the term "optionally substituted" means that 1-6 hydrogen atoms in a given structure are replaced by a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH2-O alkyl. Preferably, "optionally substituted" means that 1-4 hydrogen atoms in a given structure are replaced by the substituents mentioned above. More preferably, 1-3 hydrogen atoms are replaced by the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0038] As used herein, the term “substituted” refers to a portion of one or more carbons in the main chain that has a substituent replacing hydrogen. It should be understood that “substitution” or “substituted” includes implicit limitations, namely that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is used to encompass all permissible substituents in organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in organic compounds that satisfy the heteroatom valences described herein.

[0039] Substituents may include any substituents described herein, such as, unless otherwise specified, halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, phosphonites, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate esters, sulfonates, aminesulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, heteroaryl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the substituents themselves may be substituted where appropriate. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, azide, imino, amide, phosphoryl (including phosphonates and phosphonites), sulfonyl (including sulfates, sulfonamides, aminesulfonyls, and sulfonates), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylic acids, and esters), -CF3, -CN, and similar groups. Unless specifically stated as "unsubstituted," references to the chemical term herein should be understood to include substituted variants. For example, references to the "aryl" group may implicitly include both substituted and unsubstituted variants.

[0040] As used herein, the term "alkyl" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10, and may be, for example, C1-C2. 10 Alkyl groups or, for example, C1-C6 alkyl groups. Examples of straight-chain 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, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl and similar groups. Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent replacing one or more hydrogen atoms on the hydrocarbon backbone. "Alkyl" may optionally be substituted.

[0041] Term "C" x -C y When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it is intended to include groups containing x to y carbons in the chain. For example, the term "C x -C y "" refers to substituted or unsubstituted saturated hydrocarbon groups containing x to y carbons in the chain, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl indicates hydrogen when the group is at the end position, and indicates a single bond when it is inside.

[0042] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms, which does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and a major carbon backbone, but may optionally include heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on its connecting carbon) and ethoxy (which is linked by oxygen rather than carbon) are not. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof. The "hydrocarbon group" may optionally be substituted.

[0043] As used herein, the term "alkoxy" refers to a straight-chain or branched, saturated aliphatic (alkyl) hydrocarbon group bonded to an oxygen atom attached to a core structure. Preferably, the alkoxy group has 1-6 carbon atoms, i.e., a C1-C6 alkoxy group. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and similar groups. "Alkoxy" may optionally be substituted.

[0044] As used herein, the term "alkoxyalkyl" refers to an alkoxy-substituted alkyl group (as defined above) and may be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethylidene and ethyl-O-ethylidene. "Alkoxyalkyl" may optionally be substituted.

[0045] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogens. For example, a monohaloalkyl group may have chlorine, bromine, iodine, or fluorine atoms. Dihaloalkyl and polyhaloalkyl groups may have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to: chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and similar groups. "Haloalkyl" may optionally be substituted.

[0046] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3). "Haloalkoxy" may optionally be substituted.

[0047] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon atom. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (fused rings), at least one of which is aromatic; for example, the other ring may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. The term "fused" refers to the connection or formation of a second ring by sharing two adjacent atoms with a first ring. The term "fused" is equivalent to the term "condensation." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrene, phenol, aniline, or dihydroindenyl and similar groups. Unless otherwise specified, all aryl groups described herein may optionally be substituted.

[0048] As used herein, the terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) in which one or more atoms are shared by two adjacent rings, such as "fused rings." Each ring in a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring in a polycyclic compound contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0049] As used herein, the term "acyl" refers to the group -C(=O)-R. w , where R wAlkyl groups that are optionally substituted. Examples of "acyl" include, but are not limited to: wherein R w For C1-C 10 Alkyl (C1-C) 10 Acyl) or C1-C 6- In the case of alkyl (C1-C6 acyl) groups, in some embodiments, the optionally substituted substituents are selected independently each time they appear: 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.

[0050] As used in this article, the term "formyl" refers to the group -C(=O)H.

[0051] As used herein, the terms "sulfonamide" and "sulfonamido" are denoteed as follows: or Where R x R y and R z Each time it appears, it independently represents hydrogen, an optionally substituted hydrocarbon group, or R. z The group, together with the N atom it is attached to, forms a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0052] As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and their salts, for example, as can be represented by the following portions: or , Where R z Independently representing hydrogen or optionally substituted hydrocarbon groups, or R z The group, together with the N atom it is attached to, forms a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0053] As used herein, the terms "amide" and "amide group" each refer to a group represented by the following: or , Where R x R y and R z Each independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R z Together with the N atom it is attached to, it forms a heterocycle with 4-8 atoms in the ring structure, which can be optionally substituted.

[0054] As used herein, the term "amidinium" refers to a group represented by: Where R x R y and R z Each independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R z The group, together with the N atom it is attached to, forms a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0055] As used herein, the term "phosphine oxide" refers to a group represented by the following: Where R z Each can be represented independently as hydrogen or an optionally substituted hydrocarbon group.

[0056] As used herein, the term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group.

[0057] As used herein, the term "amide-alkyl" refers to an alkyl group that has been substituted with an amide group.

[0058] As used herein, the term "cyanoalkyl" refers to an alkyl group that has been substituted with a cyano group.

[0059] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkyl-S-.

[0060] As used herein, the term "thioalkyl" refers to an alkyl group that has been substituted with a thiol group.

[0061] As used herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0062] As used herein, the term "cycloalkyl," alone or in combination with other terms, refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic hydrocarbons. Typically, unless otherwise defined, monocyclic cycloalkyl groups have 3 to approximately 10 carbon atoms, more commonly 3–8 carbon atoms (e.g., C3–C4). 10 cycloalkyl or, for example, C 3-C6 cycloalkyl. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similar groups. The second or third ring of a bicyclic or tricyclic cycloalkyl group may be self-saturated, unsaturated, or aromatic. Cycloalkyl groups include bicyclic and tricyclic molecules in which one, two, three, or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl group in which each ring shares two adjacent atoms with the other ring. The second or third ring of a fused bicyclic or tricyclic cycloalkyl group may be self-saturated, unsaturated, or aromatic. "Cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and similar groups. Cycloalkyl groups may alternatively be polycyclic with more than two rings. Examples of polycyclic cycloalkyl groups include bridged, fused, and spirocyclic carbocyclic groups.

[0063] As used herein, the term "cycloalkylalkyl" refers to an alkyl group that has been substituted with a cycloalkyl group.

[0064] As used herein, the term "carbocyclic" or "of a carbocyclic" includes bicyclic molecules in which the two rings share one, two, three, or more atoms. The term "fused carbocyclic" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. The rings of a fused carbocyclic ring may be self-saturated, unsaturated, or aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused with 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 ring where valence permits. Exemplary "carbocyclic" includes cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decahydronaphthalene, 4,5-naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, and 4,5,6,7-tetrahydro-1 H -Indene and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” can be substituted at any one or more positions capable of carrying hydrogen atoms.

[0065] As used in this article, the term "cyano" refers to the -CN group.

[0066] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0067] As used herein, the term “halogen” or “halogen” alone or in combination with other terms refers to chlorine, fluorine, bromine, and iodine.

[0068] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0069] As used herein, the terms “heterocyclic,” “heterocyclic alkyl,” “heterocycle,” and “heterocyclic” refer to a non-aromatic, saturated, or partially saturated ring system having 3 to 15 members, including monocyclic, polycyclic (e.g., bicyclic, tricyclic) bridged or fused rings, wherein the members have at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclic groups" include, but are not limited to: azacyclic butyl, oxacyclic butyl, imidazoalkyl, pyrrolyl, oxazolyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl, indololinyl, indololinylmethyl, 2-azabicyclo[2.2.2]octyl, acrylyl, chromyl, oxanthyl and their N-oxides. The connection of heterocyclic alkyl substituents can occur via carbon atoms or via heteroatoms. Heterocyclic alkyl groups may optionally be substituted by one or more of the aforementioned groups via one or more suitable groups. Preferably, "heterocyclic group" refers to a 4-6 membered ring selected from the following: azirrobutyl, oxacyclobutyl, imidazoalkyl, pyrrolyl, oxazolyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxane and their N-oxides. More preferably, "heterocyclic group" includes azirrobutyl, pyrrolyl, morpholinyl and piperidinyl. All heterocyclic groups are optionally substituted with one or more of the aforementioned groups.

[0070] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic structure, preferably a 5-7 membered ring, more preferably a 5-6 membered ring, whose ring structure includes at least one heteroatom, preferably 1-4 heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), containing 8-20 ring atoms, suitably 5-10 ring atoms, which may be covalently linked or fused, wherein two or more atoms are shared by two adjacent rings, wherein at least one of these rings is heteroaromatic, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. These rings may contain N or S atoms, wherein the N or S atom is optionally oxidized, or the N atom is optionally quaternized. All heteroaryl groups are optionally substituted. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryl groups include, but are not limited to: furanyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazoleyl, oxazolyl, cyclolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothiopheneyl, benzotriazinyl, phthalazinyl, thiaanthracene, dibenzofuranyl, dibenzothiopheneyl, benzimidazolyl, indoleyl, isoindoleyl, indazoleyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purineyl, pteridinyl, 9 H -Carbazolyl, α-carbazoline, indoleazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanopyridyl, purinel, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothiadiazolyl, 7-azaindolyl, 7-azaindolyl, pyrrolopyridyl, pyrrolopyrimidinyl, oxazolinone pyridyl, oxazolinone pyrimidinyl, imidazolinone pyridyl, imidazolinone pyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, tetrahydronaphridyl, tetrahydropyridinephenol pyrimidinyl, dihydronaphridinone, naphridinone, oxazinone pyridyl, oxazinone pyrimidinyl, carbazolyl, dibenzothiaphenyl, acridinel and similar groups.

[0071] As used herein, the terms "sulfonyl" or "sulfonyl" refer to the group -S(O)2-R. 6d , where R 6d This indicates a hydrocarbon group that is optionally substituted.

[0072] As used in this article, When valence allows, the inner ring refers to a single or double bond that leads to the formation of a stable ring portion.

[0073] "Combination therapy" refers to treatment that involves administering two or more therapeutic agents, such as the compounds of this invention and MAPK pathway inhibitors, to a patient in need.

[0074] The terms “disease,” “symptom,” and “condition” can be used interchangeably in this article.

[0075] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds described herein can be administered not only to mammals such as humans but also to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, and similar animals), agricultural animals (e.g., cows, sheep, pigs, horses, and similar animals), and laboratory animals (e.g., rats, mice, guinea pigs, and similar animals).

[0076] The MAPK pathway used in this paper is a signal transduction pathway that includes RAS→RAF→MEK→ERK.

[0077] "MAPK pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120, encofenib), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996, ERAS-007). The terms "MAPK pathway inhibitor" and "MAPK kinase inhibitor" are used interchangeably in this document.

[0078] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that, when properly administered to animals or humans, do not produce adverse, allergic, or other undesirable reactions. For human use, formulations should meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA Office of Biologics Standards.

[0079] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutical acceptable excipient” refer to any and all solvents, dispersion media, coatings, isotonics, absorption delay agents, and the like that compatible with drug administration. The use of these media and agents for the active pharmaceutical ingredient is well known in the art. Compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0080] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0081] As used herein, the term "pharmaceutically acceptable salt" refers to a salt having acidic or basic groups that may be present in the compounds used in the composition. The compounds included in the compositions of this invention, which are inherently basic, are capable of forming a wide variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to: malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronide, glucosidate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate). The compounds included in the compositions of this invention, which are inherently acidic, are capable of forming basic salts with a variety of pharmacologically 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. The compounds included in the compositions of this invention, including basic or acidic portions, can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or basic salts.

[0082] The compounds disclosed herein may contain one or more chiral centers and thus exist in stereoisomer form. The term "stereoisomer," as used herein, comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereoforming carbon atom, these compounds may be designated by the symbol "R" or "S," but those skilled in the art will recognize that the structure may implicitly represent the chiral center. These compounds may also be designated by "(+)" and "(-)" based on their optical rotational properties. The compounds described in this invention encompass various stereoisomers of these compounds and mixtures thereof. Enantiomers or mixtures of diastereomers may be designated by the symbol "(±)" in the nomenclature, but those skilled in the art will recognize that the structure may implicitly represent the chiral center.

[0083] In this specification, the term "therapeuticly effective amount" refers to the amount of the compound of the invention that researchers, veterinarians, medical professionals, or other clinicians are seeking to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human). The compounds described herein are administered in therapeutically effective amounts to treat a condition.

[0084] "Treatment" includes any action that causes improvement in a condition, disease, symptom, etc., such as reducing, decreasing, regulating, or eliminating it.

[0085] This invention also covers isotopically labeled compounds consistent with those described herein, except that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively as follows: 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, compounds disclosed herein may have one or more deuterated H atoms.

[0086] Individual enantiomers and diastereomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by analytical methods well known to those skilled in the art. These analytical methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, with the auxiliary agent releasing an optically pure product; (2) forming a salt using an optically active analytical agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) performing kinetic analysis using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved to their constituent enantiomers by well-known methods such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis of unequal mixtures of stereoisomers formed by chemical or enzymatic reactions during the generation of new stereocenters or during the transformation of pre-existing stereocenters is well known in the art. Stereoselective synthesis encompasses both enantiomeric 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.

[0087] As used herein, “compounds of the present disclosure” includes compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof.

[0088] compound In some embodiments, this document provides a compound represented by formula IA: Formula IA, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 -LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 5 and X 6 Each is independently selected from: CH, CF, and N; X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 1 X 2 X 3 and X 4 No more than two of them are N; Its constraint is X 5 and X 6 No more than one of them is N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; Its restriction condition is when X 2 When X is N, 3 For CQLE, CLE, N, or CH; Its restriction condition is when X 3 When X is N, 2For N, CH or CN(R) 4 )-LE; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, and cyano; and m can be 0, 1, 2, 3, or 4. Its restrictions are: When X 2 Let N, X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 When the other two are CH, R 2 Not H; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5For CF3, X 2 Let N be the number of elements, and X be the number of elements. 1 and X 4 When it is CH, X 3 Not for , or .

[0089] In some embodiments, this document provides a compound represented by formula IB: Formula IB Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 -LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 3 and X 4 No more than one of them is N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 2 Let N, X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 When the other two are CH, R 2 Not H; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 For CF3, X 2 Let N be the number of elements, and X be the number of elements. 1 and X 4 When it is CH, X 3 Not for , or .

[0090] In some embodiments, this document provides a compound represented by formula IC: IC type Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4); X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 1 X 3 and X 4 When it is CH, X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 The other two are CH and R. 2Not H; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 It is CF3, and X 1 and X 4 When it is CH, X 3 Not for , or .

[0091] In some embodiments, this document provides a compound represented by formula ID: Formula ID, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 It is CF3, and X 1 and X 4 When it is CH, QLE is not , or .

[0092] In some embodiments, this document provides a compound represented by the formula IE: Formula IE, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; and When X 7 X 8 and X 9 One of them is N and X 7 X 8 and X 9 When the other two are CH, R 2 Not H.

[0093] In some embodiments, this document provides a compound represented by the formula IF: Formula IF, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 -LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 5 and X 6 Each is independently selected from: CH, CF, and N; X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 1 X 2 X 3 and X 4 No more than two of them are N; Its constraint is X 5 and X 6 No more than one of them is N; Its constraint is X 7 and X 9 No more than one of them is N; Its restriction condition is when X 2 When X is N, 3 For CQLE, CLE, N, or CH; Its restriction condition is when X 3 When X is N, 2 For N, CH or CN(R) 4 )-LE; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 2 Let N be the number of elements, and X be the number of elements. 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 and X 9 One of them is N and X 7 and X 9 When the other is CH, R 5 Not H; and When X 7 and X 9 For CH, R 5 For CF3, X 2 Let N be the number of elements, and X be the number of elements.1 and X 4 When it is CH, X 3 Not for , or .

[0094] In some embodiments, this document provides a compound represented by the formula IG: IG style Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 7 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 2 Let N be the number of elements, and X be the number of elements. 7 and X 9 When it is CH, R 5Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 and X 9 One of them is N and X 7 and X 9 When the other is CH, R 5 Not H; and When X 7 and X 9 It is CH, and R 5 When it is CF3, X 3 Not for , or .

[0095] In some embodiments, this document provides a compound represented by the formula IH: Formula IH, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 7 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 7 and X 9 For CH and R 5 When it is CF3, QLE is not , or .

[0096] In some embodiments, this document provides a compound represented by formula IJ: Formula IJ, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 7 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 7 and X 9 When it is CH, R 5 Not N(CH3)2; and When X 7 and X 9One of them is N and X 7 and X 9 When the other is CH, R 5 Not H.

[0097] In some embodiments, this document provides a compound represented by the formula IK: Formula IK, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: O and N(R) 4 ); R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4.

[0098] In some embodiments, this document provides a compound represented by the formula IL: Formula IL, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4.

[0099] In some embodiments, this document provides a compound represented by the formula IM: IM style Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4.

[0100] In some implementation schemes, X 1 For CH.

[0101] In some implementation schemes, X 2 Let N be the number of elements in the array.

[0102] In some implementation schemes, X 3 Selected from: N, CH, COLE and CN(R) 4 )-LE.

[0103] In some implementation schemes, X 3 Selected from: N and CH.

[0104] In some implementation schemes, X 3 Selected from: CO-CH(R) 4 )-CH2-OH and C-NH-CH(R 4 )-CH2-OH.

[0105] In some implementation schemes, X 5 For CH.

[0106] In some implementation schemes, X is included 2 X 3 X 4 and X 5 The ring is selected from: and Where s1 indicates a connection to N and R 3 The replacement ring, and s2 indicates connection to the ring containing X. 5 and X 6 The ring.

[0107] In some implementation schemes, X 5 For CH.

[0108] In some implementation schemes, X 6 For CH.

[0109] In some implementation schemes, X 7 Let N be the number of elements in the array.

[0110] In some implementation schemes, X 8 For CR 5 .

[0111] In some implementation schemes, R 5 Selected from: alkyl, cycloalkyl, haloalkyl and halogen.

[0112] In some implementation schemes, X 9 For CH.

[0113] In some implementation schemes, R 1 Selected from: alkyl and halogens.

[0114] In some implementation schemes, R 1 Selected from: methyl.

[0115] In some implementation schemes, R 2 Selected from: H, halogens, alkyl groups, alkoxy groups, amines, and haloalkyl groups.

[0116] In some implementation schemes, R 2 Selected from: trifluoromethyl and H.

[0117] In some implementation schemes, R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms is formed in the ring structure, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence.

[0118] In some implementations, it contains (R 3 ) m The ring is selected from: and .

[0119] In some implementations, it contains (R 3 ) m The ring is selected from: and . In some implementations, it contains (R 3 ) m The ring is .

[0120] In some implementation schemes, R 4 For H.

[0121] In some implementation schemes, R 5 Selected from: H, alkyl, alkenyl, alkoxy, amine, amide, haloalkyl, cycloalkyl, phosphine oxide, halogen, haloalkoxy, cyano and cyanoalkyl.

[0122] In some implementation schemes, R 5 Selected from: H, trifluoromethyl, isopropyl, cyclopropyl, cyclobutyl, alkenyl, cyano, chlorine, bromine, and .

[0123] In some implementation schemes, R 5 Selected from: trifluoromethyl, cyclopropyl and .

[0124] In some implementation schemes, R 5 It is trifluoromethyl.

[0125] In some embodiments, L is an optionally substituted C1-C6 alkyl group.

[0126] In some implementation schemes, L is selected from: and .

[0127] In some implementation schemes, L is selected from: and .

[0128] In some implementations, E is selected from: H, methyl, cyclopropyl, and hydroxyl.

[0129] In some implementation schemes, the compound is selected from: And its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers.

[0130] Treatment The compounds described herein (e.g., compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers) can act as dual RAF and tubulin inhibitors and are therefore suitable for treating diseases and conditions in patients in need, 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, hematogenous 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 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 a RAS Q61R or Q61K mutation. 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. In some embodiments, the lung cancer is non-small lung cancer (NSCL). In some embodiments, the colorectal cancer is colon cancer. In some embodiments, the colorectal cancer is rectal cancer.

[0131] The compounds described herein can provide doses with optimal pharmaceutical efficacy for administration to patients (animals and humans) requiring this treatment. It should be understood that the dose required for any particular application will vary from patient to patient, not only with the specific compound or composition chosen, but also with the route of administration, the nature of the condition being treated, the patient's age and condition, concurrent drug therapy, or any special diet followed by the patient, and other factors that will be recognized by those skilled in the art. The appropriate dose is ultimately determined by the attending physician. For the treatment of the clinical conditions and diseases mentioned above, the compounds described herein can be administered orally, subcutaneously, topically, non-enterally, by inhalation spray, or rectally in dosage form containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, and mediators. Non-enteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0132] Treatment can be continued for extended or shorter periods as needed. The composition can be administered, for example, once to four times daily or more. Suitable treatment durations may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinite. Treatment may be terminated when the desired results are achieved.

[0133] Combination therapy The compounds described herein, such as compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, may be administered in combination with one or more additional therapeutic agents to treat the conditions described herein, such as cancers. For example, this disclosure provides a pharmaceutical composition comprising the compounds described herein, such as compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof; one or more additional therapeutic agents; and a pharmaceutically acceptable excipient. In some embodiments, a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, or IM, or a pharmaceutically acceptable salt thereof, an enantiomer, stereoisomer, or tautomer, and an additional therapeutic agent are administered. In some embodiments, a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, or IM, or a pharmaceutically acceptable salt thereof, an enantiomer, stereoisomer, or tautomer, and two additional therapeutic agents are administered. In some embodiments, a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, or IM, or a pharmaceutically acceptable salt thereof, an enantiomer, stereoisomer, or tautomer, and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each formulated and administered separately. For example, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, and IM, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, along with additional therapeutic agents, can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in the form of a single formulation, such as a pharmaceutical composition comprising compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, and IM, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, as one therapeutic agent and one or more additional therapeutic agents, such as MAPK pathway inhibitors or chemotherapeutic agents.For example, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, along with additional therapeutic agents, may be administered as a single formulation. Combination therapy also encompasses other combinations. Although two or more agents in a combination therapy may be administered simultaneously, this is not always the case. For example, the administration of the first agent (or combination of agents) may precede the administration of the second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the administration of two or more agents may occur 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, 9, 10, 12, or 9 weeks of each other. In some cases, even longer time intervals are possible. While in many cases, the two or more drugs used in combination therapy need to be present in the patient's body simultaneously, this is not always the case.

[0134] Combination therapy may also include two or more administrations of one or more of the drugs used in combinations of component drugs in different sequences. For example, if drug X and drug Y are used together, they can be administered one or more times in any combination sequence, such as XYX, XXY, YXY, YYX, XXYY, etc.

[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, immunomodulation enhances adaptive immune responses. In some embodiments, immunomodulation enhances the activity of antigen-presenting cells. In some embodiments, immunomodulators enhance the antitumor activity of bone marrow cells, including macrophages. In some embodiments, immunomodulation enhances the antitumor activity of natural killer cells. In some embodiments, immunomodulators enhance the activity of effector T cells, including cytotoxic T cells.

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

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

[0139] In some implementations, the additional therapeutic agent may be an immunomodulatory agent, including but not limited to: anti-PD-1 or anti-PD-L1 therapeutic agents, including pembrolizumab, nivolumab, pidilizumab, cemiplimab, atezolizumab, durvalumab, BMS-936559, or avelumab. In some embodiments, the additional therapeutic agent may be an anti-TIM3 (anti-HAVcr2) therapeutic agent, including but not limited to: TSR-022 or MBG453; an anti-LAG3 therapeutic agent, including but not limited to: relatlimab, LAG525, or TSR-033; an anti-4-1BB (anti-CD37, anti-TNFRSF9); a CD40 agonist therapeutic agent, including but not limited to: SGN-40, CP-870, 893, or RO7009789; an anti-CD47 therapeutic agent, including but not limited to: Hu5F9-G4; an anti-CD20 therapeutic agent; an anti-CD38 therapeutic agent; or a STING agonist, including but not limited to: ADU-S100, MK-1454, ASA404, or amide benzimidazole. In some embodiments, the additional therapeutic agent may be an anti-CTLA4 agent, including ipilimumab and tremelimumab. In some implementations, the additional therapeutic agent may be a hypomethylating agent, including but not limited to azacytidine or decitabine, and other immunomodulatory agents, including but not limited to: epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some implementations, the additional therapeutic agent may be an immunotherapeutic agent, including targeted therapies, cancer vaccines, and CAR-T cell therapy.

[0140] The compounds described herein can be administered in combination with other known therapeutic agents used to treat cancer. These other therapeutic agents include radiotherapy, anti-microtubule agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, anti-estrogens, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 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, the additional therapeutic agent may be a chemotherapeutic agent, including but not limited to: anti-microtubule agents (e.g., paclitaxel, paclitaxel protein-binding particles for injectable suspensions, including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, and DNA alkylating agents (including but not limited to: cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide). mozolomide), DNA intercalation agents, or DNA topoisomerase inhibitors (including but not limited to anthracyclines such as doxorubicin, pegylated lipid doxorubicin, donomycin, idarubicin, mitoxantrone or epirubicin, camptothecin such as topotecan, irinotecan or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate).

[0142] In some implementations, the additional treatment agent may be a kinase inhibitor, including but not limited to: erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, and temsirolimus. mus), abemaciclib, LEE011, palbociclib, cabozantinib, ripretinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ederaris, ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib.

[0143] In some implementations, these additional therapeutic agents may be anti-estrogens, including but not limited to: tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; and anti-androgens, including but not limited to: abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate. Acetate); steroid medications, including but not limited to: prednisone and dexamethasone; PARP inhibitors, including but not limited to: neraparib, olaparib, talazoparib, and rucaparib; topoisomerase I inhibitors, including but not limited to: irinotecan, camptothecin, ezeticotin, and toponotecan; topoisomerase II inhibitors, including but not limited to: anthracycline, etoposide, etoposide phosphate, and mitoxantrone; histone deacetylase (HDAC) inhibitors, including but not limited to: vorinostat. Romidesin, 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 biologics, including but not limited to trastuzumab, ADO-trastuzumab, pertuzumab, cetuximab, and panitumumab.

[0144] In some implementations, the additional therapeutic agent may be an anti-angiogenic agent, including but not limited to: bevacizumab, rebastinib, aflibercept, and AMG386.

[0145] In some implementations, the additional therapeutic agent may be an antibody-drug conjugate (ADC), including but not limited to ADCs containing DM1, DM4, MMAE, MMAF or camptothecin, brentuximab vedotin and trastuzumab emtansine, radiotherapy, and therapeutic vaccines including but not limited to Sipuleucel-T.

[0146] In some embodiments, the additional therapeutic agent may be an autophagy inhibitor, a vesicle transport inhibitor, including but not limited to ULK inhibitors such as ULK1 inhibitors, ULK2 inhibitors, ULK1 / ULK2 inhibitors, VPS34 inhibitors, PPT1 inhibitors, or lysosomal blockers. In some embodiments, the additional therapeutic agent may be DCC-3116, SAR405, SB02024, hydroxychloroquine, chloroquine, and LYS05.

[0147] In some implementations, the additional therapeutic agent may be an EGFR inhibitor, including but not limited to cetuximab, osimertinib, and afatinib, and pharmaceutically acceptable salts thereof.

[0148] In some implementations, the additional treatment agent is selected from luteinizing hormone-releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0149] In some implementations, the additional treatment agent is selected from: 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, Oregomab, Lep-etu, Nolatrexed, AZD 2171, Batabulin, Ofatumtunab, Zanolimumab, Eotecarin, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Ticilimumab, Ipilimumab, Gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanthone, LY 317615, Neuradiab, Vitespan, RTA744, Alanosine (SDX 102), Talampanel, Atrasentan, XR 311, Romidipsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, DoxorubicinIrinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (Dixem), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolinone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate Acetate), CP-724714, TAK-165, HKI-272, Erlotinib, Lapatinib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, Tipifarnib, Amifostine, NVP-LAQ824, Suberoyl Analide Hydroxamic Acid, Valproic Acid, Trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginaseBCG vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, cisplatin, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin Diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan Melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotan, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexate trexed), rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoids, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, fluorouracil, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycinCalcitriol, Valrubicin, Mitramycin, Vincristine, Vinorelbine, Topotecan, Razoxin, Marimastat, COL-3, Neovastat, BMS-275291, Squalamine, Endothelial Somatostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiotensin II, Vitaxin, Droloxifen, Idoxyfene, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denileukin Diftitox, gefitinib, bortezomib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclovir), erbitux, paclitaxel (without cetyl alcohol polyoxyethylene ether), and epihilone. B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, azoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, 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, Wortmannin, ZM336372, L-779450, PEG-Figrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, ZolendronatePrednisone, 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, Dexpromethazine, Alemtuzumab, All-trans Retinoic Acid, Ketoconazole, Interleukin-2, Medroxyprogesterone acetate, Immunoglobulin, Nitrogen Mustard, Methylprednisolone, Ibritumomab Tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotin, tositumomab, arsenic trioxide, corticosteroids, editronate, mitotane, cyclosporine, liposomal donomycin, edwina-asparaginase, strontium-89, caspopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine Metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilimumab and mixtures thereof.

[0150] Pharmaceutical Compositions and Kits Another aspect of the invention provides pharmaceutical compositions comprising compounds as disclosed herein formulated with a pharmaceutically acceptable carrier. Specifically, this disclosure provides a pharmaceutical composition comprising compounds disclosed herein (e.g., compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof) formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, non-intestinal (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or nebulized administration; however, in any given case, the most suitable form of administration will depend on the extent and severity of the condition being treated and on the nature of the particular compound used. For example, the compositions of this disclosure may be formulated in unit dose form and / or may be formulated for oral or subcutaneous administration.

[0151] Exemplary pharmaceutical compositions may be used in pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more of the compounds described herein as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or non-enterogonal administration. The active ingredient may be formulated, for example, with a commonly used, non-toxic, pharmaceutically acceptable carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form of use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0152] For the preparation of solid compositions such as lozenges, the main active ingredient may be mixed with a drug carrier (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other drug diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the compounds described herein or their non-toxic, pharmaceutically acceptable salts. When these preformed 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 further divided into equally effective unit dosage forms, such as lozenges, pills, and capsules.

[0153] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules and the like) for oral administration, the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any one of the following substances: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; 3) Humectants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption enhancers, such as quaternary ammonium compounds; (7) Wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) Colorants. In the case of capsules, tablets and pills, the composition may also contain buffers. Excipients such as lactose and high molecular weight polyethylene glycol and the like may also be used as fillers in soft-filled and hard-filled gelatin capsules.

[0154] Tablets can be manufactured by compression or molding, optionally together with one or more auxiliary components. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be manufactured by molding a mixture of the compositions of the invention moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules can optionally be scored or coated and shelled with coatings such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

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

[0156] In addition to the compositions of the present invention, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyethylene oxide sorbitol and dehydrated sorbitol ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragacanth gum and mixtures thereof.

[0157] Formulations for rectal or vaginal administration may be presented in suppository form, which may be prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and thus will melt in the body cavity and release the active agent.

[0158] Dosage forms for transdermal application of the compositions of the present invention include: powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredients may be mixed under aseptic conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required.

[0159] In addition to the compositions of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0160] In addition to the compositions of this invention, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0161] The compositions and compounds of the present invention can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Acoustic nebulizers can be used because they minimize the exposure of the agent to shear forces that could lead to degradation of the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are manufactured by formulating an aqueous solution or suspension of the compositions of the present invention with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the specific composition of the present invention, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol); harmless proteins such as serum albumin; dehydrated sorbitol esters; oleic acid; lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0162] The pharmaceutical compositions of the present invention suitable for non-enteral administration comprise the composition of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use. These sterile powders may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0163] Examples of 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, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate), and cyclodextrins. Appropriate flowability can be achieved, for example, by using a coating material such as lecithin, and by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0164] In another embodiment, an enteric pharmaceutical formulation is provided, comprising the compounds of this disclosure, an enteric-coated material, and a pharmaceutically acceptable carrier or excipient thereof. An enteric-coated material is a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5.

[0165] Therefore, the enteric material is insoluble, for example up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include: cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose succinate (HPMCAS); cellulose trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose hexahydrophthalate; cellulose propionate; cellulose maleate; cellulose acetate butyrate; cellulose propionate; copolymers of methyl methacrylate and methyl methacrylate; methyl acrylate, methyl methacrylate and methacrylate copolymers; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers; natural resins such as corn gluten, shellac and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit...). FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be readily determined in vitro. The foregoing materials are a list of possible materials, but those skilled in the art will recognize that this list is incomplete and that other enteric-coated materials exist that satisfy the objectives described herein.

[0166] Advantageously, this document provides kits for use by consumers, for example, who require treatment for cancer. These kits include suitable dosage forms such as those described above; and instructions describing methods of using the dosage form to mediate, reduce, or prevent inflammation. The instructions will guide the consumer or medical professional to administer the dosage form according to administration methods known to those skilled in the art. These kits can advantageously be packaged and sold in single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging drug unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a relatively rigid material sheet covered with a foil, preferably of a transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the relatively rigid material sheet is sealed against the plastic foil at the foil side opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet is strong enough that pressure can be manually applied to the groove to create an opening in the sheet at the groove location, allowing removal of the tablet or capsule from the blister pack. The tablet or capsule can then be removed through this opening.

[0167] Memory aids may need to be provided on the kit, for example, in the form of numbers immediately preceding the tablets or capsules, corresponding to the number of days in the regimen for which the prescribed tablets or capsules should be taken. Another example of such memory aids is a schedule printed on a card, such as "Week 1, Monday, Tuesday, ... etc.; Week 2, Monday, Tuesday, ... etc." Other variations of memory aids are self-evident. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a specified date. Furthermore, the first compound of the daily dose may consist of one tablet or capsule, while the second compound of the daily dose may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0168] Example The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the following description of the synthetic methods, it should be understood that, unless otherwise stated, all reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) proposed are standard conditions for the reaction. Those skilled in organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art, and therefore alternative methods are indicated. The starting materials in the examples are commercially available or readily prepared from known materials using standard methods.

[0169] The following abbreviations are used in this invention and have the following definitions: "ADP" is adenosine diphosphate, "AgNO3" is silver nitrate, "aq" is aqueous solution, "ATP" is adenosine triphosphate, "Ar" is argon, "B2pin2" is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane), "BAST" is bis(2-methoxyethyl)aminothiotrifluoride, "BINAP" is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, "Boc" is tert-butyl carbonate, "BSA" is bovine serum albumin, "CaCl2" is calcium chloride, and "cataCXiumA-Pd-G2" is chloro[(di(1-adamantyl)- N [-Butylphosphine)-2-(2-aminobiphenyl)]palladium(II), "CDCl3" is chloroform-deuterium, "Cs2CO3" is cesium carbonate, "DAST" is diethylaminosulfur trifluoride, "DCE" is 1,2-dichloroethane, "DCM" is dichloromethane, and "DIEA" is... N , N -Diisopropylethylamine, "DMF" is N , N -Dimethylformamide, "dppf" is 1,1'-bis(diphenylphosphino)ferrocene, "DMSO-d6" is dimethyl sulfoxide-deuterium, "DSC" is... N , N' - Disuccinyl imino carbonate, "DTT" is dithiothreitol, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" is electrospray ionization, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is hours, "HATU" is tetramethyluronium hexafluorophosphate, "H2" is hydrogen, "HCl" is hydrochloric acid, "H2O" is water, "H2O2" is hydrogen peroxide, "HOBT" is 1H-benzo[d][1,2,3]triazol-1-ol, "HPLC" is high performance liquid chromatography, "IC 50 "Half-maximum inhibition concentration", "iso-PrOH" is isopropanol, "K2CO3" is potassium carbonate, "LiHMDS" is lithium bis(trimethylsilyl)amino, "LiOH" is lithium hydroxide, "MeCN" is acetonitrile, "MeOH" is methanol, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is min, "MS" is mass spectrometry, "m / z" is mass / charge number, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, "NaHCO3" is sodium bicarbonate, "Na2CO3" is sodium carbonate, "NaOAc" is sodium acetate, "Na2SO4" is sodium sulfate, "NH4Cl" is ammonium chloride, "NH4OH" is ammonium hydroxide, "NMP" is...N -Methylpyrrolidone, "NMR" stands for Nuclear Magnetic Resonance, "PBS" stands for Phosphate-Buffered Saline, "Pd" stands for Palladium, "Pd-C" stands for Palladium / Carbon, "Pd2(dba)3" stands for Tris(diphenylmethyleneacetone)dipalladium(O), "pet-ether" stands for Petroleum Ether, "PPh3" stands for Triphenylphosphine, "rt" stands for Room Temperature, also known as "Ambient Temperature," which should be understood as a series of normal laboratory temperatures within the range of 15-25°C, "sat'd." stands for Saturated, "SFC" stands for Supercritical Fluid Chromatography, "SM" stands for Starting Material, "S N "Ar" represents nucleophilic aromatic substitution, "T3P" represents 1-propane phosphoric anhydride, "TBDMS" represents tert-butyldimethylsilyl, "TCFH" represents N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate, and "TEA" represents triethylamine. tert "-BuONa" stands for sodium tert-butoxide, "TFA" stands for trifluoroacetic acid, "THF" stands for tetrahydrofuran, "TLC" stands for thin-layer chromatography, "Tris" stands for tris(hydroxymethyl)aminomethane, and "Xantphos" stands for 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene.

[0170] General chemical reactions The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the following schemes, intermediate preparations, and examples.

[0171] Synthesis scheme Option 1 Scheme 1 illustrates an exemplary preparation of boronic esters 1-4. Amine 1-1 (commercially available or synthesized by those skilled in the art) reacts with carboxylic acid 1-5 (commercially available or synthesized by those skilled in the art) to give amide 1-2. Compound 1-2, upon borylation, provides boronic ester 1-4. Borylation is, to those skilled in the art, a well-documented reaction (e.g., a Pd(0)-catalyzed reaction with B2pin2). Alternatively, boronic ester 1-4 can be prepared by amide coupling reaction of 1-3 (commercially available or synthesized via Pd-catalyzed 1-1 borylation) with carboxylic acid 1-5 in the presence of a coupling agent (such as HATU, T3P, and EDC).

[0172] Option 2 Scheme 2 illustrates the exemplary preparation of intermediates 2-7a, 2-7b, 2-7c, and 2-7d. Commercially available compound 2-1 is reacted with various morpholines (commercially available or synthesized by those skilled in the art) via S... N The Ar reaction occurs in the presence of a base to yield 2-2. Compound 2-2 (Y=F) reacts with alcohols EL-OH or amines ELN(R)4 H through S N The Ar reaction occurs in the presence of a base to yield 2-4(Q=O, N(R)). 4 In another embodiment, compound 2-1 is reacted with alcohol EL-OH or amine ELN(R). 4 H through S N The Ar reaction occurs in the presence of bases such as DIEA, K2CO3, or NaH, yielding 2-3(Q = O, N(R)). 4 In a similar manner, 2-3 are reacted with various morpholines (commercially available or synthesized by those skilled in the art) with S. N Ar reaction yields 2-4(Q = O, N(R) 4 Finally, iodides 2-4 were treated with borate esters 1-3 in the presence of a palladium catalyst (Suzuki reaction) to obtain 2-7a (X). 3 = COLE), 2-7b(X) 3 = CN(R 4 )-LE). Intermediate 2-7c(X) 3 = CH) and 2-7d(X) 3 = C-alkyl) can be prepared by the Suzuki reaction of 2-2 (Y = H, alkyl) with borate esters 1-3. In another embodiment, borate ester 2-5 is reacted with bromide 1-1 under Suzuki conditions to give 2-6, which can be reacted with various morpholines (commercially available or synthesized by those skilled in the art) via S N The Ar reaction occurs in the presence of a base to obtain 2-7c(X). 3 = CH) and 2-7d(X) 3 = C alkyl).

[0173] Option 3 Scheme 3 illustrates an exemplary preparation of intermediates 3-7 and 3-8. Treatment of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)pyridine 3-1 (Suzuki coupling) with bromide 1-1 in the presence of a palladium catalyst yields 3-2. Compound 3-2 is then reacted with various morpholines (commercially available or synthesized by those skilled in the art) via S... N The Ar reaction, in the presence of a base, yields 3-3. The nitro reduction of 3-3 under mild reducing conditions (zinc or iron metal with ammonium chloride) yields 3-5. In another embodiment, 3-2 reacts with an alcohol EL-OH or an amine ELN(R) 4 H in companies such as DIEA and K2CO 3、 S in the presence of NaH base NAr reaction yields 3-4. Nitro reduction of 3-4 under mild reducing conditions (zinc or iron metal with ammonium chloride) yields 3-6. Finally, 3-5 and 3-6 are respectively amide-coupled with carboxylic acid 1-5 (commercially available or synthesized by those skilled in the art) to yield 3-7 and 3-8.

[0174] Option 4 Scheme 4 illustrates an exemplary preparation of pyrimidine intermediate 4-4. 2,4,6-Trichloropyridine 4-1 is reacted with various morpholines (commercially available or synthesized by those skilled in the art) in an S... N Ar reaction yields 4-2. Chloride 4-2 reacts with Molander salt, borate ester, or borate YB(OR)2 under Suzuki conditions to give 4-3, which can be reduced if desired. Finally, 4-3 reacts with borate ester 1-3 under Suzuki conditions to give 4-4.

[0175] Option 5 Similar to Scheme 4, Scheme 5 illustrates an exemplary preparation of intermediate 5-3. 4,6-Dichloropyrimidine 5-1 is reacted with various morpholines (commercially available or synthesized by those skilled in the art) in the presence of a base to give 5-2. 5-2 is then treated with borate ester 1-3 in the presence of a palladium catalyst (Suzuki reaction) to give 5-3.

[0176] Option 6 Scheme 6 describes pyrimidine intermediate 6-4 (Q=O, N(R)). 4 Exemplary preparation of 2,4,6-trichloropyrimidine 6-1 reacts with various morpholines (commercially available or synthesized by those skilled in the art) in the presence of a base (S N Ar reaction) to give a mixture of intermediates 6-2a and 6-2b, which can be purified by SFC, crystallization or chromatography. Compound 6-2a is separated by SFC. N Ar reacts with alcohols (EL-OH) or amines (ELN(R) 4 The reaction yields 6-3(Q=O, N(R)). 4 Intermediate 6-3 reacts with borate ester 1-3 in the presence of a palladium catalyst (Suzuki reaction) to give 6-4 (Q=O, N(R)). 4 )).

[0177] Option 7 Scheme 7 illustrates the exemplary preparation of pyrimidine intermediates 7-2a and 7-2b. 6-2b (Scheme 6) is prepared with an alcohol (EL-OH) or an amine (ELN(R)).4 S of H) N Ar reaction yields 7-1a(Q=O, N(R) 4 )), and 7-1b(Q=O, N(R) 4 The mixture of intermediates 7-1a and 7-1b can be separated by suitable methods (e.g., SFC purification, column chromatography, or recrystallization). Finally, the intermediates 7-1a and 7-1b are reacted with borate ester 1-3 in the presence of a palladium catalyst (Suzuki reaction) to give 7-2a and 7-2b, respectively.

[0178] Option 8 Similar to Scheme 5, Scheme 8 describes an exemplary preparation of intermediate 8-3. 5-Bromo-3-chloropyridazine 8-1 is reacted with various morpholines (commercially available or synthesized by those skilled in the art) in the presence of a base to give 8-2. 8-2 is then treated with borate ester 1-3 in the presence of a palladium catalyst (Suzuki reaction) to give 8-3.

[0179] Option 9 Scheme 9 describes an exemplary preparation of intermediates 9-3a, 9-3b, and 9-3c. 1-Bromo-3-iodobenzene 9-1(X) 1 X 3 =CH, and Y=I) with various morpholines (commercially available or synthesized by those skilled in the art) via Buchwald-Hartwig amination (Pd-catalyzed coupling conditions: Pd2(dba)3, BINAP, tert -BuONa) reaction yields 9-2a. Similarly, 3-bromo-5-iodopyridine 9-1(X) reacts to give 9-2a. 1 =CH, X 3 =N, and Y=I) with various morpholines (commercially available or synthesized by those skilled in the art) via Buchwald-Hartwig amination yields 9-2b. 2,6-Dibromopyrazine, 9-1(X 1 X 3 =N, and Y=Br) and various morpholines (commercially available or synthesized by those skilled in the art) S N The Ar reaction yields 9-2c. Intermediates 9-2a, 9-2b, and 9-2c react with borate esters 1-3 in the presence of a palladium catalyst (Suzuki reaction) to give intermediate 9-3a (X). 1 X 3 =CH), 9-3b(X) 1 =CH, X 3 =N) and 9-3c(X) 1 X 3 =N).

[0180] Option 10 Scheme 10 illustrates the exemplary preparation of pyrimidine intermediates 10⁻⁴a, 10⁻⁴b, 10⁻⁴c, and 10⁻⁴d. 2-Bromo-4,6-dichloropyrimidine 10⁻¹ reacts with an alcohol (EL-OH) or an amine (ELN(R)). 4 S of H) N Ar reaction yields 10⁻³ (Q=O, N(R)) 4 It can react with borate esters 1-4 in the presence of a palladium catalyst (Suzuki reaction) to give 10⁻⁴a(-OLE) and 10⁻⁴b(-N(R)) respectively. 4 )-LE). In another embodiment, 2,6-dichloro-N-methylpyrimidin-4-amine 10-2 is reacted with borate ester 1-4 under Suzuki reaction conditions to give a mixture of 10-4c and 10-4d, which can be separated by a suitable method (e.g., SFC purification, column chromatography or recrystallization).

[0181] Option 11 Scheme 11 illustrates an exemplary preparation of compounds of Formula I. Compounds of Formula I can be prepared by: (1) the Suzuki reaction of A (2-2, 2-4, 4-2a, 4-2b, 4-2c, 5-2, 6-3, 7-1a, 7-1b, 8-2, 9-2a, 9-2b and 9-2c) with borate esters 1-4, and (2) the typical amide coupling reaction of B (2-7a, 2-7b, 2-7c, 2-7d, 4-3a, 4-3b, 4-3c, 5-3, 6-4, 7-2a, 7-2b, 8-3, 9-3a, 9-3b and 9-3c) with carboxylic acids 1-5 (commercially available or synthesized by those skilled in the art), and (3) the reaction of 3-7 with alcohols EL-OH or amines ELN (R 4 S (commercially available or synthesized by those skilled in the art) N Ar reaction, (4) 3-8 with various morpholines (commercially available or synthesized by those skilled in the art) S N Ar reaction. In another embodiment, 5-bromo-3-chloropyridazine 11-1 with The Suzuki reaction of esters 1-4 yields 11-2. Chlorides 10-4a, 10-4b, 10-4c, 10-4d, and 11-2 react with various morpholines (commercially available or synthesized by those skilled in the art) in the S... N The Ar reaction yields compound I.

[0182] Preparation of intermediates The following compounds were prepared using the synthetic procedures and methods described herein and methods known to those skilled in the art: Preparation of intermediate A1: 4-(4-bromopyridin-2-yl)morpholine A solution of 4-bromo-2-fluoro-pyridine (1.0 g, 5.7 mmol) and morpholine (0.6 mL, 6.8 mmol) in DMF (20 mL) was treated with Cs₂CO₃ (5.6 g, 17 mmol). The reaction mixture was heated at 100 °C for 16 hours and then cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (3 times). The combined organic matter was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–15% EtOAc / petroleum ether) to give 4-(4-bromopyridin-2-yl)morpholine (Al, 1.0 g, 72%) as a yellow solid. 1 H NMR (400 MHz, methanol-d4): δ 7.95 (d, J = 5.4 Hz, 1H), 6.98 (d, J =1.4 Hz, 1H), 6.84 (dd, J =1.4, 5.4 Hz, 1H), 3.73-3.79 (m, 4H), 3.44-3.51 (m, 4H); MS (ESI) m / z: 242.9(M+H + ).

[0183] Preparation of intermediate A2: 4-(3-bromophenyl)morpholine A solution of 1-bromo-3-iodobenzene (0.9 mL, 7.1 mmol) and morpholine (0.62 mL, 7.1 mmol) in toluene (15 mL) was prepared using... tert -BuONa (1.4 g, 14 mmol) treatment. The mixture was degassed and purged with N2 for 5 min. Pd2(dba)3 (0.65 g, 0.1 eq) and BINAP (0.44 g, 0.1 eq) were added, and the mixture was then heated at 60 °C for 4 h under N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3×). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-35% EtOAc / petroleum ether) to give a yellow gel-like 4-(3-bromophenyl)morpholine (A2, 1.3 g, 76%). 1H NMR (400MHz, methanol-d4): δ 7.14 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.96 (d,J = 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 3.66-3.79 (m, 4H), 3.08-3.18 (m,4H); MS (ESI) m / z: 241.9 (M+H + ).

[0184] The following compounds were prepared primarily by the method used to prepare intermediate A1. The following compounds are basically prepared by the method used to prepare intermediate A2. Preparation of intermediate B1: 4-(4-chloro-6-cyclopropylpyridin-2-yl)morpholine A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (A8, 0.62 g, 2.7 mmol), cyclopropylboronic acid (0.34 g, 4.0 mmol), and 1,4-dioxane (10 mL) and H₂O (2 mL) was treated with Na₂CO₃ (0.56 g, 5.3 mmol). The reaction mixture was purged with N₂ for 5 min, followed by the addition of Pd(dppf)Cl₂ (0.19 g, 0.27 mmol), and then heated at 100 °C for 3 h under N₂ atmosphere. The reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC silica gel column chromatography (10% MeOH / DCM) to obtain 4-(4-chloro-6-cyclopropylpyridin-2-yl)morpholine (B1, 0.15 g, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.69 (d, J = 1.4Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 1.94 (m, 1H),0.82-0.91 (m, 4H); MS (ESI) m / z: 239.2 (M+H + ). Preparation of intermediate B2: ( R )-2-((4-iodo-6-morpholinopyridin-2-yl)amino)prop-1-ol (2) R A mixture of 2-aminoprop-1-ol (6.1 mL, 78 mmol), 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (A5, 12 g, 39 mmol), and K2CO3 (10.77 g, 77.90 mmol, 2 eq) in NMP (120 mL) was heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (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% EtOAc / petroleum ether) to give a purple solid. R )-2-(4-iodo-6-morpholinopyridin-2-yl)amino)-1-propanediol (B2, 8.0 g, 57%). 1 H NMR (400 MHz, CDCl3): δ 6.17 (s, 1H), 6.12 (s, 1H), 4.28 (brs, 1H), 3.97 (m, 1H), 3.76 (m, 4H), 3.66 (m, 1H), 3.46 (m, 1H), 3.29 (m, 4H), 3.19 (br s, 1H), 1.19 (d, J = 6.8 Hz, 3H). The following compounds were prepared primarily by methods for preparing intermediates B1 and B2. Preparation of intermediate C1: tert-butyl (3-(2-chloro-6-methylpyridin-4-yl)-4-methylphenyl)carbamate A solution of 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (3.0 g, 12 mmol) and 3-bromo-4-methylaniline (3.3 g, 18 mmol) in a mixture of 1,4-dioxane (50 mL) and H2 (10 mL) was treated with Na2CO3 (2.5 g, 24 mmol). The reactants were degassed with N2 for 4 min, and Pd(dppf)Cl2 (0.87 g, 1.2 mmol) was added. The reactants were then heated at 100 °C for 3 h under an N2 atmosphere. The reactants were cooled to room temperature and quenched with water, and extracted with EtOAc (3×). The combined organic compounds were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-7% EtOAc / petroleum ether) to give 3-(2-chloro-6-methyl-4-pyridyl)-4-methylaniline (C1, 2.2 g, 80%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ7.21 (s, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 2.4, 8.2 Hz, 1H), 6.45(d, J = 2.4 Hz, 1H), 5.01 (s, 2H), 2.50 (s, 3H), 2.06 (s, 3H); MS (ESI) m / z:233.1 (M+H + ).

[0185] The following compounds are basically prepared by the method of preparing intermediate C1. Preparation of intermediate C3: 4-(6-fluoro-4-(2-methyl-5-nitrophenyl)pyridin-2-yl)morpholine A solution of 2,6-difluoro-4-(2-methyl-5-nitrophenyl)pyridine (C2, 1.5 g, 6.0 mmol) and morpholine (1.6 mL, 18 mol) in EtOH (30 mL) was treated with DIEA (3.1 mL, 18 mmol). The reaction mixture was sealed and heated to 65 °C for 4 h, followed by cooling to room temperature. The reaction mixture was diluted with water and sonicated for 5 min. The solid was filtered and washed with water. The material was dried overnight under high vacuum to give 4-(6-fluoro-4-(2-methyl-5-nitrophenyl)pyridin-2-yl)morpholine (C3, 1.64 g, 86%) as a golden-brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.18(dd, J = 2.4, 8.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.4 Hz,1H), 6.71 (s, 1H), 6.41 (s, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.49 (t, J = 4.8Hz, 4H), 2.36 (s, 3H); MS (ESI) m / z: 318.2 (M+H + ). The following compounds are basically prepared by the method of preparing intermediate C3. Preparation of intermediate C5: 3-(2-fluoro-6-morpholinopyridin-4-yl)-4-methylaniline A solution of 4-(6-fluoro-4-(2-methyl-5-nitrophenyl)pyridin-2-yl)morpholine (C3, 2.0 g, 6.3 mmol) in EtOH (30 mL) was treated with 10% palladium on carbon (50% wetted with water) (1.34 g, 0.63 mmol). The reaction mixture was placed under a H2 atmosphere (50 Psi) and shaken at room temperature for 5 h. The reaction mixture was filtered through a diatomaceous earth pad and washed with EtOH. The filtrate was concentrated to dryness under reduced pressure to give 3-(2-fluoro-6-morpholinopyridin-4-yl)-4-methylaniline (C5, 1.81 g, 100%) as a pale yellow oil. 1H NMR (500 MHz, DMSO-d6): δ 6.92 (d, J = 8.0Hz, 1H), 6.52 (m, 2H), 6.44 (d, J = 2.4 Hz, 1H), 6.22 (s, 1H), 4.96 (s, 2H), 3.67 (t, J = 4.8 Hz, 4H), 3.44-3.46 (m, 4H), 2.05 (s, 3H). Preparation of intermediate D1: ( R )-2-((4-(5-amino-2-methylphenyl)-6-morpholinopyridin-2-yl)amino)prop-1-ol Will( R A mixture of 1,4-dioxane (135 mL) and water (15 mL) was prepared by purging with Ar for 5 min. The mixture of 4-iodo-6-morpholinopyridin-2-yl)amino)prop-1-ol (B2, 11 g, 30 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)aniline (7.0 g, 30 mmol), and K2CO3 (10.4 g, 75 mmol) was added. The mixture was then sealed and heated to 80 °C overnight. The mixture was cooled to room temperature and then diluted with saturated NaHCO3 (aqueous solution). The aqueous solution was extracted with DCM (3×). The combined organic compounds were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexane) to obtain a brown solid. R )-2-((4-(5-amino-2-methylphenyl)-6-morpholinopyridin-2-yl)amino)prop-1-ol (D1, 7.1 g, 69%). MS (ESI) m / z: 343.2 (M+H + ).

[0186] Preparation of intermediates D2 and D3: 2-((4-(5-amino-2-methylphenyl)-6-morpholinopyridin-2-yl)oxy)eth-1-ol (D2), 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-morpholinopyridin-4-yl)-4-methylaniline, and intermediate (D3). and A solution of 2-((tert-butyldimethylsilyl)oxy)ethanol-1-ol (37 g, 209 mmol) in a mixture of 1,4-dioxane and NMP (4:1, 150 mL) was slowly treated with NaH (5.2 g, 131 mmol, 60% dispersion in mineral oil). The resulting mixture was stirred for 15 min at room temperature under an Ar atmosphere. 3-(2-fluoro-6-N-morpholinopyridin-4-yl)-4-methylaniline (C5, 15 g, 52 mmol) was added, and the reaction mixture was then heated at 120 °C for 2 h. The reaction mixture was cooled to room temperature and poured into a cold saturated NH4Cl solution (aqueous solution, 200 mL). The mixture was extracted with DCM (3×). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (0-40% EtOAc / hexane) to give two major products: 2-((4-(5-amino-2-methylphenyl)-6-morpholinopyridin-2-yl)oxy)ethanol-1-ol (D2, 6.5 g, 55%), a brown liquid. 1 H NMR (400 MHz, DMSO-d6): δ 6.89 (d, J = 8.2 Hz,1H), 6.48 (dd, J = 2.0, 8.0 Hz, 1H), 6.41 (br s, 1H), 6.16 (m, 1H), 5.95 (m,1H), 4.9 (br s, 2H), 4.78 (t, J = 5.6 Hz, 1H), 4.23 (t, J = 5.2 Hz, 2H), 3.69(m, 6H), 3.39 (m, 4H), 2.01 (s, 3H); MS (ESI) m / z: 330.0 (M+H) + ), and 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-morpholinopyridin-4-yl)-4-methylaniline (D3, 7.0 g, 30%), which is a brown liquid. 1H NMR (400 MHz, DMSO-d6): δ 6.89 (d, J = 8.0 Hz, 1H), 6.48 (dd, J= 2.4, 8.0 Hz, 1H), 6.41 (s, 1H), 6.16 (s, 1H), 5.91 (s, 1H), 4.9 (br s, MS (ESI) m / z: 444.1 (M+H + ) The following compounds were prepared primarily by the method used to prepare intermediate D1. Preparation of intermediate E1: Methyl 6-chloro-5-cyclobutylpyridazine-3-carboxylate A solution of methyl 6-chloropyridazine-3-carboxylate (25 g, 145 mmol) in a mixture of sulfolane (50 mL), H₂O (250 mL), and MeCN (50 mL) was treated with cyclobutanecarboxylic acid (21 mL, 217 mmol) and AgNO₃ (25 g, 145 mmol). The mixture was heated at 50 °C, and then H₂O (150 mL) containing H₂SO₄ (22 mL, 419 mmol) was added dropwise. H₂O (150 mL) containing ammonia (52 mL, 239 mmol) was added dropwise over 35 min. The reaction mixture was stirred at 70 °C for 20 min. The mixture was then cooled to room temperature and stirred for 12 h. The reaction mixture was alkalized to pH 7 with 30% NaOH (aqueous solution) at 0 °C. The solution was extracted with EtOAc (3×). The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (0-40% EtOAc / petroleum ether) to give methyl 6-chloro-5-cyclobutylpyridazine-3-carboxylate (E1, 7.2 g, 19%), which was a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ8.08 (s, 1H), 3.98 (s, 3H), 3.70-3.78 (m, 1H), 2.36-2.45 (m, 2H), 2.20-2.24(m, 2H), 2.01-2.19 (m, 1H), 1.78-1.88 (m, 1H). Preparation of intermediate E2: 3-chloro-5-cyclopropylpyridazine A mixture of 5-bromo-3-chloropyridazine (10 g, 52 mmol), cyclopropylboronic acid (4.4 g, 52 mmol), Na₂CO₃ (16 g, 155 mmol) in a mixture of 1,4-dioxane (100 mL) and H₂O (20 mL) was purged with N₂ for 5 min. Pd(dppf)Cl₂ (3.0 g, 4.2 mmol) was added, and the mixture was then heated at 90 °C under N₂ atmosphere for 12 h. The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted with EtOAc (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 (0–50% EtOAc / petroleum ether) to give 3-chloro-5-cyclopropylpyridazine (E₂, 4.1 g, 51%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.08 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 1.9 Hz, 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 + ).

[0187] Preparation of intermediate E3: 3-chloro-5-(1-ethoxyvinyl)pyridazine A 2 L three-round-bottom flask equipped with a stir bar was loaded with 500 mL of DMF containing 40 g (208 mmol) of 5-bromo-3-chloropyridazine, 70 mL (208 mmol) of tributyl(1-ethoxyvinyl)stanane, and 87 mL (620 mmol) of TEA, and purged with N2 for 3 min. Pd(PPh3)2Cl2 (7.3 g, 10 mmol) was added, and the mixture was then heated at 90 °C under N2 atmosphere for 3 h. The reaction mixture was cooled to room temperature and quenched at 0 °C with saturated NH4Cl (100 mL aqueous solution) and saturated KF (1 L). The mixture was stirred at room temperature for 0.5 h, followed by extraction with EtOAc (3 times). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / petroleum ether) to obtain 3-chloro-5-(1-ethoxyvinyl)pyridazine (E3, 30 g, 79%) as a yellow solid. 1 H NMR (400 MHz, methanol-d4): δ 9.41 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 5.29 (d, J = 3.8 Hz, 1H), 4.76 (d, J = 3.9 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H),1.47 (t, J = 7.0 Hz, 3H). The following compounds were prepared primarily by the method used to prepare intermediate D2. Preparation of intermediate E5: 2-(6-chloropyridazine-4-yl)prop-2-ol 3-Chloro-5-isopropenyl-pyridazine (E4, 1.0 g, 6.5 mmol), phenylsilane (4 mL, 32 mmol), and ginseng were added. Z [1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (3.9 g, 6.5 mmol) in DCM (10 mL) and isoThe mixture of -PrOH (30 mL) was purged with O2 for 5 min, and then stirred at 0 °C under an O2 atmosphere for 0.5 h. The reaction mixture was quenched with saturated Na2SO3 (aqueous solution) and extracted with EtOAc (3×). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20-100% EtOAc / petroleum ether) to give 2-(6-chloropyridazine-4-yl-)prop-2-ol (E5, 0.78 g, 63%) as a white solid. 1 ¹H NMR (400 MHz, methanol-d6): δ 9.28 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 1.56 (s, 6H); MS (ESI) m / z: 173.1 (M+H) + ). Preparation of intermediate E6: 3-chloro-5-(2-fluoroprop-2-yl)pyridazine A solution of 2-(6-chloropyridazin-4-yl)prop-2-ol (E5, 0.6 g, 3.5 mmol) in DCE (6 mL) was treated with BAST (2.3 mL, 10 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was poured into water (10 mL) and extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to give a yellow gel-like 3-chloro-5-(2-fluoroprop-2-yl)pyridazine (E6, 0.5 g, 80%). MS (ESI) m / z: 175.1 (M+H + ).

[0188] Preparation of intermediate F1: Methyl 5-cyclobutylpyridazine-3-carboxylate A solution of methyl 6-chloro-5-cyclobutylpyridazine-3-carboxylate (E1, 5.5 g, 24 mmol) in MeOH (30 mL) was treated with Pd-C (5.5 g, 5.2 mmol, 10%) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h under H2 (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give methyl 5-cyclobutylpyridazine-3-carboxylate (F1, 4.0 g, crude product) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.10 (s, 1H), 3.95 (s,3H), 3.65-3.73 (m, 1H), 2.29-2.37 (m, 2H), 2.13-2.26 (m, 2H), 1.99-2.08 (m,1H), 1.83-1.91 (m, 1H). Preparation of intermediate F2: Methyl 6-(trifluoromethyl)pyridazine-3-carboxylate A solution of 3-chloro-6-(trifluoromethyl)pyridazine (2.0 g, 11 mmol) and Pd(dppf)Cl2 (0.8 g, 1.1 mmol) in MeOH (20 mL) was treated with DIEA (3.8 mL, 22 mmol). The mixture was purged with CO for 5 min. The mixture was stirred at 80 °C for 3 h under CO (50 Psi). The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The solution was extracted with EtOAc (3×). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-25% EtOAc / petroleum ether) to give methyl 6-(trifluoromethyl)pyridazine-3-carboxylate (F2, 1.0 g, 44%) as a white solid. MS (ESI) m / z: 207.1 (M+H + ).

[0189] The following compounds were prepared primarily by methods for preparing intermediates F1 and F2. Preparation of intermediate F8: Methyl 5-(1,1-difluoroethyl)pyridazine-3-carboxylate A solution of methyl 5-acetylpyridazine-3-carboxylate (F7, 30 g, 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 heated to room temperature. The reaction mixture was stirred at room temperature for 10 hours. Water (300 mL) was added, followed by extraction with DCM (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% EtOAc / petroleum ether) to give methyl 5-(1,1-difluoroethyl)pyridazine-3-carboxylate (F8, 11 g, 33%) as a white solid. 1¹H NMR (400 MHz, methanol-d⁴): δ 9.48 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 3.99 (s, 3H), 1.95 (t, J = 18.9 Hz, 3H). Preparation of intermediate G1: 6-(trifluoromethyl)pyridazine-3-carboxylic acid To a solution of methyl 6-(trifluoromethyl)pyridazine-3-carboxylate (F2, 1.0 g, 4.8 mmol) in a mixture of THF (5 mL) and MeOH (5 mL), LiOH•H2O (0.41 g, 9.7 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The aqueous residue was acidified to pH 3 with 1.0 N HCl (aqueous solution). The solution was extracted with EtOAc (3×). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6-(trifluoromethyl)pyridazine-3-carboxylic acid (G1, 0.80 g, 80%) as a brown solid. 1 ¹H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), carboxylic acid proton deletion; MS (ESI) m / z: 193.0 (M+H) + ).

[0190] The following compounds were prepared primarily by the method used to prepare intermediate G1. Preparation of intermediate H1: N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide A solution of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (6.4 g, 33 mmol), HATU (14 g, 36 mmol), and DIEA (17 mL, 99 mmol) in DMF (66 mL) was stirred at 0 °C for 15 min. 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)aniline (7.7 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 residue was collected by filtration as a white solid. N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (H1, 12 g, 87%). 1 H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.92 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz,1H), 7.85 (dd, J = 2.4, 8.2 Hz,1H), 7.19 (d, J = 8.2 Hz, 1H), 2.44 (s, 3H), 1.30 (d, J = 1.4 Hz, 12H); MS(ESI) m / z: 408.2 (M+H + ).

[0191] The following compounds were prepared primarily by the method of preparing intermediate H1. Preparation of intermediate H4: 5-cyano- N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)phenyl)pyridazine-3-carboxamide Will N A solution of 3-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]pyridazine-3,5-dicarboxamide (H3, 16.5 g, 43 mmol) in THF (200 mL) was treated with methoxycarbonyl-(triethylammonium)sulfonyl-amino compound (51.4 g, 216 mmol). The mixture was stirred at 20 °C for 1 h, and the resulting precipitate was collected by filtration to give a yellow solid of 5-cyano- N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]pyridazine-3-carboxamide (5.0 g, 31%). The mother liquor was concentrated under reduced pressure, and the residue was then wet-milled with water (50 mL). The solid was filtered to give a second batch of 5-cyano- N -[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]pyridazine-3-carboxamide (H4, 4.2 g, 25%). 1 H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H), 9.86 (d, J = 1.8 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 2.2, 8.2 Hz, 1H), 7.20 (d, J = 8.2Hz, 1H), 2.45 (s, 3H), 1.32 (s, 12H); MS (ESI) m / z: 365.1 (M+H + ). Preparation of intermediate I1: N -(3-(6-chloropyridazin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazin-3-carboxamide 5-Bromo-3-chloropyridazine (0.26 g, 1.35 mmol) and N A mixture of 1,4-dioxane (10 mL) and water (1.25 mL) containing 4-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-pentane-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (H1, 0.55 g, 1.35 mmol) was treated with K2CO3 (0.56 g, 4.05 mmol). The mixture was purged with Ar for 5 min, followed by the addition of PdCl2(dppf)-DCM adduct (0.11 g, 0.14 mmol). The reaction mixture was sealed and heated to 90 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give a yellow solid. N -(3-(6-chloropyridazin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazin-3-carboxamide (I1, 0.50 g, 94%). MS m / z: 394.2 (M+H) + ).

[0192] The following compounds were prepared primarily by the method of preparing intermediate I1. Preparation Example 1: N -(4-Methyl-3-(2-morpholinopyridin-4-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide A solution of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (0.12 g, 0.61 mmol), 4-methyl-3-(2-morpholino-4-pyridyl)aniline (D6, 0.15 g, 0.56 mmol), HATU (0.32 g, 0.84 mmol), and DIEA (0.2 mL, 1.1 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C-18 preparative HPLC (25-55% water (HCl) / MeCN) to give a pale yellow solid. N -(4-methyl-3-(2-morpholinopyridin-4-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (1, 0.11 g, 45%). 1 H NMR (400 MHz, methanol-d4): δ 9.76 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 1.4 Hz, 1H), 8.03 (d, J = 6.5Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = MS (ESI) m / z: 444.0 (M+H + ). Preparation Example 2: 5-Cyclopropyl- N -(4-Methyl-3-(2-morpholinopyridin-4-yl)phenyl)pyridazine-3-carboxamide 4-(4-bromopyridin-2-yl)morpholine (A1, 0.10 g, 0.34 mmol), 5-cyclopropyl- N A mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridazine-3-carboxamide (H2, 0.13 g 0.34 mmol) in a mixture of 1,4-dioxane (3 mL) and H2O (0.6 mL) was treated with Na2CO3 (0.07 g, 0.69 mmol). The reaction mixture was purged with N2 for 3 min, followed by the addition of Pd(dppf)Cl2 (25 mg, 34 μmol). The mixture was heated at 100 °C under N2 atmosphere for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic matter was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (0-100% EtOAc / petroleum ether) to give 5-cyclopropyl- N -(4-methyl-3-(2-morpholinopyridin-4-yl)phenyl)pyridazine-3-carboxamide (2, 0.13 g, 89%). 1 H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 2.4, 8.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.4Hz, 1H), 6.77 (s, 1H), 6.71 (dd, J = 1.2, 4.8 Hz, 1H), 3.72 (m, 4H), 3.50 (m,4H), 2.25 (s, 3H), 2.16 (m, 1H), 1.21-1.26 (m, 2H), 1.04-1.07 (m, 2H); MS(ESI) m / z: 416.2 (M+H + ). The following compounds were prepared essentially by the methods described in Examples 1 and 2. Preparation Example 21: N -(4-Methyl-3-(6-morpholinopyridazin-4-yl)phenyl)-5-(trifluoromethyl)pyridazin-3-carboxamide Will N A solution of 3-(6-chloropyridazin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazin-3-carboxamide (I1, 0.62 g, 1.6 mmol) and morpholine (0.20 mL, 2.4 mmol) in EtOH (5 mL) was treated with triethylamine (0.66 mL, 4.7 mmol). The reaction mixture was stirred overnight at room temperature, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give a white solid. N -(4-methyl-3-(6-morpholinopyridazine-4-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (21, 0.043 g, 7%). 1 H NMR (400 MHz, methanol-d4): δ11.32 (s, 1H), 9.96 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 7.98 (dd, J = 2.3,8.2 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.25 (s,1H), 3.75 (t, J = 4.6 Hz, 4H), 3.62 (d, J = 4.8 Hz, 3H), 2.28 (s, 3H); MS(ESI) m / z: 445.2 (M+H) + ).

[0193] The following compounds were prepared essentially by the method of Preparation Example 21. Preparation Example 57: ( R )- N -(3-(2-((1-hydroxypropyl-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-6-isopropylpyrazin-2-carboxamide Towards N -[3-[2-[[(1 R [2-Hydroxy-1-methyl-ethyl]amino]-6-morpholino-4-pyridyl]-4-methyl-phenyl]-6-isopropenyl-pyrazin-2-carboxamide (0.15 g, 0.31 mmol) was added to a solution of MeOH (2 mL), followed by the addition of MeOH (2 mL) containing Pd-C (0.33 g, 0.31 mmol, 50% wetted with water). The mixture was degassed and purged three times with H2, and then stirred at room temperature for 0.5 h under H2 atmosphere. The reaction mixture was filtered through a diatomaceous earth pad and washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by C-18 preparative HPLC (40-70% H2O (10 mM NH4HCO3) / MeCN) to give a pale yellow solid. R )- N -(3-(2-((1-hydroxypropyl-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-6-isopropylpyrazine-2-carboxamide (57, 0.067 g, 44%). 1H NMR (400 MHz, DMSO-d6): δ10.35 (s, 1H), 9.09 (s, 1H), 8.87 (s, 1H), 7.78 (dd, J = 2.2, 8.4 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 5.80 (s, 2H), 4.66 (t, J = 5.4 Hz, 1H), 3.90 (m, 1H), 3.68 (m, 4H), 3.50 (m,1H), 3.38 (m, 4H), 3.21-3.31 (m, 2H), 2.23 (s, 3H), 1.37 (d, J = 7.0 Hz, 6H), 1.13 (d, J = 6.6 Hz, 3H); MS (ESI) m / z: 491.2 (M+H + ). Biochemical analysis of B-Raf The activity of β-Raf kinase (SEQ ID NO: 1) was determined spectroscopically using a continuous monitoring assay of ATP hydrolysis-dependent NADH oxidation coupled with pyruvate kinase / lactate dehydrogenase (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Analysis was performed in 384-well plates (100 µL final volume) using an analysis 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) containing 0.13 nM β-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. Inhibition of B-Raf was measured by adding serially diluted test compounds (final analytical concentration: 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored for 6 hours at 30°C using a multimodal microplate reader (BioTek). Reaction rates were calculated over a time range of 4–5 hours. Reaction rates at each concentration were converted to percentage inhibition using controls (i.e., reactions without the test compound and reactions with known inhibitors), and IC50 was calculated by fitting a four-parameter sigmoid curve to the data using Prism (GraphPad software). 50 value.

[0194] B-Raf protein sequence residues 416-766 with an N-terminal GST tag (SEQ ID NO: 1) LQKSPGPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATVKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH Biochemical analysis of C-Raf The activity of C-Raf kinase (SEQ ID NO: 2) was determined spectroscopically using a continuous monitoring assay of ATP hydrolysis-dependent NADH oxidation coupled with pyruvate kinase / lactate dehydrogenase (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Analysis was performed in 384-well plates (100 µL final volume) using an analysis 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) containing 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. Inhibition of C-Raf was measured by adding serially diluted test compounds (final analytical concentration: 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored for 6 hours at 30°C using a multimodal microplate reader (BioTek). Reaction rates were calculated over a time range of 4–5 hours. Reaction rates at each concentration were converted to percentage inhibition using controls (i.e., reactions without the test compound and reactions with known inhibitors), and IC50 was calculated by fitting a four-parameter sigmoid curve to the data using Prism (GraphPad software). 50 value.

[0195] C-Raf residue 306-terminus; Y340D, Y341D and N-terminal GST tag (SEQ ID NO: 2) QPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSDDWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLH EGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF Table 1. Inhibition of the biochemical activity of BRAF and CRAF kinases by exemplary compounds (“Example No.”).

[0196] For Table 1, "++++" refers to ICs less than or equal to 100 nM. 50 "++" refers to an IC with a current rating greater than 100 nM and less than or equal to 500 nM. 50 "++" refers to an IC with a current greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "+" indicates an IC value greater than 1000 nM and less than or equal to 10000 nM. 50 .

[0197] MiaPaca-2 cell proliferation analysis Miapaca-2 cells (catalog number CRL-1420) were obtained from the American Type Culture Collection (ATTC, Manassas, VA). In short, cells were grown in DMEM supplemented with 10% premium fetal bovine serum (Invitrogen, Carlsbad, CA), 2.5% New Zealand horse serum, and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded to 70-95% confluence, at which point they were subcultured or collected for analysis. Serial dilutions of the test compounds were aliquoted into triplicate into 384-well black clear plates. 750 cells were added to each well of the 384-well plate in 50 µL of complete growth medium. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 67-72 hours. At the end of incubation, 10 µL of a 440 µM resazurin (Sigma, St. Louis, MO) solution in PBS was added to each well of the plate, and the plate was incubated for another 5–6 hours at 37°C, 5% CO2, and 95% humidity. The plate was read using a Synergy2 or equivalent reader (Biotek, Winooski VT) with excitation at 540 nm and emission at 600 nm. The data were analyzed using Prism software (GraphPad, San Diego, CA) to calculate the IC50. 50 value.

[0198] HCT-116 cell proliferation analysis HCT-116 cells (catalog number CCL-247) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). In short, cells were grown in McCoy's 5A supplemented with 10% premium fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded until they reached 70-95% confluence, at which point they were subcultured or collected for analysis. Serial dilutions of the test compounds were aliquoted into 384-well black clear plates. 375 cells were added to each well of the 384-well plate in 50 µL of complete growth medium. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 67-72 hours. At the end of incubation, 40 µL of a 440 mM resazurin (Sigma, St. Louis, MO) solution in PBS was added to each well of the plate, and the plate was incubated for another 4–5 hours at 37°C, 5% CO2, and 95% humidity. The plates were read using a Synergy2 or equivalent reader (Biotek, Winooski VT) with 540 nm excitation and 600 nm emission. The data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0199] HPAF-II cell proliferation analysis HPAF-II cells (catalog number CRL-1997) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). In short, the cells were grown in minimum essential medium supplemented with 10% fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded until they reached 70-95% confluence, at which point they were subcultured or collected for analysis. Serial dilutions of the test compounds were aliquoted into triplicate into 384-well black clear plates. 750 cells were added to each well of the 384-well plate in 50 µL of complete growth medium. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 115-120 hours. At the end of incubation, 40 µL of a 440 mM resazurin (Sigma, St. Louis, MO) solution in PBS was added to each well of the plate, and the plate was incubated for another 18–24 hours at 37°C, 5% CO2, and 95% humidity. The plates were read using a Synergy2 or equivalent reader (Biotek, Winooski VT) with 540 nm excitation and 600 nm emission. The data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0200] Pa16c cell proliferation analysis Pa16c cells were obtained from Dr. Channing Derb (University of North Carolina, Chapel Hill). In short, cells were grown in Dulbecco's Modified Eagle Medium supplemented with 10% Invitrogen (Carlsbad, CA) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded until they reached 70-95% confluence, at which point they were subcultured or collected for analysis. Serial dilutions of the test compounds were aliquoted into triplicate into 384-well black clear plates. 750 cells were added to each well of the 384-well plate in 50 µL of complete growth medium. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 67-72 hours. At the end of the incubation, 40 µL of a 440 mM resazurin (Sigma, St. Louis, MO) solution in PBS was added to each well of the plate, and the plate was incubated for another 18–24 hours at 37°C, 5% CO2, and 95% humidity. The plates were read using a Synergy2 or equivalent reader (Biotek, Winooski VT) with 540 nm excitation and 600 nm emission. The data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0201] Table 2. Inhibition of cell proliferation of MiaPaca-2, HCT-116, HPAF-II and Pa16c by exemplary compounds (“Example No.”).

[0202] For Table 2, "++++" refers to ICs less than or equal to 100 nM. 50 "++" refers to an IC with a current rating greater than 100 nM and less than or equal to 500 nM. 50 "++" refers to an IC with a current greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "+" indicates an IC value greater than 1000 nM and less than or equal to 10000 nM. 50 .

[0203] Biochemical microtubule polymerization analysis Porcine brain tubulin (T240) and the tubulin polymerization assay kit (BK011P) were purchased from Cytoskeleton (Denver, CO). Briefly, serially diluted test compounds were aliquoted into three portions into 384-well black plates. 25 µL of the assay mixture containing buffer, glycerol, GTP, and porcine brain tubulin from the assay kit was added to each well of the 384-well plate. The plates were briefly centrifuged, then read at 37°C on a Synergy Neo2 or equivalent reader (BioTek, Winooski, VT) every 2 minutes with 335 nm excitation and 450 nm emission for 1 hour to generate kinetic data and maximum polymerization rate for 0–1 hour. Data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate IC50. 50 value.

[0204] Figure 1 This indicates the maximum rate of tubulin polymerization in the presence of increased concentrations of the known tubulin depolymerizing agent plinabulin. In this recombinant biochemical tubulin analysis, plinabulin showed an IC50 concentration of 2.7 μM. 50 Inhibits tubulin polymerization.

[0205] Cellular microtubule polymerization analysis HCT-116 cells (catalog number CCL-247) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). In short, the cells were grown in McCoy's 5A supplemented with 10% premium fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded until they reached 70-95% confluence, at which point they were subcultured or collected for analysis. 450,000 cells were added to each well of a 12-well plate containing 1500 μL of complete growth medium prepared for tissue culture. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 18-24 hours. At the end of incubation, 2000 μL of alkaline medium was added to each well, followed by serial dilutions of the compound. The plates were incubated for another 1 hour at 37°C, 5% CO2, and 95% humidity. Lysates were generated by adding 100 µL of dissolution buffer (LMS01, Cytoskeleton Inc., Denver, CO) supplemented with a mixture of GTP (BST06, Cytoskeleton Inc.), ATP (BSA04, Cytoskeleton Inc.), and protease inhibitor stock solution (PIC02, Cytoskeleton Inc.). Cells were scraped from each well using a rubber cell scraper and collected in clean 96-well plates. The lysates were centrifuged at 1000 × g for 10 min at 37°C, and the supernatant was transferred to an additional 96-well plate. The remaining pellet was reconstituted in 100 µL of LMS01 buffer and sonicated for 10 min. α-Tubulin was detected in the precipitate and supernatant fractions by Western blot analysis on the JessSystem or its equivalent (Bio-techne, Minneapolis, MN). Data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0206] Figure 2 This represents the ratio of precipitate (polymerized tubulin) to supernatant (tubulin dimers) to DMSO control at increasing concentrations of the known tubulin depolymerizing agent punabulin. In this cellular tubulin analysis, punabulin inhibited tubulin polymerization, with an IC50 concentration of [missing value]. 50 It is 5 nM.

[0207] The compounds disclosed herein unexpectedly exhibit a dual mechanism of action: 1) inhibition of BRAF and CRAF MAP kinases, and 2) inhibition of microtubule polymerization. While this dual-mechanism inhibition can be achieved by combining several anticancer agents, the compounds disclosed herein provide this dual inhibition within the same pharmacophore. This unexpected dual mechanism of action enables potent single-agent inhibition of mutant RAS cancer cell lines, which cannot be achieved with previously reported BRAF / CRAF inhibitors.

[0208] Representative examples are illustrated in Table 3. These examples are based on biochemical ICs as shown in Table 3. 50 The values ​​inhibited BRAF and CRAF. These examples also inhibited tubulin polymerization in the microtubule biochemical analysis. In cellular analysis, these examples demonstrated potent single-agent antiproliferative activity in the MiaPaca-2 mutant KRAS pancreatic cancer cell line, the HCT-116 mutant KRAS colorectal cancer cell line, and the HPAF-II mutant KRAS pancreatic cancer cell line.

[0209] Other chemical classes of the reported BRAF and / or CRAF inhibitors are shown in Table 4. Although these compounds inhibit BRAF and / or CRAF, none of them strongly inhibited tubulin polymerization. The compounds in Table 4 exhibited weak antiproliferative activity in the MiaPaca-2 mutant KRAS pancreatic cancer cell line, weak antiproliferative activity in the HCT-116 mutant KRAS colorectal cancer cell line, and weak antiproliferative activity in the HPAF-II mutant KRAS pancreatic cancer cell line.

[0210] Table 3. Representative Compounds

[0211] For Table 3, regarding BRAF, CRAF, MiaPaca-2, HCT-116, HPAF-II, and microtubule cell analysis, "++++" indicates an IC50 value less than or equal to 100 nM. 50 "++" refers to an IC with a current rating greater than 100 nM and less than or equal to 500 nM. 50 "++" refers to an IC with a current greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "+" indicates an IC value greater than 1000 nM and less than or equal to 10000 nM. 50 For microtubule biochemical analysis, "****" refers to an IC50 concentration of less than or equal to 3 μM. 50 "***" refers to ICs with a micrometer size greater than 3 μM and less than or equal to 20 μM. 50"**" refers to ICs with a micrometer size greater than 20 μM and less than or equal to 100 μM. 50 Furthermore, "*" indicates an IC larger than 100μM. 50 .

[0212] Table 4. Previously disclosed BRAF / CRAF inhibitors

[0213] For Table 4, regarding BRAF, CRAF, MiaPaca-2, HCT-116, HPAF-II, and microtubule cell analysis, "++++" indicates an IC50 value less than or equal to 100 nM. 50 "++" refers to an IC with a current rating greater than 100 nM and less than or equal to 500 nM. 50 "++" refers to an IC with a current greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "+" indicates an IC value greater than 1000 nM and less than or equal to 10000 nM. 50 For microtubule biochemical analysis, "****" refers to an IC50 concentration of less than or equal to 3 μM. 50 "***" refers to ICs with a micrometer size greater than 3 μM and less than or equal to 20 μM. 50 "**" refers to ICs with a micrometer size greater than 20 μM and less than or equal to 100 μM. 50 Furthermore, "*" indicates an IC larger than 100μM. 50 .

[0214] equivalent Although specific embodiments have been described, the above description is exemplary and not restrictive. Many variations of the embodiments will be apparent to those skilled in the art upon reading this description. The full scope of the disclosure, its equivalents, and the full scope of this description and these variations should be determined with reference to the claims.

[0215] Unless otherwise indicated, all figures used in this specification and claims to represent the quantities of components, reaction conditions, etc., should in all cases be understood to be modified by the term "about". Therefore, unless indicated to the contrary, the numerical parameters described in this specification and the appended claims are approximate values ​​that may vary depending on the desired properties being sought.

Claims

1. A compound represented by formula IA: Formula IA, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 -LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 5 and X 6 Each is independently selected from: CH, CF, and N; X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 1 X 2 X 3 and X 4 No more than two of them are N; Its constraint is X 5 and X 6 No more than one of them is N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; Its restriction condition is when X 2 When X is N, 3 For CQLE, CLE, N, or CH; Its restriction condition is when X 3 When X is N, 2 For N, CH or CN(R) 4 )-LE; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected from: alkyl, halogen, amine, hydroxyl, and cyano in each occurrence; and m can be 0, 1, 2, 3, or 4. Its restrictions are: When X 2 Let N, X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 When the other two are CH, R 2 Not H; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 For CF3, X 2 Let N be the number of elements, and X be the number of elements. 1 and X 4 When it is CH, X 3 Not for , or .

2. A compound represented by formula IB: Formula IB Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 -LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 3 and X 4 No more than one of them is N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 2 Let N, X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 When the other two are CH, R 2 Not H; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 For CF3, X 2 Let N be the number of elements, and X be the number of elements. 1 and X 4 When it is CH, X 3 Not for , or .

3. A compound represented by formula IC: IC type Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 1 X 3 and X 4 When it is CH, X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 When the other two are CH, R 2 Not H; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 It is CF3, and X 1 and X 4 When it is CH, X 3 Not for , or .

4. A compound represented by formula ID: Formula ID, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; and When X 7 and X 9 For CH, X 8 For CR 5 R 2 For H, R 5 It is CF3, and X 1 and X 4 When it is CH, QLE is not , or .

5. A compound represented by the formula IE: Formula IE, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 7 and X 9 Each is independently selected from: CH and N; X 8 Selected from: CR 5 and N; Its constraint is X 7 X 8 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 2 Selected from: H, halogens, haloalkyls, alkyl groups, cycloalkyl groups, and amines; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 8 For CR 5 And X 7 and X 9 When it is CH, R 5 Not N(CH3)2; and When X 7 X 8 and X 9 One of them is N, and X 7 X 8 and X 9 When the other two are CH, R 2 Not H.

6. A compound represented by the formula IF: Formula IF, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from: CH and N; X 2 Selected from: N, CH, CN(R) 4 -LE and NLE; X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 5 and X 6 Each is independently selected from: CH, CF, and N; X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 1 X 2 X 3 and X 4 No more than two of them are N; Its constraint is X 5 and X 6 No more than one of them is N; Its constraint is X 7 and X 9 No more than one of them is N; Its restriction condition is when X 2 When X is N, 3 For CQLE, CLE, N, or CH; Its restriction condition is when X 3 When X is N, 2 For N, CH or CN(R) 4 )-LE; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 2 Let N be the number of elements, and X be the number of elements. 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 and X 9 One of them is N, and X 7 and X 9 When the other is CH, R 5 Not H; and When X 7 and X 9 For CH, R 5 For CF3, X 2 Let N be the number of elements, and X be the number of elements. 1 and X 4 When it is CH, X 3 Not for , or .

7. A compound represented by the formula IG: IG style Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 3 Selected from: N, CH, CQLE, CLE, and NLE; Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 7 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 2 Let N be the number of elements, and X be the number of elements. 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 2 Let N, X 1 X 3 and X 4 For CH, X 7 and X 9 One of them is N, and X 7 and X 9 When the other is CH, R 5 Not H; and When X 7 and X 9 It is CH, and R 5 When it is CF3, X 3 Not for , or .

8. A compound represented by the formula IH: Formula IH, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: O and N(R) 4 ); X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 7 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 7 and X 9 When it is CH, R 5 Not N(CH3)2; When X 7 and X 9 It is CH, and R 5 When it is CF3, QLE is not , or .

9. A compound represented by formula IJ: Formula IJ, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 7 and X 9 Each is independently selected from: CH and N; Its constraint is X 7 and X 9 No more than one of them is N; R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4; Its restrictions are: When X 7 and X 9 When it is CH, R 5 Not N(CH3)2; and When X 7 and X 9 One of them is N, and X 7 and X 9 When the other is CH, R 5 Not H.

10. A compound represented by the formula IK: Formula IK, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: O and N(R) 4 ); R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 4 Selected from: H and alkyl groups; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl; L is selected from: direct bonds and optionally substituted C1-C6 alkyl groups; E is selected from: H, alkyl, hydroxyl, cycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, heteroaryl, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected each time it appears from: alkyl, halogen, amine, hydroxyl, oxo, and cyano; and m can be 0, 1, 2, 3, or 4.

11. A compound represented by the formula IL: Formula IL, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4.

12. A compound represented by the formula IM: IM style Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 Selected from: alkyl, H, halogen, and alkoxy groups; R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3 to 7 atoms in the ring structure is formed, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence; R 5 Selected from: haloalkyl, cycloalkyl, cyano, H, alkyl, alkenyl, alkoxy, amine, amide, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl; and m can be 0, 1, 2, 3, or 4.

13. The compound of any one of claims 1, 2, and 6, wherein X 1 For CH.

14. The compound of any one of claims 1, 2, 6 and 13, wherein X 2 Let N be the number of elements in the array.

15. The compound of any one of claims 1, 2, 6, 13 and 14, wherein X 3 Selected from: N, CH, COLE and CN(R) 4 )-LE.

16. The compound according to any one of claims 1, 2, 6 and 13-15, wherein X 3 Selected from: N and CH.

17. The compound according to any one of claims 1, 2, 6 and 13-15, wherein X 3 Selected from: CO-CH(R) 4 )-CH2-OH and C-NH-CH(R 4 )-CH2-OH.

18. The compound of any one of claims 1, 2, 6 and 13-17, wherein X 5 For CH.

19. The compound of claim 1, 2 or 6, wherein the compound contains X 2 X 3 X 4 and X 5 The ring is selected from: and , Where s1 indicates a connection to N and R 3 The replacement ring, and s2 indicates connection to the ring containing X. 5 and X 6 The ring.

20. The compound of any one of claims 1, 6 and 13-19, wherein X 5 For CH.

21. The compound according to any one of claims 1, 6 and 13-20, wherein X 6 For CH.

22. The compound according to any one of claims 1-9 and 13-21, wherein X 7 Let N be the number of elements in the array.

23. The compound according to any one of claims 1-5 and 13-22, wherein X 8 For CR 5 .

24. The compound according to any one of claims 1-5 and 13-23, wherein R 5 Selected from: alkyl, cycloalkyl, haloalkyl and halogen.

25. The compound according to any one of claims 1-9 and 13-24, wherein X 9 For CH.

26. The compound of any one of claims 1-25, wherein R 1 Selected from: alkyl and halogens.

27. The compound of any one of claims 1-26, wherein R 1 Selected from: methyl.

28. The compound of any one of claims 1-27, wherein R 2 Selected from: H, halogens, alkyl groups, alkoxy groups, amines, and haloalkyl groups.

29. The compound of any one of claims 1-28, wherein R 2 Selected from: trifluoromethyl and H.

30. The compound of any one of claims 1-29, wherein R 3 Selected from: H, alkyl, haloalkyl, alkoxy, haloalkoxy, and halogen, or two of the Rs. 3 Optionally, together with the carbon atom to which it is attached, a cycloalkyl or heterocyclic ring having 3-7 atoms is formed in the ring structure, wherein the cycloalkyl or heterocyclic ring is optionally substituted with a substituent selected from alkyl, haloalkyl, alkoxy, CN and halogen in each occurrence.

31. The compound according to any one of claims 1-30, wherein the compound contains (R) 3 ) m The ring is selected from: and .

32. The compound according to any one of claims 1-31, wherein the compound contains (R) 3 ) m The ring is .

33. The compound according to any one of claims 1-4, 6-8, 10 and 13-32, wherein R 4 For H.

34. The compound of any one of claims 1-33, wherein R 5 Selected from: H, alkyl, alkenyl, alkoxy, amine, amide, haloalkyl, cycloalkyl, phosphine oxide, halogen, haloalkoxy, cyano and cyanoalkyl.

35. The compound of any one of claims 1-34, wherein R 5 Selected from: H, trifluoromethyl, isopropyl, cyclopropyl, cyclobutyl, alkenyl, cyano, chlorine, bromine, and .

36. The compound of any one of claims 1-35, wherein R 5 Selected from: trifluoromethyl, cyclopropyl and .

37. The compound of any one of claims 1-36, wherein R 5 It is trifluoromethyl.

38. The compound of any one of claims 1-4, 6-8, 10 and 13-37, wherein L is an optionally substituted C1-C6 alkyl group.

39. The compound according to any one of claims 1-4, 6-8, 10 and 13-38, wherein L is selected from: and .

40. The compound according to any one of claims 1-4, 6-8, 10 and 13-39, wherein L is selected from: and .

41. The compound of any one of claims 1-4, 6-8, 10 and 13-40, wherein E is selected from: H, methyl, cyclopropyl and hydroxyl.

42. A compound selected from: And its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers.

43. A pharmaceutical composition comprising a compound of any one of claims 1-42 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

44. A method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-42 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 43.

45. The method of claim 44, wherein the cancer is selected from: 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, hematogenous cancer, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

46. ​​The method of claim 44 or 45, wherein the cancer has a BRAF oncogenic mutation.

47. The method of any one of claims 44-46, wherein the cancer has a RAS oncogenic mutation.

48. The method of any one of claims 44-47, wherein the cancer has an NRAS oncogenic mutation.

49. The method of claim 48, wherein the NRAS oncogenic mutation is an NRAS Q61R or NRAS Q61K mutation.

50. The method of any one of claims 44-49, wherein the cancer has a KRAS oncogenic mutation.

51. The method of claim 50, wherein the KRAS oncogenic mutation is KRAS G12D, KRAS G12V, KRASG12C, KRAS G12R, or KRAS G13D.

52. The method of any one of claims 44-51, wherein the cancer has an NF1 oncogenic mutation.

53. A method of treating a patient with a condition selected from: 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, hematogenous cancer, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-42 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 43.

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