Dual RAF and tubulin inhibitors and methods of use thereof

Abstract

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

Description

CROSS-REFERENCE

[0001] This application claims priority to U.S. Provisional Application No. 63 / 507,785, filed June 13, 2023, and U.S. Provisional Application No. 63 / 587,806, filed October 4, 2023, each of which is incorporated by reference herein in its entirety. BACKGROUND

[0002] BRAF V600X(i.e., V600E) mutants of BRAF are known to be oncogenic, and a variety of BRAF inhibitors are now commercially available to inhibit signaling by oncogenic BRAF V600E in melanoma and other cancers. BRAF V600E signals as a monomer and has constitutive activity independent of upstream RAS control. Commercially available BRAF V600E inhibitors include vemurafenib, dabrafenib, and encorafenib.

[0003] In addition to BRAF V600Xmutants, nearly all other oncogenic forms of BRAF signal through formation of homodimers (BRAF-BRAF dimers) or heterodimers (e.g., BRAF-CRAF dimers), which are refractory to treatment with BRAF V600Xinhibitors (e.g., vemurafenib, dabrafenib, and encorafenib). Such dimers form in cancers driven by BRAF fusions, atypical BRAF mutations, or RAS mutations.

[0004] Carcinogenic BRAF fusion genes arise from genomic rearrangements that place the 3' portion of the BRAF gene, which encodes the kinase domain, after the 5' end of another gene. The result of the rearrangement is the expression of oncogenic proteins that exhibit constitutive kinase activity due to the loss of the N-terminal autoinhibitory domain of BRAF as a result of the genomic rearrangement. These BRAF fusion proteins have constitutive kinase activity due to spontaneous dimerization and thus are able to aberrantly signal in cancer cells independent of upstream effectors or regulatory mechanisms. Furthermore, some 5' translocation partner genes facilitate N-terminal domains that are able to further induce dimerization, enhancing the activated dimerization of the BRAF fusion protein kinase domain. Because expression of these genomic rearrangements is controlled by the promoter of the 5' partner, overexpression of the BRAF fusion transcript often results from high or excessive promoter activity. BRAF fusions are one of the most common kinase translocations in solid tumors. Since their first description as oncogenes in papillary thyroid cancer in 2005, hundreds of tumors have been identified in at least 15 different tumor types, in which the BRAF kinase domain is fused to one of over 110 different 5' partner genes. BRAF fusions are found in papillary thyroid cancer, astrocytoma, melanoma, and also in drug-resistant EGFR mutant lung cancer. BRAF fusion proteins signal in a RAS-independent dimerization manner and are resistant to many BRAF inhibitors such as vemurafenib and dabrafenib, which cannot simultaneously inhibit both protomers of the signaling homodimer BRAF fusion. Rare CRAF fusion proteins have also been shown to be tumor drivers. These CRAF fusion proteins signal as CRAF-CRAF homodimers.

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

[0006] RAS mutant cancers account for approximately 26-30% of all human cancers. RAS mutant cancers signal through the RAS-RAF-MEK-ERK MAPK signaling pathway. In this signaling cascade, kinase-inactive RAF monomers (comprising ARAF, BRAF, CRAF isoforms) are recruited to oncogenic RAS, which then induces them to form signaling RAF dimers with kinase activity. The predominant RAF heterodimer recruited to mutant RAS is the wild-type BRAF / CRAF heterodimer.

[0007] A combinatorial siRNA screening approach identified that knockdown of BRAF and CRAF, along with knockdown of the autophagy gene ATG7, produced the best synthetic lethal inhibition of RAS mutant signaling. Moreover, this combined knockdown strategy provided the best therapeutic window between inhibition of RAS mutant cell signaling and normal RAS wild-type cell signaling. Furthermore, it has been reported that inhibition of the RAF MEK ERK pathway in combination with autophagy inhibitors effectively blocked the growth of RAS mutant cancers in vitro and in vivo.

[0008] Vertical inhibition of the RAF MEK ERK pathway by pan-inhibition of RAF (BRAF + CRAF) and ERK kinase activity was shown to produce highly synergistic effects in blocking MAPK pathway signaling in KRAS mutant pancreatic cancer cells, organoid studies, and murine models of KRAS mutant pancreatic cancer. Vertical inhibition of RAF (BRAF + CRAF) and MEK kinase activity was also shown to be synergistic in KRAS mutant tumors.

[0009] The importance of inhibiting both BRAF and CRAF isoforms, and the necessity for inhibitors to successfully bind and inhibit both protomers of the signaling RAF dimer, has been well established. In RAS mutant cancers, RAF inhibitors, particularly BRAF V600X inhibitors, have failed to successfully bind and inhibit both protomers of the signaling RAF dimer, resulting in paradoxical pathway stimulation rather than the 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. In particular, there is a need to identify RAF inhibitors that can simultaneously inhibit both RAF protomers present in the signaling BRAF / BRAF homodimer, as well as both protomers in the BRAF / CRAF heterodimer. Such pan-RAF inhibitors can be useful for the treatment of BRAF V600X driven cancers, atypical BRAF mutant cancers, BRAF fusion cancers, CRAF fusion cancers, and RAS mutant cancers.

[0011] Microtubules (MTs) are the main components of the cytoskeleton in eukaryotic cells and play an important role in a variety of cellular functions, including maintenance of cell morphology, signaling, organelle transport, cell motility, cell division, and mitosis. These cytoskeletal filaments are composed of a- and β-tubulin heterodimers. Microtubule dynamics (assembly and disassembly) are critical for the proper functioning of the mitotic spindle and completion of mitosis. This highly regulated process is driven by GTP hydrolysis on the β-tubulin subunit. Therefore, interference with MT dynamics is suitable for anticancer therapy. Interfering with MT dynamics has been shown to exhibit anticancer activity in tumors driven by mutant RAS and mutant RAF.

[0012] Microtubule-targeting agents (MTAs) have antiangiogenic and vascular disrupting effects in addition to their other effects on cellular functions. By affecting the microtubular network, MTAs are able to inhibit the proliferation, migration, and tube formation of endothelial cells and cause significant changes in the morphology of endothelial cells. MTAs are also evaluated as potential vascular disrupting agents (VDAs). VDAs are known to block blood flow primarily in solid tumors, while leaving blood vessels in normal tissues intact.

[0013] MTAs are primarily classified into three categories according to their binding sites with a- or β-tubulin. MTAs that bind to the taxane site include taxanes and epothilones. These microtubule stabilizers bind to already formed microtubules and prevent the disassembly of tubulin subunits. In contrast, vinca alkaloids act on the vinca domain in the tubulin dimer and inhibit its polymerization into microtubules (i.e., as microtubule destabilizers). Colchicine and colchicine-binding site inhibitors (CBSIs) act on a unique site on tubulin (at the interface of the a- and β-subunits of the tubulin heterodimer), constituting a third class of antimitotic agents. Like vinca alkaloids, these agents also act as microtubule destabilizers.

[0014] Compounds that alter microtubule function have been shown to be highly active in cancer patients. Currently, taxanes and vinca alkaloids are widely used in a variety of indications, including solid tumors and hematological malignancies. There is no orally available CBSI approved as an anticancer agent.

[0015] The main challenges faced by currently clinically used MTAs, especially taxanes, include systemic toxicity, acquired resistance, limited route of administration to intravenous route only, poor water solubility requiring the use of surfactants for intravenous administration (with the risk of anaphylaxis), and disease recurrence in the treatment of advanced patients. The MTAs approved for clinical use have dose-limiting neurotoxicity and hematopoietic system toxicity.

[0016] A common mechanism of multi-drug resistance (MDR), ATP-binding cassette (ABC) transporter-mediated drug efflux, limits the efficacy of taxane drugs. P-glycoprotein (P-gp, encoded by the MDRl gene) is an important member of the ABC superfamily. P-gp prevents the intracellular accumulation of these cancer drugs by increasing their efflux from cancer cells. Overexpression of MDR proteins is prevalent in most solid tumors and can lead to treatment failure and uncontrolled disease progression. Other mechanisms of resistance include upregulation of drug efflux pumps, multidrug resistance-associated protein 1 (MRPl), breast cancer resistance protein (BCRP), or altered expression of tubulin isoforms, and mutations in the beta-tubulin gene.

[0017] Drug combinations involving agents with different anticancer mechanisms are often used to enhance tumor response and improve patient survival, especially in the treatment of advanced cancer patients. There is a close interaction between the RAS / MAPK pathway and the microtubule-dependent MYC regulatory pathway. For example, a large genetic loss-of-function siRNA screening study found that TUBB3 (encoding the beta III-tubulin isoform) is a key vulnerability target in pancreatic cancer. Genetic silencing of TUBB3 sensitized KRAS mutant pancreatic ductal adenocarcinoma (PDAC) cells to ERK inhibition, suggesting that pharmacological inhibition of proteins that support MYC expression (e.g., microtubulin inhibitors) can be an effective therapeutic strategy to target mutant KRAS-dependent PDAC. TUBB3 is also clinically relevant because overexpression of this beta-tubulin isoform is associated with poor treatment response to microtubule-targeting drugs such as taxanes. Stronger 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, with abnormal expression of TUBB3 being associated with enhanced chemoresistance and poor prognosis in NSCLC, ovarian cancer, gastric cancer, breast cancer, and uterine serous carcinoma.

[0018] Microtubulin disruptors have also been shown to upregulate MAPK pathway signaling, which limits the efficacy of microtubulin disruptors. A dual-targeting agent that can both target microtubulin and inhibit MAPK pathway signaling would overcome this MAPK pathway reactivation-mediated resistance mechanism.

[0019] Dual-targeting drugs (a single molecule that interacts with two different biological targets) can also offer advantages over combination therapy, particularly lower risk of drug-drug interactions, more predictable pharmacokinetic (PK) profiles, simplified dosing regimens, and increased patient compliance.

[0020] In view of the current high resistance to MAPK-targeted therapeutics, identifying agents that possess both BRAF inhibition and microtubule disruption activity is expected to overcome BRAF inhibitor resistance and bring significant clinical benefits to patients with various solid tumors, including ovarian cancer, colorectal cancer, and papillary thyroid cancer. Meanwhile, drugs that can both inhibit BRAF and CRAF (i.e., pan-RAF inhibitors) and disrupt tubulin are also expected to benefit patients with mutant RAS cancers, thereby providing more in-depth and durable anticancer effects. The compounds, compositions, and methods of use described herein are designed to meet this need. SUMMARY

[0021] Described herein are compounds that are dual inhibitors of RAF and tubulin and methods of use thereof.

[0022] In one embodiment, the present application provides a compound represented by Formula I-A: Formula I-A or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein Z is selected from the group consisting of: , , and an optionally substituted 5-membered ring heteroaryl; Q 1 and Q 2 are each independently selected from O or NH; X 1 , X 2 , and X 5 are each independently selected from CH or N; X 3 and X 4 are each independently selected from the group consisting of N, CH, C=0, C-0-L-E, C-L-E, C-N(R 4 )-L-E, and N-L-E; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 or N; provided that no more than two of X 2 , X 3 , X 4 , and X 5 are N; no more than one of X 6 and X 7 is N; no more than one of X 8 , X 9 , and X 10 is N; when X 3 is N, X 4For COLE, CLE, CN(R) 4 -LE, N, or CH; when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; when X 3 When C=O, X 4 For NLE; when X 4 When C=O, X 3 For NLE; R 1 Selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently and optionally substituted with a substituent selected from the group consisting of: amino, halogen, cyano, cycloalkyl, and heterocyclic; wherein the cycloalkyl or cycloalkylalkyl substituent is independently and optionally substituted with a substituent selected from halogen and alkyl; wherein the heterocyclic substituent is independently and optionally substituted with a substituent selected from halogen and alkyl; wherein the heteroaryl substituent is independently and optionally substituted with a substituent selected from halogen and alkyl; R 1a and R 1b Independently selected from H, alkyl, and cycloalkyl; when R 1a and R 1b When it is an alkyl group, it can react with R. 1a and R 1b The attached N atoms cyclize together to form a heterocyclic base ring; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocyclic ring having 4-6 atoms in the ring structure; L is selected from the group consisting of direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected from the group consisting of alkyl, halogen, amino, hydroxyl, oxo, and cyano groups each time it appears; and p is 0 or 1.

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

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

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

[0026] In another embodiment, described herein is a compound described herein (e.g., a compound of the present application described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein, for use in therapy. ， In another embodiment, described herein is a compound described herein (e.g., a compound of the present application described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein, for use in therapy.

[0027] In another embodiment, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of the present application described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein. ， In another embodiment, described herein is a compound described herein (e.g., a compound of the present application described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein, for use in a method of treating cancer in a patient in need thereof.

[0028] In another embodiment, described herein is a compound described herein (e.g., a compound of the present application described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a composition described herein, for use in a method of treating cancer in a patient in need thereof. ，The compound described herein (or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer), or the composition described herein, in a method of treating a patient in need of a condition selected from the group consisting of 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. Attached Figure Description

[0029] Figure 1 This is a graph showing the maximum rate of tubulin polymerization as the concentration of the known tubulin depolymerizing agent plinabulin increases.

[0030] Figure 2 This is a graph showing the ratio of precipitate (polymerized tubulin) to supernatant (tubulin dimers) relative to the DMSO control group as the concentration of the known tubulin depolymerizing agent purnabulin increases. Invention Details The features and other details of this application are now detailed below. Specific terms used in this specification, embodiments, and appended claims are compiled herein. These definitions should be understood in conjunction with the remainder of this application 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 one of ordinary skill in the art.

[0032] Definitions The definitions set forth in this application are intended to clarify the terminology used throughout this application.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Unless otherwise stated, the following terms have the meanings assigned to facilitate understanding of this application as used in the specification and appended claims.

[0034] 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 a substituent is bonded to any atom of the remaining part of the compound in the given formula, such a substituent may be bonded to any atom of such a substituent. Such combinations are permitted only if the combination of substituents, substituent positions, and / or variables produces a stable compound.

[0035] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0036] As used herein, the term "herein" refers to the entire application.

[0037] As used herein, "deuterated" means at least one hydrogen atom is replaced with deuterium. In any sample of a deuterated compound, some discrete molecules of the compound can have hydrogen instead of deuterium at the indicated position. However, the percentage of molecules of the deuterated compound that have deuterium at the indicated position will be substantially greater than the naturally occurring compound. The deuterium at the deuterated position is enriched.

[0038] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes situations where the event or circumstance occurs and situations where it does not. For example, "optionally substituted alkyl" means that the alkyl can be substituted and that the alkyl can be unsubstituted.

[0039] It will be appreciated by those skilled in the art that the substituents and substitution patterns for the disclosed compounds can be selected to generate chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and those set forth below. Where a substituent is itself substituted with more than one group, it will be understood that the groups can be on the same carbon or on different carbons, as long as a stable structure results.

[0040] As used herein, the term "optionally substituted" means from 1 to 6 hydrogen atoms in the indicated structure are replaced with groups of the indicated substituents, including but not limited to: hydroxy, hydroxyalkyl, alkoxy, halo, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OC(=0)-CH2-0alkyl. Preferably, "optionally substituted" means from 1 to 4 hydrogen atoms in the indicated structure are replaced with the substituents mentioned above. More preferably 1 to 3 hydrogen atoms are replaced with the substituents as mentioned above. It will be appreciated that the substituents can be further substituted.

[0041] As used herein, the term “substituted” refers to a portion of the main chain having a substituent with a hydrogen substituted group on one or more carbons. It should be understood that “substitution” or “substituted” includes the implicit limitation 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 transformation (e.g., by rearrangement, cleavage, decomposition, cyclization, elimination, or other reactions). As used herein, the term “substituted” encompasses all permissible substituents, including those 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, for example, a nitrogen heteroatom may have a hydrogen substituent, and / or any permissible substituent in organic compounds that satisfies the heteroatom valence as described herein.

[0042] Substituents may include any substituents described herein, such as those that, unless otherwise specified, may include, for example, halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, phosphonites, amino groups, amide groups, amidine groups, imino groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate esters, sulfonates, aminesulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, heteroaralkyl 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 in 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 part herein should be understood to include substituted variants. For example, references to the "aryl" group or part of the reference implicitly include both substituted and unsubstituted variants.

[0043] 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. 10alkyl, or, for example, C1-C6alkyl. Examples of straight- chain and branched- chain alkyl groups include, but are not limited to, methyl, ethyl, 1 -propyl (n-propyl), 2-propyl, n-butyl, sec-butyl, t-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 the like. Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having one or more hydrogens on the hydrocarbon backbone replaced by a substituent group. "Alkyl" groups can be optionally substituted.

[0044] The term "C x -C y " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is intended to include groups containing from x to y carbons in the chain. For example, the term "C x -C y " refers to a substituted or unsubstituted saturated hydrocarbon group, containing from 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, and the like. Co alkyl represents a hydrogen when the group is at a terminal position and a bond when internal.

[0045] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom that does not have =0 or =S substituents, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but can optionally include heteroatoms. Thus, for the purposes of the present application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl, but substituents such as acetyl (which has a =0 substituent on the connecting carbon) and ethoxy (which is connected through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. "Hydrocarbyl" groups can be optionally substituted.

[0046] As used herein, the term "alkoxy" refers to a straight- chain or branched- chain, saturated aliphatic (alkyl) hydrocarbyl group bonded to an oxygen atom that is attached to a core structure. Preferably, the alkoxy group has 1-6 carbon atoms, i.e., can be a C1-C6alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, 3-methylbutoxy, and the like. "Alkoxy" groups can be optionally substituted.

[0047] As used herein, the term "alkoxyalkyl" refers to an alkyl group (as defined above) substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to: methyl-O-ethylene-, ethyl-O-ethylene-. An "alkoxyalkyl" group can be optionally substituted.

[0048] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogen. For example, a monohaloalkyl group can have a chlorine, bromine, iodine, or fluorine atom. Di- and polyhaloalkyl groups can have two or more halogen atoms, which can be the same or different. 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 the like. A "haloalkyl" group can be optionally substituted.

[0049] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group is replaced with one or more halogen. Representative examples of "haloalkoxy" groups include, but are not limited to: difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3). A "haloalkoxy" group can be optionally substituted.

[0050] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom in the ring is carbon. 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 in which two or more carbons are shared by two adjacent rings (fused rings), at least one of which is aromatic, for example, the other of which can be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl group. The term "fused" means attached or formed by sharing two adjacent atoms with a first ring by a second ring. The term "fused" is equivalent to the term "condensed." Examples of aryl groups include, but are not limited to: phenyl, naphthyl, phenanthryl, phenol, aniline, or dihydroindenyl groups, and the like. Unless otherwise specified, all aryl groups described herein can be optionally substituted.

[0051] As used herein, the terms "polycyclyl," "polycyclic," and "polycyclic ring" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl), in which one or more atoms are shared by two adjacent rings, e.g., the rings are "fused." Each ring in a polycyclic ring can be substituted or unsubstituted. In certain embodiments, each ring in a polycyclic ring contains 3-10, preferably 5-7 atoms in the ring.

[0052] As used herein, the term "acyl" refers to the group -C(=0)-R w wherein Rw The alkyl group may be substituted. Examples of "acyl" include (but are not limited to) alkyl groups in which 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 optional substituents are selected independently from the group consisting of H, OH, alkoxy, cyano, F, and amino groups each time they appear. Other examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3)2.

[0053] As used in this article, the term "formyl" refers to the group -C(=O)H.

[0054] As used herein, the terms "sulfonamide" and "sulfonamido" are represented 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, completes a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0055] As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and their salts, for example, portions that can be represented by the following formula: or Where R z Independently representing hydrogen or an optionally substituted hydrocarbon group, or R z The group, together with the N atom to which it is attached, completes a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0056] As used herein, the terms "amide" and "amide group" refer to groups represented by the following: 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 completes a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0057] As used herein, the term "amidine" refers to a group represented by: wherein R x , R y and R z each independently represents hydrogen or optionally substituted hydrocarbyl, or R y and R z together with the N atom to which they are attached complete a heterocyclic ring having 4-8 atoms in the ring which can be optionally substituted.

[0058] As used herein, the term "phosphine oxide" refers to a group represented by: wherein R z each independently represents hydrogen or optionally substituted hydrocarbyl.

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

[0060] As used herein, the term "amidoalkyl" refers to an alkyl group substituted with an amido group.

[0061] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0062] 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-.

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

[0064] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

[0065] As used herein, the term "cycloalkyl," alone or in combination with other terminology, refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic rings. Typically, unless otherwise defined, monocyclic cycloalkyl groups have 3 to about 10 carbon atoms, more typically 3-8 carbon atoms (e.g., C3-C8cycloalkyl). "Cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. 10 cycloalkyl, or for example, C 3-C6cycloalkyl). Examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The second ring of a bicyclic cycloalkyl group, or the second or third ring of a tricyclic cycloalkyl group, can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl groups include bicyclic and tricyclic molecules in which two rings share one, two, or three or more atoms. The term "fused cycloalkyl" refers to bicyclic or tricyclic cycloalkyl groups in which each of the rings shares two adjacent atoms with another ring. The second ring of a fused bicyclic cycloalkyl group, or the second or third ring of a fused tricyclic cycloalkyl group, can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyl groups can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like. Cycloalkyl groups can alternatively be polycyclic having more than two rings. Examples of polycyclic cycloalkyl groups include bridged, fused, and spirocyclic carbocyclic groups.

[0066] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

[0067] As used herein, the term "carbocyclic" or "carbocyclic" includes bicyclic molecules in which two rings share one, two, or three or more atoms. The term "fused carbocyclic" refers to bicyclic carbocyclic rings in which each of the rings shares two adjacent atoms with another ring. Each ring of a fused carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can 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 carbocyclic, as 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: decalin, 4,5-naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-l H indene, and bicyclo[4.1.0]hept-3-ene. A "carbocyclic" can be substituted at any one or more positions capable of having a hydrogen atom.

[0068] As used herein, the term "cyano" refers to a -CN group.

[0069] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0070] As used herein, the term "halo" or "halogen," alone or in combination with other terminology, refers to chloro, fluoro, bromo, and iodo.

[0071] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0072] As used herein, the terms "heterocyclyl," "heterocycloalkyl," "heterocycle," and "heterocyclic" refer to non-aromatic, saturated or partially saturated, including monocyclic, polycyclic (e.g., bicyclic rings, tricyclic rings) bridged or fused 3-15 membered ring systems, the members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), with the remaining ring atoms independently selected from carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclyl" include, but are not limited to: azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur through a carbon atom or through a heteroatom. A heterocycloalkyl group can be optionally substituted by one or more of the foregoing groups through one or more suitable groups. Preferably, "heterocyclyl" refers to a 5- to 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and N-oxides thereof. More preferably, "heterocyclyl" includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. All heterocyclyl groups are optionally substituted by one or more of the foregoing groups.

[0073] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic ring, preferably 5- to 7-membered ring, more preferably 5- to 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 (bi-, tri-, or polycyclic), containing 8-20 ring atoms, suitably 5-10 ring atoms, which can be covalently linked or fused, wherein two or more atoms are shared by two adjacent rings, wherein at least one of the rings is heteroaromatic, for example, another cyclic ring can be: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The ring can contain N or S atoms, wherein the N or S atoms are optionally oxidized, or the N atoms are optionally quaternized. All heteroaryl groups are optionally substituted. Any suitable ring position of the heteroaryl moiety can be covalently linked to the defined chemical structure. Examples of heteroaryl groups include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothiophenyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9 H - carbazolyl, a-carboline, indolizidinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridinyl, furanopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriadiazolyl, 7-azaindolyl, 7-azaindazolyl, pyrrolopyrimidinyl, oxazolotinyl, imidazolotinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, oxazolonepyridinyl, oxazolonepyrimidinyl, imidazolonepyridinyl, imidazolonepyrimidinyl, tetrahydronaphthyridinyl, tetrahydropyridopyrimidinyl, dihydronaphthyridonyl, naphthyridonyl, oxazinonepyridinyl, oxazinonepyrimidinyl, carbazolyl, dibenzothiophenyl, acridinyl, and the like.

[0074] As used herein, the term "sulfonyl" or "sulfonyl group" refers to the group -S(O)2-R 6d wherein R 6d represents an optionally substituted hydrocarbyl group.

[0075] As used herein, within a ring, when valence permits and results in a stable ring moiety, refers to a single bond or a double bond. In certain embodiments, the variable X 2 , X3 , X 4 and X 5 the ring, where valence number permits, contains single or double bonds to form a stable aromatic ring moiety.

[0076] “Combination therapy” is a treatment that includes administration of two or more therapeutic agents, e.g., a compound of the application and a MAPK pathway inhibitor, to a patient in need thereof.

[0077] “Disease,” “disorder,” and “condition” are used interchangeably herein.

[0078] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds described herein can be administered not only to mammals such as humans, but also to other mammals such as animals in need of veterinary treatment, e.g., domestic animals (such as dogs, cats and the like), farm animals (such as cows, sheep, pigs, horses and the like) and laboratory animals (such as rats, mice, guinea pigs and the like).

[0079] As used herein, the MAPK pathway is a signal transduction pathway comprising RAS→RAF→MEK→ERK.

[0080] A “MAPK pathway inhibitor” is an inhibitor of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (such as AMG-510, MRTX 849), RAF inhibitors (such as dabrafenib, vemurafenib, LY3009120, encorafenib), MEK inhibitors (such as trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (such as ulixertinib, SCH772984, LY3214996, ERAS-007). The terms “MAPK pathway inhibitor” and “MAP kinase inhibitor” are used interchangeably herein.

[0081] “Pharmaceutically or pharmacologically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal or a human as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0082] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonics, and absorption delay agents, and the like, compatible with drug administration. The use of such media and agents for the active pharmaceutical ingredient is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0083] As used herein, the term "pharmaceutical composition" means a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0084] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing an acidic or basic group that may be present in the compound 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 a variety of inorganic and organic acids. The acid used to prepare such basic compounds is an acid that forms a non-toxic acid addition salt; said non-toxic acid addition salt is a salt containing a pharmacologically acceptable anion, including but not limited to: malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, trans-butenedioate, gluconate, glucuronide, glucosyl ether, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, etc. Against Toluenesulfonate and dihydroxynaphthyl salt (i.e., 1,1'-methylene- Double -(2-hydroxy-3-naphthylcarbamate)). 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 of this application may contain 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.

[0085] The compounds of the present application can contain one or more chiral centers and, therefore, exist as stereoisomers. The term "stereoisomers" when used in this text comprises all enantiomeric or diastereomeric forms. These compounds can be designated by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. Those skilled in the art will recognize that the structure can implicitly indicate the chirality center. These compounds can also be designated by "(+)" and "(-)", based on their optical rotational properties. The compounds described in the present application encompass the various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomeric or diastereomeric forms can be designated in nomenclature by the symbol "(±)", but those skilled in the art will recognize that the structure can implicitly indicate the chirality center.

[0086] In this specification, the term "therapeutically effective amount" refers to the amount of a compound of the present application that will elicit the biological or medical response of a tissue, system, or animal (e.g., mammal or human) that is being sought by a researcher, veterinarian, medical doctor or other clinician. The compounds described herein are administered in therapeutically effective amounts to treat a disorder.

[0087] "Treat" includes any effect, e.g., alleviating, reducing, modulating, or eliminating, that results in improvement of a condition, disease, disorder, etc.

[0088] The present application also encompasses isotopically-labeled compounds identified herein, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, respectively 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, the compounds of the present application can have one or more H atoms replaced by deuterium.

[0089] Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials incorporating asymmetric or stereocenters, or by preparation of racemic mixtures followed by resolution by methods well known to those skilled in the art. These resolution methods are exemplified by: (1) attachment to a chiral auxiliary, separation of the resulting mixture of diastereomers, and release of the optically pure product from the auxiliary; (2) formation of a salt with an optically active resolving agent; (3) direct separation of the mixture of optical enantiomers on chiral liquid or solid chromatographic columns; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallization in a chiral solvent. Stereo-selective synthesis, which forms stereoisomeric mixtures of unequal amounts of the stereoisomers of a single reactant either during the creation of a new stereocenter or during the transformation of a pre-existing stereocenter, is well known in the art. Stereo-selective synthesis encompasses both enantio- and diastereo-selective transformations, and can involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis , Wiley-VCH: Weinheim, 2009.

[0090] As used herein, “a compound of the application” includes a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0091] Compounds In one embodiment, provided herein is a compound represented by Formula I-A: Formula I-A or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: Z is selected from the group consisting of: 、 、 and an optionally substituted 5-membered ring heteroaryl; Q 1 and Q 2 are each independently selected from O and NH X 1 , X 2 and X 5 are each independently selected from CH and N; X 3 and X 4each independently selected from the group consisting of N, CH, C=0, C-0-L-E, C-L-E, C-N(R 4 )-L-E, and N-L-E; X 6 is selected from CH or N; X 7 is selected from CH, CF, and N; X 8 and X 10 each independently is selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 or N; provided that: no more than two of X 2 , X 3 , X 4 , and X 5 are N; provided that: no more than one of X 6 and X 7 is N; provided that: no more than one of X 8 , X 9 , and X 10 is N; provided that: when X 3 is N, X 4 is C-0-L-E, C-L-E, C-N(R 4 )-L-E, N, or CH; provided that: when X 4 is N, X 3 is N, CH, C-0-L-E, C-L-E, or C-N(R 4 )-L-E; provided that: when X 3 is C=0, X 4 is N-L-E; provided that: when X 4 is C=0, X 3 is N-L-E; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; R 1a and R 1b are independently selected from the group consisting of H, alkyl, cycloalkyl; when R 1a and R 1b are alkyl, they can be cyclized together with the N atom to which they are attached to form a heterocyclyl ring; 1a and R 1b are alkyl, they can be cyclized together with the N atom to which they are attached to form a heterocyclyl ring; R 2 is selected from the group consisting of alkyl, H, halo, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 is selected from H or alkyl; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halo, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R 3 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently at each occurrence selected from the group consisting of alkyl, halo, amino, hydroxyl, oxo, and cyano; and p is 0 or 1.

[0092] In some embodiments, Q 1 is O and Q 2 is O. In other embodiments, Q 1 is O and Q 2 is NH. In some embodiments, Q 1 is NH and Q 2 is O.

[0093] In some embodiments, Z is an optionally substituted 5-membered ring heteroaryl represented by ; wherein R 6 is independently at each occurrence selected from H or alkyl.

[0094] In some embodiments, provided herein is a compound of Formula I-B: Formula I-B or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: Q 1 and Q 2 are each independently selected from O or NH; X 1 , X 2 , and X 5 are each independently selected from CH or N; X 3 and X 4 are each independently selected from the group consisting of N, CH, C=0, C-0-L-E, C-L-E, C-N(R 4 )-L-E, and N-L-E; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 and N; provided that no more than two of X 2 , X 3 , X 4 , and X 5 are N; provided that no more than one of X 6 and X 7 is N; provided that no more than one of X 8 , X 9 , and X 10 is N; provided that when X 3 is N, X 4 is C-0-L-E, C-L-E, C-N(R 4 )-L-E, N, or CH; provided that when X 4 is N, X 3 is N, CH, C-0-L-E, C-L-E, or C-N(R 4 )-L-E; provided that when X 3 is C=0, X4 is N-L-E; provided that when X 4 is C=O, X 3 is N-L-E; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy; wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen or alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen or alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen or alkyl; R 2 is selected from the group consisting of alkyl, H, halogen, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 is selected from H and alkyl; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R 3 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently at each occurrence selected from the group consisting of alkyl, halogen, amino, hydroxy, oxo, and cyano.

[0095] In one embodiment, provided herein is a compound of Formula I-C: Formula I-C or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 X 2 X 5 each independently is selected from CH and N; X 3 X 4 each independently is selected from the group consisting of N, CH, C=0, C-0-L-E, C-L-E, C-N(R 4 )-L-E, and N-L-E; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 X 10 each independently is selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 or N; provided that no more than two of X 2 , X 3 , X 4 , and X 5 are N; provided that no more than one of X 6 and X 7 is N; provided that no more than one of X 8 , X 9 , and X 10 is N; provided that when X 3 is N, X 4 is C-0-L-E, C-L-E, C-N(R 4 )-L-E, N, or CH; provided that when X 4 is N, X 3 is N, CH, C-0-L-E, C-L-E, or C-N(R 4 )-L-E; provided that when X 3 is C=0, X 4 is N-L-E; provided that when X 4 is C=0, X 3 is N-L-E; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halo, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; R 2 selected from the group consisting of alkyl, H, halo, and alkoxy; R 3 selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 selected from the group consisting of H and alkyl; R 5 selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halo, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; 3 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently at each occurrence selected from the group consisting of alkyl, halo, amino, hydroxyl, oxo, and cyano.

[0096] In one embodiment, provided herein is a compound of Formula I-D: Formula I-D or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: X 4 selected from the group consisting of N, CH, C-O-L-E, C-L-E, and C-N(R 4 )-L-E; X 5 selected from CH or N; X 6 selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from the group consisting of CR 5 and N; provided that: no more than one of X 4 and X 5 is N; provided that: no more than one of X 6 and X 7 is N; provided that: no more than one of X 8 , X 9 and X 10 is N; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; R 2 is selected from the group consisting of alkyl, H, halogen, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 is selected from the group consisting of H and alkyl; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R 3 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optionally substituted substituent is independently at each occurrence selected from the group consisting of alkyl, halo, amino, hydroxy, oxo, and cyano.

[0097] In one embodiment, provided herein is a compound of Formula I-E: Formula I-E or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: X 8 and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from the group consisting of CR 5 and N; with the proviso that no more than one of X 8 , X 9 , and X 10 is N; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halo, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; R 2 is selected from the group consisting of alkyl, H, halo, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; and R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halo, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R5 R 3 and the carbon atom to which each is attached together form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure.

[0098] In some embodiments, R 3 is H or haloalkyl.

[0099] In one embodiment, provided herein is a compound of Formula I-F: Formula I-F or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: X 8 is selected from the group consisting of CH, CF, and N; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen and alkyl; and R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl.

[0100] In one embodiment, provided herein is a compound of Formula I-G: Formula I-G or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; and R 5 selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halo, phosphine oxide, haloalkoxy, and cyanoalkyl.

[0101] In one embodiment, provided herein is a compound of Formula I-H: Formula I-H or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: R 1 selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halo, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl; and R 3 selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, alkoxy, and amino.

[0102] In one embodiment, provided herein is a compound of Formula I-J: Formula I-J or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: X 1 , X 2 , and X 5 are each independently selected from CH and N; X 4 selected from the group consisting of N, CH, C-O-L-E, C-L-E, and C-N(R 4 )-L-E; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 and N; provided that no more than two of X 2 , X 4 , and X 5 are N; provided that no more than one of X 6 and X 7 is N; provided that no more than one of X 8 , X 9 , and X 10 is N; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from halogen and alkyl; R 2 is selected from the group consisting of alkyl, H, halogen, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 is selected from H and alkyl; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R 3and the carbon atom to which each is attached together form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, amino, hydroxyl, oxo, and cyano.

[0103] In some embodiments, X 1 , X 5 , X 6 , and X 7 are each CH.

[0104] In some embodiments, X 2 is CH.

[0105] In some embodiments, X 4 is C-L-E.

[0106] In some embodiments, X 8 is CH. In some embodiments, X 8 is N.

[0107] In some embodiments, X 9 is CR 5 .

[0108] In some embodiments, X 10 is CH.

[0109] In one embodiment, provided herein is a compound of Formula I-K: Formula I-K or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: X 1 , X 2 , and X 5 are each independently selected from CH and N; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 , and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 , and N; provided that: X2 and X 5 no more than one of which is N; provided that: X 6 and X 7 no more than one of which is N; provided that: X 8 , X 9 and X 10 no more than one of which is N; R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, haloalkyl, and haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halogen and alkyl; R 2 is selected from the group consisting of alkyl, H, halogen, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R 3 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl; and E is selected from the group consisting of H, alkyl, hydroxy, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently at each occurrence selected from the group consisting of alkyl, halogen, amino, hydroxy, oxo, and cyano.

[0110] In some embodiments, X 1 , X 5 , X 6 and X7 Each is CH.

[0111] In some implementation schemes, X 2 For CH.

[0112] In some implementation schemes, X 8 For CH. In some implementations, X 8 Let N be the number of elements in the array.

[0113] In some implementation schemes, X 9 For CR 5 .

[0114] In some implementation schemes, X 10 For CH.

[0115] In one embodiment, this document provides an IL compound: Formula IL Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q 2 Selected from O and NH; X 1 X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10not more than one is N; provided that when X 3 is N, X 4 is C-O-L-E, C-L-E, C-N(R 4 )-L-E, N, or CH; provided that when X 4 is N, X 3 is N, CH, C-O-L-E, C-L-E, or C-N(R 4 )-L-E; provided that when X 3 is C=O, X 4 is N-L-E; provided that when X 4 is C=O, X 3 is N-L-E; when p is 1, R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, and haloalkyl, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halo, cycloalkyl, and heterocyclyl; wherein the cycloalkyl or cycloalkylalkyl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; when p is 0, R 1 is selected from the group consisting of heterocyclyl and heteroaryl; wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; wherein the heteroaryl substituent is independently at each occurrence optionally substituted with a substituent selected from halo and alkyl; R 2 is selected from the group consisting of alkyl, H, halo, and alkoxy; R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 is selected from H and alkyl; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halo, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R3 and the carbon atom to which each is attached together form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, amino, hydroxyl, oxo, and cyano; and p is 0 or 1.

[0116] In some embodiments, Q 2 is O.

[0117] In some embodiments, X 1 , X 5 , X 6 , and X 7 are each CH.

[0118] In some embodiments, X 2 is CH.

[0119] In some embodiments, X 3 is N.

[0120] In some embodiments, X 4 is CH.

[0121] In some embodiments, X 8 is CH. In some embodiments, X 8 is N.

[0122] In some embodiments, X 9 is CR 5 .

[0123] In some embodiments, X 10 is CH.

[0124] In one embodiment, provided herein is a compound of Formula I-M: Formula I-M or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, wherein: Q 2 is selected from O and NH; X 1 , X 2 , and X 5 are each independently selected from CH and N; X 3 , and X4 each independently selected from the group consisting of N, CH, C=0, C-0-L-E, C-L-E, C-N(R 4 )-L-E, and N-L-E; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 and X 10 each independently selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 and N; provided that no more than two of X 2 , X 3 , X 4 , and X 5 are N; provided that no more than one of X 6 and X 7 is N; provided that no more than one of X 8 , X 9 , and X 10 is N; provided that when X 3 is N, X 4 is C-0-L-E, C-L-E, C-N(R 4 )-L-E, N, or CH; provided that when X 4 is N, X 3 is N, CH, C-0-L-E, C-L-E, or C-N(R 4 )-L-E; provided that when X 3 is C=0, X 4 is N-L-E; provided that when X 4 is C=0, X 3 is N-L-E; R 1a and R 1b are independently selected from the group consisting of H, alkyl, and cycloalkyl, or R 1a and R 1b together with the nitrogen atom to which each is attached form a heterocyclyl ring having 4-7 atoms in the ring structure; R 2 is selected from the group consisting of alkyl, H, halogen, and alkoxy; R 3selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 and R 5 together with the carbon atom to which each is attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 is selected from the group consisting of H and alkyl; R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 and R 3 together with the carbon atom to which each is attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halogen, amino, hydroxyl, oxo, and cyano.

[0125] In some embodiments, Q 2 is O.

[0126] In some embodiments, X 1 , X 5 , X 6 , and X 7 are each CH.

[0127] In some embodiments, X 2 is CH.

[0128] In some embodiments, X 3 is N.

[0129] In some embodiments, X 4 is CH.

[0130] In some embodiments, X 8 is CH. In some embodiments, X 8 is N.

[0131] In some embodiments, X 9 is CR 5 .

[0132] In some embodiments, X 10 is CH.

[0133] In one embodiment, provided herein is a compound of Formula I-N: Formula I-N or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: Q 2 is selected from O and NH; X 2 and X 5 are each independently selected from CH and N; X 3 and X 4 are each independently selected from the group consisting of N, CH, C=0, C-0-L-E, C-L-E, C-N(R 4 )-L-E, and N-L-E; X 6 is selected from CH or N; X 7 is selected from the group consisting of CH, CF, and N; X 8 and X 10 are each independently selected from the group consisting of CH, CF, and N; X 9 is selected from CR 5 and N; provided that no more than two of X 2 , X 3 , X 4 , and X 5 are N; provided that no more than one of X 6 and X 7 is N; provided that no more than one of X 8 , X 9 , and X 10 is N; provided that when X 3 is N, X 4 is C-0-L-E, C-L-E, C-N(R 4 )-L-E, N, or CH; provided that when X 4 is N, X 3 is N, CH, C-0-L-E, C-L-E, or C-N(R 4 )-L-E; provided that when X 3 is C=0, X 4 is N-L-E; provided that when X 4 is C=0, X 3 is N-L-E; R2 selected from the group consisting of alkyl, alkoxy, and halo; R 3 selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or wherein R 3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; 5 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 4 selected from the group consisting of H and alkyl; R 5 selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halo, phosphine oxide, haloalkoxy, and cyanoalkyl, or wherein R 5 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; 3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring having 4-6 atoms in the ring structure; R 6 selected from the group consisting of H and alkyl; L is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl; and E is selected from the group consisting of H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclyl, wherein the optional substituents are independently selected at each occurrence from the group consisting of alkyl, halo, amino, hydroxyl, oxo, and cyano.

[0134] In some embodiments, selected from the group consisting of: .

[0135] In some embodiments, Q 2 is O.

[0136] X 1 In some embodiments, X 1 is CH.

[0137] X 2 、X 3 、X 4 、X 5 In some embodiments, X 2 is CH.

[0138] In some embodiments, X 3 is N.

[0139] In some embodiments, X 4selected from the group consisting of N, CH, C-O-L-E, and C-N(R 4 )-L-E. In some embodiments, X 4 is selected from N and CH. In some embodiments, X 4 is selected from C-O-CH(R 4 )-CH2-OH, and C-NH-CH(R 4 )-CH2-OH.

[0140] In some embodiments, X 5 is CH.

[0141] In some embodiments, the ring containing X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of: ; wherein s1 represents the attachment to Z, , , , or , and s2 represents the attachment to the ring containing X 6 and X 7 .

[0142] X 6 、X 7 In some embodiments, X 6 is CH.

[0143] In some embodiments, X 7 is CH.

[0144] X 8 、X 9 、X 10 In some embodiments, X 8 is N.

[0145] In some embodiments, X 9 is CR 5 .

[0146] In some embodiments, R 5 is selected from the group consisting of alkyl, cycloalkyl, and haloalkyl.

[0147] In some embodiments, X 10 is CH.

[0148] R 1 In some embodiments, R 1 is selected from the group consisting of H, alkyl, (C3-C8)cycloalkyl, alkoxy, alkoxyalkyl, heterocyclyl, haloalkyl, haloalkoxy, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halo, and (C3-C8)cycloalkyl, wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl.

[0149] In some embodiments, R 1 is selected from the group consisting of H, alkyl, (C3-C8)cycloalkyl, alkoxy, alkoxyalkyl, heterocyclyl, haloalkyl, wherein the alkyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of amino, halo, and (C3-C8)cycloalkyl, wherein the heterocyclyl substituent is independently at each occurrence optionally substituted with a substituent selected from the group consisting of halo and alkyl.

[0150] In some embodiments, R 1 is selected from the group consisting of H, methyl, ethyl, methoxy, In some embodiments, wherein if p is 1, R 1 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aminoalkyl, alkoxyalkyl.

[0151] In some embodiments, if p is 0, R 1 is selected from the group consisting of heterocyclyl and heteroaryl. For example, R 1 is .

[0152] R 1a 、R 1b In some embodiments, R 1a and R 1b are independently selected from H, alkyl, cycloalkyl, or wherein R 1a and R 1b together with the carbon atom to which they are each attached form a cycloalkyl or heterocyclyl ring having 4-7 atoms in the ring structure.

[0153] R 2 In some embodiments, R 2 is selected from alkyl and halo. In some embodiments, R 2 is selected from the group consisting of methyl and fluoro.

[0154] R 3 In some embodiments, R 3 is selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, alkoxy, and amino.

[0155] In some embodiments, R 3 is selected from the group consisting of H, methyl, isopropyl, cyclopropyl, trifluoromethyl, .

[0156] In some embodiments, R 3 is H. 5 together with the carbon atom to which they are each attached form a cycloalkyl ring having 4-6 atoms in a ring structure.

[0157] R 4 In some embodiments, R 4 is H.

[0158] R 5 In some embodiments, R 5 is selected from the group consisting of haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amido, halogen, phosphine oxide, haloalkoxy, and cyanoalkyl.

[0159] In some embodiments, R 5 is selected from the group consisting of H, L In some embodiments, L is optionally substituted C1-C6 alkyl. In some embodiments, L is selected from the group consisting of: wherein E is connected to the carbon identified by *. In some embodiments, L is selected from the group consisting of: wherein E is connected to the carbon identified by *.

[0160] E In some embodiments, E is selected from the group consisting of H, methyl, and hydroxyl.

[0161] In some embodiments, the compound is selected from the group consisting of:

[0162] and pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

[0163] Therapeutic methods The compounds described herein (e.g., compounds of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof) can act as dual RAF and tubulin inhibitors, and are therefore useful for treating diseases and conditions, e.g., cancers, in a patient in need thereof. 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 tumor, solid tumors, blood-borne cancers, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS - RAF - MEK - ERK signaling pathway. In some embodiments, the cancer described herein is a BRAF V600X, atypical BRAF mutation, BRAF fusion, CRAF fusion, or RAS mutation driven cancer. In some embodiments, the cancer has a BRAF oncogenic mutation. In some embodiments, the cancer has a RAS oncogenic mutation. In some embodiments, the RAS oncogenic mutation is a RAS Q61R or Q61K mutation. In some embodiments, the cancer has a NF1 oncogenic mutation. In some embodiments, the lung cancer is a non-small lung cancer (NSCL). In some embodiments, the colorectal cancer is colon cancer. In some embodiments, the colorectal cancer is rectal cancer.

[0164] In some embodiments, provided herein is a compound described herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, for use in therapy.

[0165] In some embodiments, this document provides the compounds described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions thereof, for the treatment of cancer in patients of need. In some embodiments, the cancer is selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematogenous cancer, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway. In some embodiments, the cancer has a BRAF oncogenic mutation. In some embodiments, the cancer has a RAS oncogenic mutation. In some embodiments, the cancer has an NRAS oncogenic mutation. In some embodiments, the NRAS oncogenic mutation is NRAS Q61R or NRAS Q61K. In some embodiments, the cancer has a KRAS oncogenic mutation. In some embodiments, the KRAS oncogenic mutation is KRAS G12D, KRAS G12V, KRAS G12C, KRAS G12R, or KRAS G13D. In some embodiments, the cancer has an NF1 oncogenic mutation.

[0166] In some embodiments, this document provides the compounds described herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions thereof, for the treatment of patients in need of conditions selected from the group consisting of: melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, brain cancer, glioma, glioblastoma, astrocytoma, hematogenous cancer, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

[0167] The compounds described herein can provide doses of optimal pharmaceutical efficacy 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, any special diet followed by the patient, and other factors that will be recognized by those skilled in the art, with the appropriate dose ultimately determined by the attending physician. For the treatment of the clinical conditions and diseases mentioned above, the compounds described herein can be administered in dose-unit formulations containing conventionally non-toxic, pharmaceutically acceptable carriers, adjuvants, and mediators, via oral, subcutaneous, topical, non-enteral, inhalation spray, or rectal administration. Non-enteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0168] Treatment can be for a long or short period of time as needed. The compositions can be administered, for example, on a regimen of 1-4 or more times per day. A suitable treatment period can 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 1 year, or indefinitely. The treatment period can be terminated when the desired result is achieved.

[0169] Combination therapy A compound described herein, e.g., a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, e.g., a cancer described herein. For example, a pharmaceutical composition is provided comprising a compound described herein, e.g., a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, and one additional therapeutic agent are administered. In some embodiments, a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each separately formulated and administered. For example, a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, and an additional therapeutic agent can be separately formulated and administered. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, e.g., a pharmaceutical composition comprising a compound of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I-H, Formula I-J, Formula I-K, Formula I-L, Formula I-M, and Formula I-N, or a pharmaceutically acceptable salt, enantiomere, stereoisomer, or tautomer thereof, as one therapeutic agent and one or more additional therapeutic agents, e.g., a MAPK pathway inhibitor or a chemotherapeutic agent.For example, compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, and IN, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, and additional therapeutic agents, can 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 necessarily 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.

[0170] Combination therapy may also include two or more administrations of one or more of the ingredients 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, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] In some implementations, the additional therapeutic agent may be an immunomodulatory agent, including but not limited to: anti-PD-1 or anti-PDL-1 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 embodiments, the additional therapeutic agent may be a hypomethylating agent, including but not limited to: azoxybicosyl or decitabine; other immunomodulatory therapeutic agents, including but not limited to: epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agent may be an immunotherapeutic agent, including targeted therapies, cancer vaccines, and CAR-T cell therapy.

[0176] 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).

[0177] 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-bound particles for injectable suspensions, including but not limited to: albumin-bound paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, and DNA alkylating agents (including but not limited to: cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide). temozolomide), DNA intercalation agents, or DNA topoisomerase inhibitors (including but not limited to: anthracycline, 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).

[0178] In some implementations, the additional therapeutic agent may be a kinase inhibitor, including but not limited to: erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, and others. Beccilib, LEE011, palbociclib, cabozantinib, ripretinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib.

[0179] In some embodiments, the additional therapeutic agent may be an anti-estrogenic agent, including but not limited to: tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; or an anti-androgenic agent, 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, eczemaconazole, 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. ), romidepsin, panobinostat, valproic acid, and belinostat; DNA methylation inhibitors, including but not limited to: DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including but not limited to: bortezomib and carfilzomib; biologics, including but not limited to: trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, and panitumumab.

[0180] In some implementations, the additional therapeutic agent may be an anti-angiogenic agent, including but not limited to: bevacizumab, rebastinib, aflibercept, and AMG386.

[0181] 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 payload, brentuximab vedotin and trastuzumab emtansine, radiotherapy, and therapeutic vaccines including but not limited to sipuleucel-T.

[0182] 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.

[0183] 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.

[0184] In some implementations, the additional treatment agent is selected from luteinizing hormone-releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0185] In some implementations, the additional treatment agent is selected from the following group: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, perzopanib, GSK690693, RTA744, 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, Dasatinib, Nilotinib, Decatanib, Panitumumab, Amrubicin, Oregomab, Lep-etu, Nolatrexed, AZD 2171, Batabul, Ofatumab atumtunab), zanolimumab, edotecarin, 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, Rta 744, alanosine (Sdx) 102), talampanel, atrasentan, XR311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, lipo-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 (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-j-quinolinone, vatalanib, AG-013736, AVE-0005, [D-Ser(tBu) 6, Azgly

[10] Acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-Azgly-NH2 acetate (SEQ ID NO: 3) [C; 59 H 84 N 18 O 14 -(C2H4O2) x[where x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate Acetate), raloxifene, bicalutamide, flutanide, nilumethoxazole, medroxyprogesterone 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 aniline Analide, valproic acid, trichostocin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arsacrine, anagrelide, L-asparaginase, BCG, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine tarabine), dacarbazine, dactinomycin, danomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methamidophos, mitomycinMitotane, Mitoxantrone, Nilumet, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, plicamycin, Porfimer, Procarbazine, Raltitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vincristine, 13-cis-retinoic acid, Phenylalanine mustard, Uracil mustard, Estramustine, Altretamine, Fluorouracil, Deooxyuridine, Cytosine arabinoside, 6-Mecaptopurine rine), deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endothelial somatostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin Diftitox, Gefitinib, Bortezomib, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody), Erbitux, Cremophor-free Paclitaxel, Epothilone B, BMS-247550, BMS-310705, Droxifen, 4-Hydroxytamoxifen, Pipenoxifene, ERA-923, Arzoxifene, 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-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor. Factors, zolendronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid acid), ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab, tiuxetan, androgens, decitabine, hexamethicone, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, lipodycin, Edwina-asparaginase, strontium-89, caspopitant, netupitant, NK-1 receptor antagonist Antibiotics, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetronTropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, ipilumab, and mixtures thereof.

[0186] 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 application provides a pharmaceutical composition comprising compounds as disclosed herein (e.g., compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, and IN, 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 disclosed compositions may be formulated in unit dose form and / or may be formulated for oral or subcutaneous administration.

[0187] 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-enteral 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.

[0188] For the preparation of solid compositions, such as tablets, the main active ingredient may be mixed with a drug carrier, such as a conventional tableting component (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum), and other drug diluents, such as 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 reclassified into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0189] 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 of the following substances: (1) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) a binder, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) (3) Humectants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, 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.

[0190] Tablets can be prepared by compression or molding, optionally together with one or more excipients. 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 prepared 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 prepared with a coating and shell, such as enteric coating and other coatings well known in the art of pharmaceutical formulation.

[0191] 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 methanol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0192] In addition to the compositions of the present invention, the suspension may also contain, for example, ethoxylated isostearyl alcohol, polyethylene oxide sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragali, and mixtures thereof as suspending agents.

[0193] 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.

[0194] 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 ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0195] 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, paraffins, starches, tragali, cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0196] 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 additionally contain common propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0197] The compositions and compounds of this application can alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, liposomal formulation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic aerosols 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 invention. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions of the invention with conventionally pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the specific composition of the invention, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol); harmless proteins such as serum albumin; sorbitol esters; oleic acid; lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0198] The pharmaceutical compositions of this application suitable for non-enteral administration comprise the compositions 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 before use, said sterile powders may contain antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient, suspending agents or thickeners.

[0199] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate), and cyclodextrins. Appropriate flowability can be achieved, for example, by using a coating material such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant.

[0200] In another embodiment, an enteric pharmaceutical preparation is provided, comprising the disclosed compound and an enteric-coating material, as well as a pharmaceutically acceptable carrier or excipient. An enteric-coating material is a polymer that is substantially insoluble in the acidic environment of the stomach and 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 approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the terminal ileum is approximately 7.5.

[0201] 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 acetate benzotriglyceride; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose propionate phthalate; cellulose acetate maleate; cellulose acetate butyrate; cellulose acetate 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 readily measurable in vitro. The foregoing materials are a list of possible materials, but those skilled in the art who benefit from this application will recognize that it is incomplete and that other enteric-coated materials exist that satisfy the objectives described herein.

[0202] Advantageously, this document provides a kit for use by consumers, for example, who require treatment for cancer. The kit includes a suitable dosage form, such as the dosage form described above; and instructions for use describing methods of mediating, reducing, or preventing inflammation using the dosage form. The instructions will guide the consumer or medical professional to administer the dosage form according to routes of administration known to those skilled in the art. The kit can advantageously be packaged and sold in single or multiple kit units. An example of such a kit is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, and the like). Blister packs generally consist of a relatively rigid material sheet covered with a foil of a preferred 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 strength allows for the removal of tablets or capsules from the blister pack by manually applying pressure to the groove, thereby creating an opening in the sheet at the groove location. The tablet or capsule can then be removed through this opening.

[0203] Memory aids may need to be provided on the kit, for example, in the form of numbers immediately following the tablet or capsule number, corresponding to the number of days in the regimen for which the prescribed tablet or capsule 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 pills 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.

[0204] Example The compounds described herein can be prepared via a variety of routes based on the teachings contained herein and synthetic methods known in the art. In the following description of the synthetic methods, it should be understood that, unless otherwise stated, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) 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 apparent 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. The following abbreviations are used in this application and have the following definitions: "ADP" is adenosine diphosphate, "Ag2CO3" is silver acetate, "aq" is aqueous solution, "ATP" is adenosine triphosphate, "Ar" is argon, "BAST" is bis(2-methoxyethyl)aminosulfur trifluoride, "Boc" is tert-butyl carbonate, "BSA" is bovine serum albumin, "B2pin2" is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane), "CaCl2" is calcium chloride, "CDCl3" is deuterated chloroform, "Cs2CO3" is cesium carbonate, "DAST" is diethylaminosulfur trifluoride, "DCM" is dichloromethane, and "DIEA" is... N , N -Diisopropylethylamine, "DMF" is N , N -Dimethylformamide, "dppf" is 1,1'-bis(diphenylphosphino)ferrocene, "DMSO-d6" is deuterated dimethyl sulfoxide, and "DSC" is... N , N '-Disuccinimidyl 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 hexafluorophosphate azirzotriazole tetramethylureonium, "H2" is hydrogen, "HCl" is hydrochloric acid, "H2O" is water, "HOBT" is 1H-benzo[d][1,2,3]triazole-1-ol, "IC 50 "K2CO3" represents potassium carbonate, "KOAc" represents potassium acetate, and "LiOH" represents lithium hydroxide. m "CPBA" is Between- Chloroperoxybenzoic acid, "MeCN" for acetonitrile, "MeOH" for methanol, "mesyl" for methanesulfonyl, "MgSO4" for magnesium sulfate, "MHz" for megahertz, "min" for minutes, "MS" for mass spectrometry, "m / z" for mass / charge number, "NaCN" for sodium cyanide, "NADH" for reduced nicotinamide adenine dinucleotide, "NaH" for sodium hydride, "NaHCO3" for sodium bicarbonate, "NaOEt" for sodium methoxide, "Na2SO4" for sodium sulfate, "NH4Cl" for ammonium chloride, and "NH4OH" for ammonium hydroxide. “NMR” stands for Nuclear Magnetic Resonance, “OMs” stands for Methanesulfonate, “PBS” stands for Phosphate Buffered Salt, “Pd” stands for Palladium, “Pd / C” stands for Palladium on Carbon, “PdCl2(dtbpf)” stands for Bis(sec-tert-butylphosphino)ferrocene]palladium(II) chloride, “pet-ether” stands for Petroleum ether, “PPh3” stands for Triphenylphosphine, “rt” stands for Room Temperature, also known as “Ambient Temperature”, which usually refers to the normal laboratory temperature in the range of 15-25°C, “sat'd.” stands for Saturated, “SFC” stands for Supercritical Fluid Chromatography, “SM” stands for Starting Material, “S…” stands for S… N "Ar" indicates a nucleophilic aromatic substitution reaction, "T3P" is 1-propylphosphonic anhydride, "TBAF" is tetrabutylammonium fluoride, "TBDMS" is tert-butyldimethylsilyl, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, "THF" is tetrahydrofuran, "Tris" is tris(hydroxymethyl)aminomethane, and "tBuXPhos Pd-G3" is [(2-sec-... Tertiary -Butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate, "Xantphos" is 4,5-bis(diphenylphosphine)-9,9-dimethyldibenzopiperanone, and "X-Phos" is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0205] 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.

[0206] Synthesis scheme Option 1 Scheme 1 illustrates an exemplary preparation of borate esters 1-4. Amine 1-1 (commercially available or synthesized by those skilled in the art) reacts with carboxylic acids 1-5 (commercially available or synthesized by those skilled in the art) to give amide 1-2. Compound 1-2 is then borated to generate borate ester 1-4. Boration is a reaction well known to those skilled in the art (e.g., a Pd(0)-catalyzed reaction with B2pin2). Alternatively, borate ester 1-4 can be prepared by an amide coupling reaction: compound 1-3 (commercially available or synthesized from compound 1-1 via a Pd-catalyzed boration reaction) is coupled to carboxylic acids 1-5 in the presence of coupling agents such as HATU, T3P, and EDC.

[0207] Option 2 Scheme 2 illustrates an exemplary preparation of intermediates 2-3, 2-4, and 2-5. Borate ester 2-1 (commercially available or synthesized by those skilled in the art) is reacted with bromide 1-1 (commercially available or synthesized by those skilled in the art) in the presence of a palladium catalyst via a Suzuki reaction to give 2-2. Subsequently, 2-2 undergoes a secondary Suzuki reaction with a borate ester or borate ZB(OR)2 (commercially available or synthesized by those skilled in the art) to give 2-4. Alternatively, chloride 2-2 undergoes a borylation reaction with B2pin2 to convert to borate ester 2-3, which can be reacted with chloride (or bromide) Z-Cl(Br) (commercially available or synthesized by those skilled in the art) under typical Suzuki reaction conditions to give 2-4. In another embodiment, intermediate 2-5 can be prepared by the following steps: (1) a Suzuki reaction of 2-1 with borate ester 1-2, and (2) an amide coupling reaction of 2-2 with carboxylic acid 1-5 (commercially available or synthesized by those skilled in the art).

[0208] Option 3 Scheme 3 illustrates an exemplary preparation of intermediates 3-9a, 3-9b, 3-9c, 3-9d, and 3-11. Boronate ester 3-1 (Y = F, Cl) is reacted with bromide 1-1 in the presence of a palladium catalyst via a Suzuki reaction to give 3-3. Compound 3-3 (Y = F) is then reacted with an alcohol EL-OH or an amine ELN(R) in the presence of a base. 4 H occurs S N Ar reaction, yielding 3-7a(X) 4 = COLE) and 3-7b(X) 4 = CN(R 4 In another embodiment, compound 3-3 (Y = Cl) reacts with borate ester or borate ELB(OR)2 to give compound 3-6c. If compound 3-6c (X 4= CLE) contains unsaturated functional groups, such as double or triple bonds, and can undergo hydrogenation in the presence of a Pd catalyst. In an aprotic solvent (such as NMP) and in the presence of a base (such as K2CO3), under heating conditions, 4-bromo-2,6-dichloropyridine 3-2 (Y = Cl) reacts with alcohol EL-OH or amine ELN (R 4 The H reaction yields 3-4a(X) 4 = COLE) and 3-4b(X) 4 = CN(R 4 Under Pd(0)-catalyzed coupling conditions, 3-4a and 3-4b are reacted with borate ester 1-3 via a Suzuki reaction to give 3-6a and 3-6b, respectively. In another embodiment, 4-bromo-2-chloropyridine 3-2 (Y = H) is reacted with borate ester 1-6 (commercially available or synthesized by those skilled in the art) under Suzuki reaction conditions to give 3-5 (X... 4 =CH). Nitro reduction of 3-5 under mild reducing conditions (reduction of zinc or iron metal with ammonium chloride) yields 3-6d. 3-5(X) 4 = CH) reacts with tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridin-2-yl)carbamate via the Suzuki reaction, followed by Boc-deprotection, to give 3-8, which can react with acyl chloride R 1 A coupling reaction of -CO-Cl (commercially available or synthesized by those skilled in the art) yields 3-10. Nitro reduction of 3-10 under mild reducing conditions yields 3-11. Finally, 3-6a, 3-6b, 3-6c, and 3-6d are subjected to the Suzuki reaction with borate esters or boric acid 2-6, respectively, to yield 3-9a, 3-9b, 3-9c, and 3-9d. Similarly, 3-7a and 3-7b are reacted with borate esters or boric acid ZB(OR)2 under Suzuki reaction conditions to yield 3-9a and 3-9b, respectively.

[0209] Option 4 Scheme 4 illustrates an exemplary preparation of intermediates 4-4a and 4-4b. In the presence of a base (such as Ag₂CO₃) and in an aprotic solvent such as toluene, 4-bromo-6-chloropyridin-2-ol (4-1) reacts with an alkylating agent ELX (X = Cl, Br, I, OM) to produce… O -alkylated products (4-2a) and NA mixture of alkylation products (4-2b) can be separated by suitable methods (such as SFC purification, crystallization, or chromatography). 4-2a and 4-2b are reacted with borate esters 1-3 under Suzuki reaction conditions to give 4-3a and 4-3b, respectively. 4-3a and 4-3b are then subjected to amide coupling reactions with carboxylic acids 1-5, respectively, to give 4-4a and 4-4b, respectively. In another embodiment, 4-2a and 4-2b are reacted with borate esters 1-4 under Suzuki reaction conditions to give 4-4a and 4-4b, respectively.

[0210] Option 5 Scheme 5 illustrates an exemplary preparation of intermediates 5-4a and 5-4b. Using a method similar to that described in Scheme 4, 5-1 is reacted with an alkylating agent ELX (X = Cl, Br, I, OM) to produce… O -alkylated products (5-2a) and N A mixture of alkylation products (5-2b) can be separated by suitable methods known to those skilled in the art. 5-2a and 5-2b are reacted with borate esters 1-3 via a Suzuki reaction to yield 5-3a and 5-3b, respectively. Finally, 5-3a and 5-3b are each reacted with carboxylic acids 1-5 under amide coupling conditions to yield 5-4a and 5-4b, respectively. In another embodiment, 5-2a and 5-2b are reacted with borate esters 1-4 via a Suzuki reaction to yield 5-4a and 5-4b, respectively.

[0211] Option 6 Scheme 6 illustrates an exemplary preparation of intermediate 6-4. Dichloride 6-1 (X) 4 = CH, C-alkyl; commercially available or synthesized by those skilled in the art) reacts with boronic ester or borate ZB(OR)2 in the presence of a palladium catalyst via a Suzuki reaction to give 6-2. 6-2 undergoes a subsequent palladium-catalyzed Suzuki reaction with boronic ester 1-3 to give intermediate 6-4. Similarly, dichloride 6-1 (commercially available or synthesized by those skilled in the art) reacts with boronic ester 1-3 under Suzuki reaction conditions to give 6-3. 6-3 is then subjected to a subsequent palladium-catalyzed Suzuki reaction with boronic ester or borate ZB(OR)2 to give intermediate 6-4.

[0212] Option 7 Scheme 7 shows intermediate 7-5a(X) 4 = COLE) and 7-5b(X) 4 = CN(R 4Exemplary preparation of 4,6-dichloro-2-(methylthio)pyrimidine (7-1) with borate ester or borate ZB(OR)2 via a Suzuki reaction to give 7-2. Compound 7-2 is then reacted with borate ester 1-6 via a Suzuki reaction in the presence of a palladium catalyst to give 7-3. Compound 7-3 is then converted to compound 7-4a(X) according to a documented reaction sequence. 4 = COLE) and 7-4b(X) 4 = CN(R 4 )-LE): Using conditions known in the art (e.g., in DCM) m The oxidation reaction is carried out with CPBA, followed by the use of commercially available alcohols EL-OH or amines ELN (R). 4 The intermediate obtained was subjected to a substitution reaction by H. Finally, 7-4a and 7-4b were nitro-reduced under mild reducing conditions (zinc or iron metal with ammonium chloride) to give the corresponding amine compounds 7-5a (X). 4 = COLE) and 7-5b(X) 4 = CN(R 4 )-LE).

[0213] Option 8 Scheme 8 illustrates an exemplary preparation of intermediate 8-4. Similar to Scheme 6, 2,6-dichloropyrazine 8-1 is reacted with borate ester or boric acid ZB(OR)2 via a Suzuki reaction to give 8-2; 8-2 can then undergo a Suzuki reaction with borate ester 1-3 to give 8-4. Similarly, 2,6-dichloropyrazine 8-1 can also be reacted with borate ester 1-3 via a Suzuki reaction to give 8-3; 8-3 can then undergo another Suzuki reaction with borate ester ZB(OR)2 to give 8-4.

[0214] Option 9 Scheme 9 illustrates an exemplary preparation of intermediates 9-5 and 9-7. Compound 9-1 (2,4-dichloropyrimidine or 4-bromo-2-chloropyrimidine) is reacted with borate esters 1-6 via a Suzuki reaction to give 9-2; 9-2 can be reacted with borate esters or borate ZB(OR)2 via a Suzuki reaction to give 9-4. Mild reduction of 9-4 (with zinc or iron metal and ammonium chloride) gives the corresponding amine 9-5. Similarly, compound 9-1 is reacted with borate esters or borate ZB(OR)2 via a Suzuki reaction to give 9-5; 9-5 can be reacted with borate esters 1-3 via another Suzuki reaction to give compound 9-6.

[0215] Option 10 Scheme 10 illustrates an exemplary preparation of intermediate 10-5. 3,5-Dichloropyridine (10-1) undergoes a Suzuki reaction with borate ester 1-3 to give 10-3; 10-3 can undergo another Suzuki reaction with boric acid or borate ester ZB(OR)2 to give intermediate 10-5. Similarly, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (10-2) undergoes a Suzuki reaction with chloride (or bromide) Z-Cl(Br) in the presence of a palladium catalyst to give 10-4; 10-4 can undergo another Suzuki reaction with borate ester 1-3 to give intermediate 10-5.

[0216] Option 11 Scheme 11 illustrates an exemplary preparation of intermediate 11-3. In the presence of a palladium catalyst, dichloropyridine compound 11-1 (X...) 4 Compound 11-2 is reacted with borate esters 1-3 via a Suzuki reaction to give 11-2. Compound 11-2 is then reacted with carboxylic acid 1-5 under amide coupling conditions known to those skilled in the art to give 11-3. In another embodiment, commercially available 11-1 is reacted with borate esters 1-4 via a Suzuki reaction to give intermediate 11-3.

[0217] Option 12 Scheme 12 illustrates an exemplary preparation of intermediates 12-6a, 12-6b, and 12-6c. 1,3-Dibromo-5-iodobenzene 12-1 (Y=I) and amine ELN (R) 4 H reacts with B2pin2 under CuI / L-proline catalysis in an aprotic solvent (such as DMSO) in the presence of a base (such as K2CO3) under elevated temperature to give 12-2. Compound 12-2 undergoes a well-known borylation reaction with B2pin2 under Pd(0) catalyst to give borate ester 12-3, which can be reacted with chloride (or bromide) Z-Cl(Br) via the Suzuki reaction to give intermediate 12-5a(X). 4 = CN(R 4 In another embodiment, compound 12-1 (Y = H, alkyl) reacts with B2pin2 in the presence of a Pd(0) catalyst to give borate ester 12-4. 12-4 undergoes a Suzuki reaction with chloride (or bromide) Z-Cl(Br) (1 equivalent) to give 12-5b(X) 4 = CH) and 12-5c(X) 4 = C-alkyl). Finally, compounds 12-5a, 12-5b and 12-5c were reacted with borate ester 1-3 by the Suzuki reaction to give 12-6a, 12-6b and 12-6c respectively.

[0218] Option 13 Scheme 13 illustrates an exemplary preparation of pyridazine intermediates 13-4, 13-5, and 13-6. 5-Bromo-3-chloropyridazine 13-1 is treated with borate ester 1-3 under Suzuki reaction conditions to give 13-3. Chloride 13-3 is reacted with borate ester or boric acid ZB(OR)2 via a Pd(O)-catalyzed Suzuki reaction to give 13-4. Chloride 13-3 is reacted with carboxylic acid 1-5 under amide coupling conditions to give intermediate 13-5. Alternatively, intermediate 13-5 can be prepared directly from 13-1 and borate ester 1-4 via a Suzuki reaction. 5-Bromo-3-chloropyridazine 13-1 is treated with borate ester or boric acid ZB(OR)2 under Suzuki reaction conditions to give 13-2. Chloride 13-2 is reacted with borate ester 1-3 via a Pd(O)-catalyzed Suzuki reaction to give 13-6.

[0219] Option 14 Scheme 14 illustrates an exemplary preparation of intermediates 14-6a, 14-6b, 14-6c, 14-6d, and 14-6e. Compound 14-3 can be prepared via two routes: (1) a Suzuki reaction of 14-1 (commercially available or synthesized by those skilled in the art) with boric acid or borate ester ZB(OR)2; or (2) a Suzuki reaction of 14-2 (commercially available or synthesized by those skilled in the art) with chloride (or bromide) Z-Cl(Br) in the presence of a palladium catalyst. Subsequently, compound 14-3 (where Y = H or alkyl) undergoes a Suzuki reaction with borate ester 1-3 to yield 14-6c(X) and 14-6e respectively. 4 = CH) and 14-6d(X 4 = C-alkyl). In another embodiment, using existing literature conditions well known to those skilled in the art, compound 14-3 (Y = Cl) reacts with borate ester or borate ELB(OR)2 under Pd(0) catalytic coupling conditions to give 14-4. 14-4 reacts with borate ester 1-3 under Pd(0) catalytic coupling conditions via a Suzuki reaction to give 14-6e. If compound 14-6e (X 4 = CLE) contains unsaturated functional groups (such as double or triple bonds), and can be hydrogenated in the presence of a Pd catalyst. Alternatively, in the presence of a base, compound 14-3 (Y = F) reacts with alcohol EL-OH or amine ELN (R 4 H through S N Ar reaction, yielding 14-5a(X) 4 = COLE) and 14-5b(X 4 = CN(R4 Finally, chlorides 14-5a and 14-5b reacted with borate ester 1-3 under Suzuki reaction conditions to give intermediate 14-6a (X) and LE). 4 = COLE) and 14-6b(X 4 = CN(R 4 )-LE).

[0220] Option 15 Scheme 15 illustrates an exemplary preparation of pyrimidine intermediates 15-3a, 15-3b, 15-3c, and 15-3d. 2,4,6-Trichloropyrimidine 15-1 reacts with an alcohol (EL-OH) to form an S-reaction mixture. N Ar reaction yields 15-2a(X) 4 =COLE) and 15-2c(X) 4 =COLE) mixture; this mixture can be separated by a suitable method (e.g., SFC purification, column chromatography, or recrystallization). Similarly, 2,4,6-trichloropyrimidine 15-1 and amine (ELN(R) 3 H) in S N The reaction proceeds under Ar reaction conditions to give 15-2b(X) 4 = CN(R 4 )-LE) and 15 -2d(X 4 =CN(R 4 A mixture of (-LE); this mixture can be separated by a suitable method (e.g., SFC purification, column chromatography, or recrystallization). 15-2a and 15-2b are reacted with borate esters or boric acid ZB(OR)2 via the Suzuki reaction to give 15-3a and 15-3b, respectively. 15-2c(X) 4 = COLE) reacts with borate esters or boric acid ZB(OR)2 via a Suzuki reaction to give a mixture of 15-3c and 15-3e, which can be separated by suitable methods (e.g., SFC purification, column chromatography, or recrystallization). Similarly, 15-2d(X 4 = CN(R 4 ()-LE) is reacted with borate ester or boric acid ZB(OR)2 by the Suzuki reaction to give a mixture of 15-3d and 15-3f, which can be separated by a suitable method (e.g., SFC purification, column chromatography or recrystallization).

[0221] Option 16 Scheme 16 illustrates an exemplary preparation of compounds of formula I (16-2a, 16-2b). Compounds of formula I (16-2a and 16-2b) can be prepared by reacting chlorides A (6-2, 8-2, 9-6, 10-4, 13-2, 14-4, 14-5a, 14-5b, 15-3a, 15-3b, 15-3c, 15-3d, 15-3e, and 15-3f) with borate esters 1-4 via a Suzuki reaction. Similarly, compounds of formula I (16-2a: Q = O) are obtained by reacting chlorides B (2-5, 4-4a, 4-4b, 5-4a, 5-4b, 11-3, and 13-5) with borate esters or boric acid ZB(OR)2 (commercially available or synthesized by those skilled in the art) via a Suzuki reaction. Alternatively, chlorides B (2-5, 4-4a, 4-4b, 5-4a, 5-4b, 11-3, and 13-5) undergo a Pd-catalyzed borylation reaction with B2pin2 (Pd-boration reaction) to convert to borate ester 16-1. Borate ester 16-1 is then reacted with chloride (or bromide) Z-Cl(Br) (commercially available or synthesized by those skilled in the art) via the Suzuki reaction to give compound I (16-2a: Q = O). In another embodiment, aniline C (2-4, 3-9a, 3-9b, 3-9c, 3-9d, 3-11, 6-4, 7-5a, 7-5b, 8-4, 9-5, 9-7, 10-5, 12-6a, 12-6b, 12-6c, 13-4, 13-6, 14-6a, 14-6b, 14-6c, 14-6d, and 14-6e) is reacted with carboxylic acid 1-5 or imine ester 1-7 under typical coupling conditions to convert them into compounds of formula I (16-2a and 16-2b), respectively.

[0222] Option 17 Scheme 17 illustrates an exemplary preparation of compounds of formula II (17-3a, 17-3b, 17-3c, and 17-3d). Intermediates D (2-2, 3-6a, 3-6b, 3-6c, 3-6d, 4-3a, 4-3b, 5-3a, 5-3b, 6-3, 8-3, 10-3, 11-2, and 13-3) are reacted with borate esters or boric acid 2-6 (commercially available or synthesized by those skilled in the art) under Suzuki reaction conditions to give intermediate 17-2a (X). 1 =CH). Alternatively, compounds D (2-2, 3-6a, 3-6b, 3-6c, 4-3a, 4-3b, 5-3a, 5-3b, 6-3, 8-3, 10-3, 11-2, and 13-3) are subjected to a documented borylation reaction with B2pin2 in the presence of a Pd(0) catalyst to give borate ester 17-1. Compound 17-1 is subjected to a Suzuki reaction with chloride (or bromide) 2-7 in the presence of a Pd(0) catalyst to give 17-2b (X 1= N). Intermediates 17-2a and 17-2b react with carboxylic acid 1-5 (commercially available or synthesized by those skilled in the art) under typical amide coupling conditions to convert them into 17-3a and 17-3b, respectively (i.e., compounds of formula II: Q). 2 = O). Similarly, intermediates 17-2a and 17-2b react with imine ester 1-7 (commercially available or synthesized by those skilled in the art) to convert them into 17-3c and 17-3d (i.e., compounds of formula II: Q), respectively. 2 =NH).

[0223] Option 18 Scheme 17 illustrates exemplary preparations of compounds of formula I (18-2), compounds of formula II (18-1a, 18-1b, 18-1c, 18-1d and 18-3), and compounds of formula III (18-4a and 18-4d). The preparation of compounds of formula II (17-3a, 17-3b, 17-3c and 17-3d) with HCl: R 1 = Boc) is deprotected to obtain compounds of formula II (18-1a, 18-1b, 18-1c, and 18-1d). Compounds of formula II (18-1a, 18-1b, 18-1c, and 18-1d) are reacted with carboxylic acids 2-8 (commercially available or synthesized by those skilled in the art) or imine esters 2-9 (commercially available or synthesized by those skilled in the art) in a protic solvent (such as MeOH) under elevated temperature conditions to obtain compounds of formula I (18-2: Q). 1 Q 2 = O, NH). In another embodiment, the compounds of formula II (18-1a, 18-1b, 18-1c and 18-1d) are reacted with aldehyde R. 1a -CHO reacts under reducing amination conditions (standard conditions well known to those skilled in the art), yielding compound of formula II (18-3:R). 1 = CH2R 1a Q 2 = O, NH). In another embodiment, compounds of formula II (18-1a and 18-1b) are reacted with DMF (R) in the presence of methanesulfonyl chloride. 1 = CH3) reaction (Vilsmeier type reaction) yields compounds of formula III (18-4a and 18-4b), respectively. Alternatively, compounds of formula III (18-4a and 18-4b) can be prepared by the Suzuki reaction of B (2-5, 4-4a, 4-4b, 5-4a, 5-4b, 11-3, and 13-5) with boric acid or borate ester 2-10 (commercially available or synthesized by those skilled in the art).

[0224] Preparation of intermediates. The following compounds were prepared using the synthetic procedures and methods described herein, as well as methods known to those skilled in the art: Preparation of intermediate A1: (2-(2-(dimethylamino)acetamido)pyridin-4-yl)boronic acid A solution of 4-bromopyridin-2-amine (0.50 g, 2.9 mmol) and DIEA (2.0 mL, 12 mmol) in DCM (10 mL) was cooled to 0 °C. 2-Chloroacetyl chloride (0.25 mL, 3.2 mmol) was added dropwise to the solution, and the reaction mixture was heated to room temperature. After stirring the reaction mixture for 2 h, a solution of THF (7.2 mL, 14 mmol) containing 2.0 MN,N-dimethylamine was added. The mixture was stirred overnight at room temperature. The reactants were diluted with saturated NaHCO3 (aq) and extracted with DCM (4 times). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 10% MeOH / DCM) to give N-(4-bromopyridin-2-yl)-2-(dimethylamino)acetamide (0.48 g, 65%) as a brown solid. MS(ESI) m / z: 258.0 (M+H) + ) and 260.0.

[0225] A mixture of N-(4-bromopyridin-2-yl)-2-(dimethylamino)acetamide (0.50 g, 1.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentane) (0.74 g, 2.9 mmol), and KOAc (0.57 g, 5.8 mmol) in 1,4-dioxane (10 mL) was purged with Ar for 10 min. XPhosPdG2 (0.15 g, 0.19 mmol) was added, and the reaction mixture was sealed and heated overnight at 85 °C. The reaction mixture was cooled to room temperature and concentrated. The resulting black solid was treated with EtOAc and sonicated. The solid was filtered to give (2-(2-(dimethylamino)acetamido)pyridin-4-yl)boronic acid (0.43 g, 100%). MS(ESI) m / z: 224.0 (M+H) + ).

[0226] The following compounds are basically prepared by the method of preparing intermediate A1.

[0227] Preparation of intermediate B1: 2-chloro-6-(2-methyl-5-nitrophenyl)pyrazine A solution of 4-bromo-2-chloropyridine (5.0 g, 26.0 mmol) and 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborhexacyclopentane (6.8 g, 26 mmol) in 1,4-dioxane (70 mL) and water (8 mL) was treated with K₂CO₃ (7.9 g, mL, 57 mmol). The mixture was degassed with Ar for 5 min, followed by the addition of Pd(dppf)Cl₂ (1.1 g, 1.3 mmol). The mixture was purged with Ar and the reaction mixture was heated at 80 °C for 12 h. The solution was cooled to room temperature and quenched with a saturated aqueous solution of NaHCO₃. The mixture was extracted with EtOAc (3 times). The combined organic extracts 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 / hexane) to give 2-chloro-4-(2-methyl-5-nitrophenyl)pyridine (5.0 g, 77%) as a white solid. MS (ESI) m / z: 389.2 (M+H) + ).

[0228] Preparation of intermediate B2: 3-(2-chloropyridin-4-yl)-4-methylaniline A solution of 4-bromo-2-chloropyridine (1.7 mL, 16 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (5.4 g, 23 mmol) in 1,4-dioxane (70 mL) and water (8 mL) was treated with K₂CO₃ (5.4 g, 23 mmol). The reaction mixture was purged with nitrogen for 20 min, followed by the addition of a Pd(dppf)Cl₂-DCM adduct (0.23 g, 0.31 mmol). The reaction mixture was heated at 100 °C for 3.5 h, followed by cooling to room temperature. The solution was filtered through a diatomaceous earth mat and washed with DCM (40 mL). The filtrate was washed with saturated NaHCO₃ and water. The combined organic phases were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to obtain a light brown solid 3-(2-chloropyridin-4-yl)-4-methylaniline (3.4 g, 99%). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 1.4 Hz, 1H), 7.35 (dd, J =5.1, 1.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.56 (dd, J = 8.1, 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 5.03 (s, 2H), 2.06 (s, 3H); MS(ESI)m / z: 219.2(M+H) + ).

[0229] The following compounds were prepared primarily by the method of preparing intermediates B1 and B2.

[0230] Preparation of intermediate B26: 4-(6-fluoro-4-iodopyridin-2-yl)-1H-pyrazol-3-amine A solution of 2-(6-fluoro-4-iodopyridin-2-yl)acetonitrile (0.50 g, 1.34 mmol) and DMF-DMA (0.32 mL, 2.40 mmol) in MeOH (5 mL) was stirred at room temperature for 12 h. The resulting precipitate was filtered and washed with MeOH to give a yellow solid 3-(dimethylamino)-2-(6-fluoro-4-iodopyridin-2-yl)acrylonitrile (0.30 g, 69%). 1 H NMR (400 MHz, DMSO-d6): δ7.96 (s, 1H), 7.44 (s, 1H), 7.19 (d, J = 2.4 Hz, 1H), 3.27 (s, 6H); MS (ESI) m / z: 317.9 (M+H + ).

[0231] 3-(dimethylamino)-2-(6-fluoro-4-iodopyridin-2-yl)acrylonitrile (0.15 g, 0.47 mmol) was dissolved in EtOH (3 mL). NH₂NH₂•H₂O (0.29 mL, 4.73 mmol, 80% purity) and c-HCl (1.18 mL, 30 mL) were slowly added dropwise to this solution at room temperature. AmountThe reaction mixture was heated at 80 °C for 12 h and then cooled to room temperature. The mixture was quenched with water and extracted with EtOAc (3 times). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid 4-(6-fluoro-4-iodopyridin-2-yl)-1H-pyrazole-3-amine (0.13 g, 88%). 1 H NMR (400MHz, DMSO-d6): δ11.89 (s, 1H), 7.92 (s, 2H), 7.21 (s, 1H), 5.51-6.17 (m, 2H); MS (ESI) m / z: 305.1 (M+H) + ).

[0232] Preparation of intermediates C1 and C2: 2-((2,6-dichloropyrimidin-4-yl)amino)ethanol-1-ol (C1) and 2-((4,6-dichloropyrimidin-2-yl)amino)ethanol-1-ol (C2) and A solution of 3.3 mL (54 mmol) of 2-aminoethanol in 30 mL of THF was added dropwise to a solution of 3.1 mL (27 mmol) of 2,4,6-trichloropyrimidine in 50 mL of THF. The mixture was stirred at 20 °C for 2 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-20% EtOAc / petroleum ether) to give a white solid 2-[(4,6-dichloropyrimidin-2-yl)amino]ethanol (C1, 2.0 g, 35%). 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 8.25–8.33 (br m, ¹H), 6.56 (s, ¹H), 4.83 (t, J = 8.0 Hz, ¹H), 3.51 (m, 2H), 3.36 (m, 2H); MS (ESI) m / z: 208.0 (M+H) as a white solid. + ) and 2-[(2,6-dichloropyrimidin-4-yl)amino]ethanol (C2, 2.7 g, 48%). 1 H NMR (400 MHz, DMSO-d6): δ8.06 (t, J = 5.6 Hz, 1H), 6.85 (s, 1H), 4.70 (t, J = 5.6 Hz, 1H), 3.48 (m, 2H), 3.30 (m, 2H); MS(ESI)m / z: 208.0(M+H + ).

[0233] The following compounds are basically prepared by the C1 and C2 intermediates.

[0234] Preparation of intermediate C4: 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyridin-4-yl)-4-methylaniline A solution of 2-((tert-butyldimethylsilyl)oxy)ethanol-1-ol (0.42 g, 2.4 mmol) in DMF (5.0 mL) was slowly treated with NaH (0.15 g, 3.8 mmol, 60% in mineral oil) in an ice-water bath, and the reaction mixture was stirred for 30 min under the same conditions. A solution of 3-(2-chloro-6-fluoropyridin-4-yl)-4-methylaniline (B6, 0.45 g, 1.9 mmol) in DMF (1 mL) was added to the reaction mixture, and the mixture was heated at 40 °C for 2 h. The reaction mixture was quenched with water (20 mL) in an ice-water bath. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5%-10% EtOAc / hexane) to give 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyridin-4-yl)-4-methylaniline (0.47 g, 62%). MS (ESI) m / z: 393.2 (M+H) + ).

[0235] The following compounds are basically prepared by the method of preparing intermediate C4.

[0236] Preparation of intermediate C6: N -(6-(5-chloropyridin-3-yl)pyrimidin-4-yl)cyclopropylformamide Will NA solution of 3-(6-chloropyrimidin-4-yl)cyclopropaneformamide (3.0 g, 15 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine (3.6 g, 15 mmol) in 1,4-dioxane (100 mL) was treated with 2.0 M K₂CO₃ (15 mL, 30 mmol). The reaction mixture was purged with Ar for 3 min, followed by the addition of PdCl₂(dppf)-DCM adduct (0.37 g, 0.46 mmol). The reaction mixture was heated at 60 °C for 2 h and then cooled to room temperature. The reaction mixture was quenched with water, and the solution was subsequently extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a brown solid N-(6-(5-chloropyridin-3-yl)pyrimidin-4-yl)cyclopropaneformamide (C6, 3.5 g, 84%). 1 H NMR (400 MHz, DMSO-d6): δ11.4 (s, 1H), 9.12 (d, J =1.8 Hz, 1H), 8.99 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.44 (d, J= 2.3 Hz, 1H), 2.07 (m, 1H), 0.87-0.94 (m, 4H); MS(ESI)m / z: 275.0(M+H + ).

[0237] The following compounds are basically prepared by the method of preparing intermediate C6.

[0238] Preparation of intermediate D1: 6-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)penten-3-amine A mixture of 5-(3-chlorophenyl)-6-methylpyridin-3-amine (B22, 2.0 g, 9.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentane) (3.5 g, 14 mmol), and K2CO3 (2.7 g, 27 mmol) in 1,4-dioxane (90 mL) was degassed with Ar for 5 min. XphosPdG2 (0.72 g, 0.91 mmol) was added, and the mixture was heated at 100 °C for 2 h. The mixture was cooled to room temperature and quenched with saturated NaHCO3 (aqueous solution) and EtOAc. The mixture was extracted with EtOAc (3 times). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown residue was purified by silica gel column chromatography (0-10% MeOH / EtOAc) to give a brown solid 6-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)penten-3-amine (1.6 g, 57%). MS (ESI) m / z: 311.2 (M+H) + ).

[0239] The following compounds were prepared primarily by the method used to prepare intermediate D1.

[0240] Preparation of intermediate E1: N -(5-(5-amino-2-methylphenyl)-[3,4'-bipyridine]-2'-yl)cyclopropaneformamide 3-(5-chloropyridin-3-yl)-4-methylaniline (2.0 g, 9.1 mmol), N A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)penten-2-yl)cyclopropaneformamide (B15, 2.9 g, 10 mmol) in 1,4-dioxane (100 mL) was treated with 2.0 M K₂CO₃ (9.2 mL, 18 mmol). The mixture was purged with Ar for 3 min. XphosPdG₂ (50 mg) was added, and the mixture was then stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and quenched with water (100 mL). The solution was extracted with EtOAc (3 times), and the combined organic phases were washed with saturated brine, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH / EtOAc / hexane) to a white solid. N-(5-(5-amino-2-methylphenyl)-[3,4'-bipyridine]-2'-yl)cyclopropaneformamide (E1, 2.4 g, 76%). 1 H NMR (400 MHz, DMSO-d6): δ 10.9 (s, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J = 4.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 2.0, 8.0Hz, 1H), 6.53 (s, 1H), 5.00 (s, 2H), 2.08 (s, 3H), 2.03 (m, 1H), 0.81- 0.86(m, 4H); MS(ESI) m / z: 345.2 (M+H) + ).

[0241] The following compounds were prepared primarily by the method used to prepare intermediate E1.

[0242] Preparation of intermediate E41: 2-cyclopropyl- N -(4-(2-methyl-5-nitrophenyl)-[2,4'-bipyridine]-2'-yl)acetamide A solution of 4-(2-methyl-5-nitrophenyl)-[2,4'-bipyridine]-2'-amine (E14, 0.50 g, 1.63 mmol) in pyridine (6 mL) was cooled to 0 °C. 2-Cyclopropylacetyl chloride (0.23 g, 1.96 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 2 days. The reaction mixture was concentrated under reduced pressure. The crude product was treated with saturated NaHCO3 (aq) and the solution was extracted twice with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give a yellow solid of 2-cyclopropyl- N -(4-(2-methyl-5-nitrophenyl)-[2,4'-bipyridine]-2'-yl)acetamide (E41, 0.5 g, 79%). MS (ESI) m / z: 389.2 (M+H) + ).

[0243] The following compounds were prepared primarily by the method used to prepare intermediate E41.

[0244] Preparation of intermediate E43: N -(4-(5-amino-2-methylphenyl)-[2,4'-bipyridine]-2'-yl)-2-cyclopropylacetamide 2-Cyclopropyl- N A solution of 4-(2-methyl-5-nitrophenyl)-[2,4'-bipyridine]-2'-yl)acetamide (E41, 0.26 g, 0.67 mmol) in a mixture of EtOH (2 mL) / THF (2 mL) was treated with Pd-C (10%, wet w / 50% water) (0.071 g, 0.033 mmol). The reaction mixture was stirred at room temperature under a H2 atmosphere for 3 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with EtOH / THF (1:1, 5 mL). The filtrate was concentrated under reduced pressure to give a yellow solid. N -(4-(5-amino-2-methylphenyl)-[2,4'-bipyridine]-2'-yl)-2-cyclopropylacetamide (E43, 0.22 g, 92%). MS (ESI) m / z: 359.2 (M+H) + ).

[0245] The following compounds were prepared primarily by the method used to prepare intermediate E43.

[0246] Preparation of intermediate F1: 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 approximately 7 with 30% NaOH (aqueous solution) at 0 °C. The solution was extracted (3 times) with EtOAc. The combined extracts were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% EtOAc / petroleum ether) to give a yellow oily substance, methyl 6-chloro-5-cyclobutylpyridazine-3-carboxylate (7.2 g, 19%). 1 H 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).

[0247] Preparation of intermediate F2: 3-chloro-5-(1-ethoxyvinyl)pyridazine A solution of 5-bromo-3-chloropyridazine (40 g, 208 mmol) and tributyl(1-ethoxyvinyl)stanane (70 mL, 208 mmol) in DMF (500 mL) was treated with TEA (87 mL, 620 mmol). The mixture was purged with N2 for 3 min, followed by the addition of Pd(PPh3)2Cl2 (7.3 g, 10 mmol). The mixture was heated at 90 °C under N2 atmosphere for 3 h, and then cooled to room temperature. The mixture was quenched at 0 °C with saturated NH4Cl (100 mL) 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 phases were washed with saturated 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 yellow solid 3-chloro-5-(1-ethoxyvinyl)pyridazine (30 g, 79%). 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).

[0248] The following compounds were prepared primarily by the method used to prepare intermediate F2.

[0249] Preparation of intermediate F5: 2-(6-chloropyridazin-4-yl)prop-2-ol 3-Chloro-5-isopropenyl-pyridazine (F3, 1.0 g, 6.5 mmol), phenylsilane (4 mL, 32 mmol), and tri[( Z [1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (3.9 g, 6.5 mmol) in DCM (10 mL) and IsThe mixture of -PrOH (30 mL) was purged with O2 for 5 min. The mixture was stirred at 0 °C for 0.5 h under an O2 atmosphere. The reaction mixture was quenched with saturated Na2SO3 (aqueous solution) and extracted with EtOAc (3 times). The combined organic phases were washed with brine (i.e., saturated 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-chloropyridazin-4-yl)prop-2-ol (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) + ).

[0250] Preparation of intermediate F6: 3-chloro-5-(2-fluoropropane-2-yl)pyridazine A solution of 2-(6-chloropyridazin-4-yl)propane-2-ol (F5, 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, poured into water (10 mL), and extracted (3 times) with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to give a yellow gel-like 3-chloro-5-(2-fluoropropane-2-yl)pyridazine (0.5 g, 80%). MS (ESI) m / z: 175.1 (M+H + ).

[0251] The following compounds were prepared primarily by the method used to prepare intermediate F6.

[0252] Preparation of intermediate F8: (6-chloropyridazine-4-yl)dimethylphosphine oxide A solution of 5-bromo-3-chloropyridazine (2.0 g, 10 mmol) and methylphosphonomethane (0.89 mg, 11 mmol) in 1,4-dioxane (30 mL) was treated with K₃PO₄ (6.6 g, 31 mmol). The mixture was purged with N₂ for 3 min, followed by the addition of Xantphos (0.9 g, 1.55 mmol) and Pd(OAc)₂ (0.2 g, 1.03 mmol). The mixture was heated at 100 °C under N₂ atmosphere for 2 h, then cooled to room temperature. The mixture was diluted with H₂O (15 mL) and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by C-18 preparative HPLC (0-15% H2O (10 mM NH4HCO3) / MeCN) to give a yellow solid (6-chloropyridazine-4-yl)dimethylphosphine oxide (0.65 g, 33%). 1 H NMR (400 MHz, DMSO-d6): δ 9.54 (m, 1H), 8.23 ​​(dd, J =1.6, 11.4 Hz, 1H), 1.86 (s, 3H), 1.82 (s, 3H); MS(ESI)m / z: 191.0(M+H + ).

[0253] Preparation of intermediate F9: 3-chloro-5-(difluoromethoxy)pyridazine A solution of 3,5-dichloropyridazine (3.0 g, 20 mmol) in 1,4-dioxane (30 mL) was treated with 3.0 M NaOH (aqueous solution, 20 mL). The mixture was stirred at 25 °C for 12 h, followed by dilution with H₂O (30 mL). The solution was washed with EtOAc (3 times), and the separated aqueous phase was acidified with 1.0 N HCl (aqueous solution) to a pH of approximately 3. The precipitate was collected by filtration to give 6-chloropyridazine-4-ol (1.0 g, 23%) as a brown solid. MS (ESI) m / z: 131.1 (M+H) + ).

[0254] A mixture of 6-chloropyridazine-4-ol (0.10 g, 0.77 mmol), sodium 2-chloro-2,2-difluoroacetate (0.35 g, 2.3 mmol), and K₂CO₃ (0.32 g, 2.3 mmol) in DMF was stirred at 50 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 times). The combined organic phases were washed with brine (i.e., saturated brine), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (0–25% EtOAc / petroleum ether) to give a yellow oily compound 3-chloro-5-(difluoromethoxy)pyridazine (reaction run 9 times to prepare 0.15 g F₉: 0.15 g, 8%). 1 H NMR: (400MHz, DMSO-d6): δ 9.30 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 2.4 Hz 1H), 7.61 (t, J= 71.6 Hz, 1H); MS(ESI)m / z: 180.9(M+H + ).

[0255] Preparation of intermediate G1: Methyl 5-cyclobutylpyridazine-3-carboxylate A solution of methyl 6-chloro-5-cyclobutylpyridazine-3-carboxylate (F1, 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 a hydrogen atmosphere (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give a yellow oily product of methyl 5-cyclobutylpyridazine-3-carboxylate (4.0 g, crude). 1 H 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), 2.04(m,1H), 1.88(m,1H).

[0256] Preparation of intermediate G2: 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 and CO (50 psi) for 3 h. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The solution was extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-25% EtOAc / petroleum ether) to give methyl 6-(trifluoromethyl)pyridazine-3-carboxylate (1.0 g, 44%) as a white solid. MS (ESI) m / z: 207.1 (M+H + ).

[0257] The following compounds were prepared primarily by the method used to prepare intermediate G2.

[0258] Preparation of intermediate G16: methyl 5-(1,1-difluoroethyl)pyridazine-3-carboxylate A solution of methyl 5-acetylpyridinium-3-carboxylate (G5, 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 times). The combined organic phases 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)pyridinium-3-carboxylate (11 g, 33%) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴): δ 9.48 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 3.99 (s, 3H), 1.95 (t, J = 18.9 Hz, 3H).

[0259] Preparation of intermediate G17: 5-(trifluoromethyl)pyridazine-3-carbonylimine ester A solution of methyl 5-(trifluoromethyl)pyridazine-3-carboxylate (1.5 g, 7.3 mmol) in 7.0 M NH3 / MeOH (10 mL) was stirred at 60 °C for 1 hour. The reaction was cooled at room temperature and then concentrated under reduced pressure to give a yellow solid of 5-(trifluoromethyl)pyridazine-3-carboxamide (1.2 g, 73%). 1 H NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 8.81 (s, 1H), 8.47 (s, 1H), 8.20 (s, 1H); MS (ESI) m / z: 191.9 (M+H + ).

[0260] POCl3 (3.7 mL, 39 mmol) was added to a solution of 5-(trifluoromethyl)pyridazine-3-carboxamide (1.2 g, 6.3 mmol) in toluene (15 mL) at room temperature. The reaction mixture was heated at 100 °C for 1 h, followed by cooling to room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–10% EtOAc / petroleum ether) to give 5-(trifluoromethyl)pyridazine-3-carboxynitrile (0.8 g, 59%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3): δ 9.57(d, J = 1.8 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H); MS(ESI)m / z: 173.9(M+H + ).

[0261] To a solution of 5-(trifluoromethyl)pyridazine-3-carboxynitrile (0.2 g, 1.2 mmol) in MeOH (1 mL), NaOMe (0.46 g, 2.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was diluted with water and extracted twice with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-(trifluoromethyl)pyridazine-3-carbonylimine ester (0.2 g, 84%) as a pale yellow solid. 1 H NMR: (400 MHz, CDCl3): δ9.65 (s, 1H), 9.43 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 4.03 (s,3H); MS(ESI)m / z: 206.0(M+H) + ).

[0262] The following compounds were prepared primarily by the method used to prepare intermediate G17.

[0263] Preparation of intermediate G19: methyl 5-(2-cyanopropyl-2-yl)nicotinic acid A mixture of methyl 5-bromopyridine-3-carboxylic acid (4.0 g, 18 mmol), 2-trimethylsilylacetonitrile (3.6 mL, 26 mmol), and zinc difluoride (2.3 g, 22 mmol) in NMP (80 mL) was purged with N2 for 3 min. Xantphos PdG4 (1.8 g, 1.8 mmol) was added, and the mixture was then heated at 130 °C under N2 atmosphere for 3 h. The reaction mixture was cooled to room temperature, diluted with H2O (40 mL), and then extracted (3 times) with EtOAc. The combined organic phases were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / petroleum ether) to give methyl 5-(cyanomethyl)nicotinic acid (1.7 g, 52%) as a pink solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.05 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.31 (t, J = 2.2 Hz, 1H), 4.23 (s, 2H), 3.92 (s, 3H); MS(ESI)m / z: 177.3(M+H + ).

[0264] NaH (1.4 g, 34 mmol, 60% in mineral oil) was added to a solution of methyl 5-(cyanomethyl)nicotinic acid (1.0 g, 5.7 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 0.5 h, followed by the addition of MeI (2.1 mL, 34 mmol) at 0 °C, and stirring was continued at 0 °C under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic phases 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-(2-cyanopropan-2-yl)nicotinic acid (0.15 g, 13%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.37 (t, J = 2.2 Hz, 1H), 3.93 (s, 3H), 1.79 (s, 6H); MS(ESI)m / z:205.0(M+H + ).

[0265] Preparation of intermediate H1: 6-(trifluoromethyl)pyridazine-3-carboxylic acid LiOH·H₂O (0.41 g, 9.7 mmol) was added to a solution of methyl 6-(trifluoromethyl)pyridazine-3-carboxylic acid (1.0 g, 4.8 mmol) in a mixture of THF (5 mL) and MeOH (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The resulting aqueous residue was acidified with 1.0 N HCl to a pH of approximately 3. The solution was extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 6-(trifluoromethyl)pyridazine-3-carboxylic acid (0.80 g, 80%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H); MS (ESI) m / z: 193.0 (M+H + ).

[0266] The following compounds are basically prepared by the method of preparing intermediate H1.

[0267] Preparation of intermediate I1: N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide A solution of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (6.35 g, 33 mmol), HATU (13.8 g, 36 mmol), and DIEA (17 mL, 99 mmol) in DMF (66 mL) was stirred at 0 °C for 15 min. 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (7.71 g, 33 mmol) was added at 0 °C, and the reaction mixture was subsequently heated to room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water, and the resulting solid was collected by filtration to give a white solid. N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (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, 8.4 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 2.44 (s, 3H), 1.30 (s,12H); MS(ESI)m / z: 408.2(M+H + ).

[0268] The following compounds were prepared primarily by the method for preparing intermediate I1.

[0269] Preparation of intermediate I7: 5-cyano- N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridazine-3-carboxamide Will N A solution of 3-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]pyridazine-3,5-dicarboxamide (I6, 16.5 g, 43 mmol) in THF (200 mL) was treated with methoxycarbonyl-(triethylammonium)sulfonyl-imide (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-dioxaborhecyclopentan-2-yl)phenyl]pyridazine-3-carboxamide (5.0 g, 31%). The mother liquor was concentrated under reduced pressure, and the resulting residue was then wet-milled with water (50 mL). The solid was filtered to give a second batch of yellow solid 5-cyano- N -[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]pyridazine-3-carboxamide (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 = 8.2 Hz,1H), 2.45 (s, 3H), 1.32 (s, 12H); MS(ESI)m / z: 365.1(M+H) + ).

[0270] Preparation of intermediate J1: N -(3-(2-chloropyridin-4-yl)-4-methylphenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide A solution of 6-(trifluoromethyl)pyridazine-3-carboxylic acid (H1, 0.14 g, 0.75 mmol) in DMF (3 mL) was treated with HATU (0.31 g, 0.82 mmol). The mixture was stirred at room temperature for 30 min. A solution of 3-(2-chloropyridin-4-yl)-4-methylaniline (B2, 0.15 g, 0.69 mmol) and DIEA (0.36 mL, 2.1 mmol) in DMF (3 mL) was added to the above solution. The reaction mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated NaHCO3 and then extracted with EtOAc (3 times). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-80% EtOAc / hexane) to give a yellow solid. N -(3-(2-chloropyridin-4-yl)-4-methylphenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (0.20 g, 72%). MS (ESI) m / z: 393.0 (M+H) + ).

[0271] The following compounds were prepared primarily by the method used to prepare intermediate J1.

[0272] Preparation of intermediate J3: N -(3-(2,6-dichloropyridin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide A solution of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (B25, 1.9 g, 10 mmol) and HATU (5.8 g, 15 mmol) in DMF (50 mL) was treated with DIEA (5.3 mL, 30 mmol). The reaction mixture was stirred for 1 h, followed by the addition of 3-(2,6-dichloropyridin-4-yl)-4-methylaniline (2.6 g, 10 mmol). The reaction mixture was stirred overnight at room temperature. Since the reaction was incomplete, HATU (3.0 g) and DIEA (3 mL) were added, and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water and stirred. The brown solid was collected by filtration, washed with water, and dried under high vacuum to give a brownish-yellow solid. N -(3-(2,6-dichloropyridin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (3.5 g, 82% yield). 1 H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 9.97 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 7.90-8.07 (m, 1H), 7.66 (s, 2H), 7.39 (d, J = 8.4 Hz, 1H), 2.28 (s,3H); MS(ESI)m / z: 426.9(M+H + ).

[0273] The following compounds were prepared primarily by the method used to prepare intermediate J3.

[0274] Preparation of intermediate J15: N -(3-(2-chloro-6-(methylamino)pyridin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide Will NA solution of 3-[3-(2,6-dichloro-4-pyridyl)-4-methyl-phenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide (J3, 0.50 g, 1.2 mmol) in NMP (10 mL) was treated with DIEA (2.0 mL, 12 mmol). Methylamine HCl salt (0.79 g, 12 mmol) was added, and the mixture was then heated in a sealed tube at 100 °C for 36 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-40% EtOAc / petroleum ether) to give a white solid. N -(3-(2-chloro-6-(methylamino)pyridin-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (0.20 g, 24%). 1 H NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H), 9.95 (d, J = 1.8 Hz, 1H), 8.56 (d,J = 1.5 Hz, 1H), 7.83-7.93 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.03 (q, J =4.8 Hz, 1H), 6.51 (s, 1H), 6.36 (s, 1H), 2.79 (d, J = 4.8 Hz, 3H), 2.24 (s,3H); MS(ESI)m / z: 422.2(M+H) + ).

[0275] The following compounds were prepared primarily by the method used to prepare intermediate J15.

[0276] Preparation Example 1: N -(3-(2'-acetamido-[2,4'-bipyridin]-4-yl)-4-methylphenyl)-6-(difluoromethyl)nicotinamide Will N -(3-(2-chloropyridin-4-yl)-4-methylphenyl)-6-(difluoromethyl)nicotinamide (J7, 0.15 g, 0.40 mmol), NA mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-2-yl)acetamide (0.16 g, 0.60 mmol) and 2.0 M K₂CO₃ (aqueous solution, 0.40 mL, 0.80 mmol) in a mixture of EtOH (3 mL) and toluene (3 mL) was purged with Ar for 5 min. XPhosPdG₂ (0.032 g, 0.041 mmol) was added, and the mixture was heated overnight at 80 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO₃ (aq). The aqueous solution was extracted with DCM (4 times). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give a white solid. N -(3-(2'-acetamido-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-6-(difluoromethyl)nicotinamide (1, 0.082 g, 43%). 1 H NMR (400 MHz, DMSO-d6): δ 10.63(s, 1H), 10.59 (s, 1H), 9.19 (d, J = 1.4 Hz, 1H), 8.78-8.89 (m, 2H), 8.49(dd, J = 1.8, 8.2 Hz, 1H), 8.42 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.78-7.84 (m, 2H), 7.77 (d, J = 1.8 Hz, 1H), 7.52 (dd, J =1.4, 5.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 54.6 Hz, 1H), 2.29(s, 3H), 2.13 (s, 3H); MS(ESI)m / z: 474.1(M+H) + ).

[0277] The following compounds were prepared essentially by the method described in Example 1.

[0278] Preparation Example 2: N -(3-(2'-amino-[2,4'-bipyridin]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide A solution of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (1.0 g, 5.3 mmol), tert-butyl(4-(5-amino-2-methylphenyl)-[2,4'-bipyridin]-2'-yl)carbamate (E6, 2.0 g, 5.3 mmol), pyridine (1.3 mL, 16 mmol), and EDC (2.0 g, 11 mmol) in DMF (27 mL) was stirred overnight at room temperature. The reactants were quenched with water, filtered to obtain a brown solid, and washed with water. The brown solid was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give a yellow solid of tert-butyl(4-(2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamido)phenyl)-[2,4'-bipyridin]-2'-yl)carbamate (0.98 g, 33%). MS(ESI) m / z: 551.2 (M+H) + ).

[0279] A solution of tert-butyl(4-(2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carbamate)phenyl)-[2,4'-bipyridin]-2'-yl)carbamate (0.98 g, 1.8 mmol) in DCM (10 mL) was treated with 1,4-dioxane (1.35 mL, 5.4 mmol) containing 4.0 N HCl. The reaction mixture was heated overnight at 50 °C. The reaction mixture was concentrated to dryness to give a yellow solid. N -(3-(2'-amino-[2,4'-bipyridinin]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide hydrochloride (2, 0.86 g, 99%). MS (ESI) m / z: 451.2 (M+H) + ).

[0280] Preparation Example 3: Methyl (5-(4-fluoro-2-methyl-5-(6-(trifluoromethyl)nicotinamide)phenyl)-[3,4'-bipyridine]-2'-yl)carbamate 10966 A solution of methyl (5-(5-amino-4-fluoro-2-methylphenyl)-[3,4'-bipyridin]-2'-yl)carbamate (E32, 0.20 g, 0.57 mmol) in DMF (1.5 mL) was treated with DIEA (0.3 mL, 1.7 mmol). The reaction mixture was stirred at room temperature for 5 min. A solution of 6-(trifluoromethyl)nicotinic acid (0.16 g, 0.85 mmol) in DMF (1.5 mL) was treated with HATU (0.43 g, 1.1 mmol), and the solution was then stirred at room temperature for 5 min. This solution was added to the aforementioned amine solution, and the reaction mixture was stirred overnight at room temperature. The mixture was then diluted with water. The filtered solid was washed with water and dried under vacuum to give a white solid methyl (5-(4-fluoro-2-methyl-5-(6-(trifluoromethyl)nicotinamide)phenyl)-[3,4'-bipyridine]-2'-yl)carbamate (3, 0.060 g, 20%). 1 H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 10.36 (s, 1H), 9.27 (s, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 8.15-8.09 (m, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 5.2Hz, 1H), 7.41 (d, J = 11.3 Hz, 1H), 3.70 (s, 3H), 2.32 (s, 3H); MS(ESI)m / z: 526.2(M+H + ).

[0281] The following compounds were prepared essentially by the methods described in Examples 2 and 3.

[0282] Preparation Example 4: N -(3-(2'-(1-fluorocyclopropane-1-carboxamido)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide At room temperature N A solution of 3-(2'-amino-[2,4'-bipyridinin]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (2, 0.25 g, 0.56 mmol), 1-fluorocyclopropane-1-carboxylic acid (0.058 g, 0.56 mmol), and pyridine (2.3 mL, 2.22 mmol) in DMF (3 mL) was treated with HATU (0.25 g, 0.67 mmol). The reaction mixture was heated at 50 °C for 2 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). The white solid was collected by filtration and washed with water. The solid was purified by silica gel (0-100% EtOAc / hexane) to give a white solid. N -(3-(2'-(1-fluorocyclopropane-1-carbamate)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carbamate (4, 0.16 g, 50%). 1H NMR (400 MHz, DMSO-d6): δ11.33 (s, 1H), 10.37 (s, 1H), 9.95 (s,1H), 8.82 (d, J = 5.0 Hz, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 7.90-8.06 (m, 4H), 7.54 (d, J = 4.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 2.30 (s, 3H), 1.27-1.51 (m, 4H); MS(ESI)m / z: 537.2(M+H + ).

[0283] The following compounds were prepared essentially by the method described in Example 4.

[0284] Preparation Example 94: N -(3-(2'-(4,4-difluoro-1-methylpyrrolidin-3-carboxamido)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide Towards N A solution of 3-[2-[2-[(4,4-difluoropyrrolidine-3-carbonyl)amino]-4-pyridyl]-4-pyridyl]-4-methyl-phenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide (92 g, 0.10 g, 0.17 mmol) in MeOH (2 mL) was mixed with one drop of AcOH and one drop of HCHO. The reaction mixture was stirred at 20 °C for 0.5 h, followed by the addition of NaBH3CN (0.02 g, 0.34 mmol). The reaction mixture was stirred at 20 °C for 0.5 h, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (40-80% H2O (10 mM NH4HCO3) / MeCN) using a C-18 method to give N-(3-(2'-(4,4-difluoro-1-methylpyrrolidine-3-carboxamido)-[2,4'-bipyridin]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (94 g, 0.025 g, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 10.93 (s,1H), 9.97 (d, J = 1.8 Hz, 1H), 8.89 (s, 1H), 8.84 (d, J = 5.0 Hz, 1H), 8.58(d, J = 1.4 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.97-8.04 (m, 3H), 7.89 (dd, J= 1.6, 5.2 Hz, 1H), 7.56 (dd, J = 1.6, 5.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H),3.68-3.82 (m, 1H), 3.12-3.31 (m, 2H), 2.87 (t, J = 8.8 Hz, 1H), 2.60-2.72 (m,1H), 2.32 (s, 6H); MS(ESI)m / z: 598.2(M+H + ).

[0285] The following compounds were prepared essentially by the method described in Preparation Example 94.

[0286] Preparation Example 37: ( E )- N -(3-(2'-(((dimethylamino)methylene)amino)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide Will N A solution of 3-(2'-amino-[2,4'-bipyridinin]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (2, 1.5 g, 3.3 mmol) in DMF (17 mL) was treated with pyridine (1.4 mL, 17 mmol). Methanesulfonyl chloride (0.26 mL, 3.3 mmol) was added dropwise, and the reaction mixture was stirred for 2 h. The solid was filtered and washed with water and MeOH. The resulting solid was dried under high vacuum to give a grayish-white solid (…). E )- N -(3-(2'-(((dimethylamino)methylene)amino)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (0.74 g, 43%). 1HNMR (400 MHz, DMSO-d6): δ 11.31 (s, 1H), 9.95 (d, J = 2.2 Hz, 1H), 8.78 (d, J =5.0 Hz, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.29 (d, J = 5.2 Hz, 1H), 8.04 (s,1H), 7.93-8.01 (m, 2H), 7.63 (dd, J = 1.6, 5.3 Hz, 1H), 7.52 (s, 1H), 7.49(d, J = 5.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 3.09 (s, 3H), 3.00 (s, 3H),2.31 (s, 3H); MS(ESI)m / z: 506.2(M+H + ).

[0287] Preparation Example 96: 5-Cyano- N -(3-(2'-(cyclopropanecarbamate)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)pyridazine-3-carboxamide At 0℃ N A solution of 3-[3-[2-[2-(cyclopropylcarbamoylamino)-4-pyridyl]-4-pyridyl]-4-methyl-phenyl]pyridazine-3,5-dicarboxamide (65, 0.10 g, 0.020 mol) in toluene was mixed with POCl3 (1.0 mL, 1.0 mmol). The mixture was stirred at 80 °C for 1 h and then cooled to room temperature. The mixture was concentrated under reduced pressure. The resulting residue was purified by C-18 preparative HPLC (25-60% H2O (10 mM NH4HCO3) / MeCN) to give a yellow solid 5-cyano- N -(3-(2'-(cyclopropylcarbamoyl)-[2,4'-bipyridine]-4-yl)-4-methylphenyl)pyridazine-3-carboxamide (96, 0.05 g, 51%). 1H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 10.91 (s, 1H), 9.88 (d, J =2.0 Hz, 1H), 8.87 (s, 1H), 8.81-8.83 (m, 2H), 8.44 (d, J = 5.2 Hz, 1H), 7.96-7.98 (m, 3H), 7.82 (d, J = 5.2 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 2.30 (s, 3H), 2.05 (m, 1H), 0.82-0.85 (m, 4H); MS(ESI) m / z: 476.1 (M+H) + ).

[0288] Preparation Example 128: N-(3-(2'-(methoxyamino)-[2,4'-bipyridin]-4-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide Will N A solution of -[3-[2-(2-fluoro-4-pyridyl)-4-pyridyl]-4-methyl-phenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide (127, 0.08 g, 0.18 mmol) in pyridine (5 mL) was used O 1,3-methylhydroxylamine hydrochloride (0.74 g, 8.82 mmol) was used for treatment. The mixture was stirred at 100 °C for 16 h and then cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (3 times). The combined organic phases were washed with 10 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by C-18 preparative HPLC (H2O(10 mM NH4HCO3) / MeCN) to obtain a yellow solid. N -[3-[2-[2-(methoxyamino)-4-pyridyl]-4-pyridyl]-4-methyl-phenyl]-5-(trifluoromethyl)pyridazine-3-carboxamide (14 mg, 16%). MS (ESI) m / z: 481.1 (M+H + ).

[0289] The following compounds were prepared essentially by the method described in Preparation Example 128.

[0290] Biochemical analysis of B-Raf The activity of β-Raf kinase (SEQ ID NO: 1) was determined by spectroscopic methods using a coupled pyruvate kinase / lactate dehydrogenase assay system, which continuously monitors NADH oxidation processes dependent on ATP hydrolysis (e.g., Schindler). Equal Human (Science, 2000, 289, 1938-1942). In 384-well plates (final volume 100 μL), the reaction system contained: 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; the buffer solution in the reaction system consisted of: 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. The inhibitory effect on β-Raf was measured by adding serially diluted analytes (final analytical concentration 1% DMSO). The absorbance at 340 nm was continuously monitored for up to 6 hours at 30°C using a BioTek microplate reader. The reaction rate was calculated based on absorbance data over a 4-5 hour timeframe. The reaction rates at each compound concentration were converted to percentage inhibition based on controls (i.e., reactions without the analyte and reactions with known inhibitors), and the IC50 was calculated by fitting a four-parameter sigmoid curve to this data using Prism (GraphPad software). 50 value.

[0291] The B-Raf protein sequence used is amino acid residues 416-766, with a GST tag at its N-terminus (SEQ ID NO:1). LQKSPGPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGGSSFGTVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTV KIGDFGLATVKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH 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 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 (100 mM Tris pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100). C-Raf inhibition was measured by adding serially diluted analytes (final analytical concentration 1% DMSO). At 30°C, continuous monitoring on a BioTek microplate reader showed a decrease in absorbance at 340 nm for up to 6 hours. The reaction rate was calculated using absorbance data over a 4-5 hour timeframe. A control was used. That is The reaction rates at various concentrations of the compound (without the analyte and with known inhibitors) were converted into percentage inhibition, and the IC50 was calculated by fitting a four-parameter sigmoid curve to this data using Prism (GraphPad software). 50 value.

[0292] 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 Numbers”).

[0293] For Table 1, "+" indicates IC 50 Less than or equal to 100 nM; "++" refers to IC 50 Greater than 100 nM and less than or equal to 500 nM; "+++" refers to IC 50 Greater than 500 nM and less than or equal to 1000 nM; and "++++" refers to IC 50 Greater than 1000 nM and less than or equal to 10000 nM.

[0294] 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% superior 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 until they reached 70-95% confluence, at which point they were passaged or collected for subsequent experiments. Serial dilutions of the test compounds were aliquoted into triplicate into 96-well black clear-bottomed culture plates. 3000 cells were added to each well of 200 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 μM resazurin (Sigma, St. Louis, MO) solution in PBS was added to each well of the culture plate, and the plate was incubated at 37°C, 5% CO2, and 95% humidity for another 5–6 hours. Fluorescence signals were read using a Synergy2 or equivalent microplate reader (Biotek, Winooski VT) at an excitation wavelength of 540 nm and an emission wavelength of 600 nm. Data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0295] 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% superior fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded until reaching 70-95% confluence, at which point they were passaged or collected for analysis. Serial dilutions of the test compounds were aliquoted into triplicate into 384-well black clear-bottomed culture 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 the incubation, 40 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 at 37°C, 5% CO2, and 95% humidity for another 4–5 hours. The culture plates were read using a Synergy2 or equivalent microplate reader (Biotek, Winooski VT) with an excitation wavelength of 540 nm and an emission wavelength of 600 nm. The data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0296] 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% superior 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 passaged or collected for analysis. Serial dilutions of the test compounds were aliquoted into triplicate into 384-well black clear-bottomed culture 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 the incubation, 40 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 at 37°C, 5% CO2, and 95% humidity for another 18–24 hours. The culture plates were read using a Synergy2 or equivalent microplate reader (Biotek, Winooski VT) with an excitation wavelength of 540 nm and an emission wavelength of 600 nm. The data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0297] Pa16c cell proliferation analysis Pa16c cells were obtained from Dr. Channing Der, University of North Carolina, Chapel Hill. In short, cells were grown in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% superior fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% penicillin / streptomycin / L-glutamine at 37°C, 5% CO2, and 95% humidity. Cells were expanded until reaching 70-95% confluence, at which point they were passaged or collected for analysis. Serial dilutions of the test compounds were aliquoted into 384-well black clear-bottomed culture 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 μM resazurin (Sigma, St. Louis, MO) solution in PBS was added to each well of the plate, and the plate was incubated at 37°C, 5% CO2, and 95% humidity for another 18–24 hours. The culture plates were read using a Synergy2 or equivalent microplate reader (Biotek, Winooski VT) with an excitation wavelength of 540 nm and an emission wavelength of 600 nm. The data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate the IC50. 50 value.

[0298] Table 2. Inhibition of cell proliferation of MiaPaca-2, HCT-116, HPAF-II and Pa16c by exemplary compounds (“Example Numbers”).

[0299] For Table 2, "++++" refers to IC. 50 Less than or equal to 100 nM; "+++" refers to IC 50 Greater than 100 nM and less than or equal to 500 nM; "++" refers to IC 50 Greater than 500 nM and less than or equal to 1000 nM; and "+" indicates IC 50 Greater than 1000 nM and less than or equal to 10000 nM.

[0300] Biochemical microtubule polymerization analysis Porcine brain tubulin (T240) and the tubulin polymerization assay kit (BK011P) were purchased from Cytoskeleton, Inc. (Denver, CO). Briefly, serially diluted solutions of the test compounds were aliquoted into triplicate into 384-well black clear-bottomed culture 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 and placed in a Synergy Neo2 or equivalent microplate reader (BioteK, Winooski, VT) at 37°C. Fluorescence values ​​were read every 2 minutes for 1 hour at an excitation wavelength of 335 nm and an emission wavelength of 450 nm 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.

[0301] Figure 1 This study demonstrates the maximum rate of tubulin polymerization in the presence of increasing concentrations of the tubulin depolymerizing agent plinabulin. In this recombinant biochemical analysis of tubulin, plinabulin showed an IC50 concentration of 2.7 μM. 50 Inhibits microtubule polymerization.

[0302] Cellular microtubule polymerization 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% superior fetal bovine serum (Invitrogen, Carlsbad, CA) 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 passaged or collected for analysis. 450,000 cells were seeded into 12-well plates treated with tissue culture medium, with 1500 μL of complete growth medium added to each well. The plates were incubated at 37°C, 5% CO2, and 95% humidity for 18-24 hours. At the end of the incubation, 2000 μL of basal medium was added to each well, followed by serial dilutions of the compound. The plates were then incubated for another 1 h at 37°C, 5% CO2, and 95% humidity. Subsequently, lysates were prepared by adding 100 μL of lysis and microtubule stabilization buffer 1 (LMS01, Cytoskeleton Inc, Denver, CO) supplemented with a stock solution of GTP (BST06, Cytoskeleton Inc), ATP (BSA04, Cytoskeleton Inc), and a mixture of protease inhibitors (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, 37 °C for 10 min, and the supernatant was transferred to another 96-well plate. The remaining precipitate was resuspended in 100 μL of LMS01 buffer and sonicated for 10 min. α-tubulin in the precipitate and supernatant was detected by Western blot analysis on a Jess system or an equivalent system (Bio-techne, Minneapolis, MN). Data were analyzed using Prism software (Graphpad, San Diego, CA) to calculate IC50. 50 value.

[0303] Figure 2 The change in the ratio of precipitate (polymerized tubulin) to supernatant (tubulin dimers) with increasing concentration of the tubulin depolymerizing agent punabulin, compared to the DMSO control group, is shown. In this cellular tubulin analysis, the IC50 of punabulin inhibiting tubulin polymerization was [not specified]. 50 It is 5 nM.

[0304] 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 through the combined use of multiple anticancer drugs, the compounds disclosed herein provide this dual inhibition within the same pharmacophore. This unexpected dual mechanism of action enables single-drug therapy to effectively inhibit mutant RAS cancer cell lines, a feat previously unachieved by BRAF / CRAF inhibitors.

[0305] Representative examples are shown in Table 3. The inhibitory activities of these example compounds against BRAF and CRAF, and their biochemical IC50 values ​​are also presented. 50 The values ​​are listed in Table 3. These compounds also exhibited microtubule polymerization inhibitory activity in microtubule biochemical analysis. In cell experiments, these compounds, as single agents, demonstrated potent 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. In contrast, Table 4 lists representative compounds from those disclosed in PCT / US2022 / 081242.

[0306] Other reported BRAF and / or CRAF inhibitors in various chemical classes are listed in Table 5. While these compounds inhibit BRAF and / or CRAF, none effectively inhibited tubulin polymerization. The compounds in Table 5 exhibited weak 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.

[0307] Table 3. Representative Compounds

[0308] In Table 3, for BRAF, CRAF, MiaPaca-2, HCT-116, HPAF-II, and microtubule cell experiments, "++++" indicates IC50. 50 Less than or equal to 100 nM; "+++" refers to IC 50 Greater than 100 nM and less than or equal to 500 nM; "++" refers to IC 50 Greater than 500 nM and less than or equal to 1000 nM; and "+" indicates IC 50 Greater than 1000 nM and less than or equal to 10000 nM; for microtubule biochemical analysis, "****" refers to IC50. 50 Less than or equal to 3 μM; "***" refers to IC50 Greater than 3 μM and less than or equal to 20 μM; "**" refers to IC 50 Greater than 20 μM and less than or equal to 100 μM; and "*" indicates IC 50 Greater than 100 μM.

[0309] Table 4. Representative compounds from PCT / US2022 / 081242

[0310] In Table 4, for BRAF, CRAF, MiaPaca-2, HCT-116, HPAF-II, and microtubule cytology experiments, "++++" indicates IC50. 50 Less than or equal to 100 nM; "+++" refers to IC 50 Greater than 100 nM and less than or equal to 500 nM; "++" refers to IC 50 Greater than 500 nM and less than or equal to 1000 nM; and "+" indicates IC 50 Greater than 1000 nM and less than or equal to 10000 nM; for microtubule biochemical analysis, "****" refers to IC50. 50 Less than or equal to 3 μM; "***" refers to IC 50 Greater than 3 μM and less than or equal to 20 μM; "**" refers to IC 50 Greater than 20 μM and less than or equal to 100 μM; and "*" indicates IC 50 Greater than 100 μM.

[0311] Table 5. Previously disclosed BRAF / CRAF inhibitors

[0312] In Table 5, for BRAF, CRAF, MiaPaca-2, HCT-116, HPAF-II, and microtubule cell experiments, "++++" indicates IC50. 50 Less than or equal to 100 nM; "+++" refers to IC 50 Greater than 100 nM and less than or equal to 500 nM; "++" refers to IC 50 Greater than 500 nM and less than or equal to 1000 nM; and "+" indicates IC 50 Greater than 1000 nM and less than or equal to 10000 nM; for microtubule biochemical analysis, "****" refers to IC50. 50 Less than or equal to 3 μM; "***" refers to IC 50 Greater than 3 μM and less than or equal to 20 μM; "**" refers to IC50 Greater than 20 μM and less than or equal to 100 μM; and "*" indicates IC 50 Greater than 100 μM.

[0313] equivalent Although specific embodiments have been discussed, the above description is exemplary and non-limiting. Many variations of the embodiments will be apparent to those skilled in the art upon review of this specification. The full scope of the disclosure, its equivalents, and the full scope of this specification and its variations should be determined with reference to the claims.

[0314] Unless otherwise indicated, all figures used in this specification and claims to indicate the quantity 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 appended claims are approximate values, and their specific values ​​may vary depending on the desired properties.

Claims

1. A compound represented by formula IA: Formula IA Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Z is selected from the following group: , , and optionally substituted 5-membered ring heteroaryl groups; Q 1 and Q 2 Each is independently selected from O and NH; X 1 X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; The prerequisite is: when X 3 When X is N, 4 For COLE, CLE, CN(R) 4 -LE, N, or CH; The prerequisite is: when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; The prerequisite is: when X 3 When C=O, X 4 For NLE; The prerequisite is: when X 4 When C=O, X 3 For NLE; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 1a and R 1b Independently selected from H, alkyl, and cycloalkyl; when R 1a and R 1b When it is an alkyl group, it can react with R. 1a and R 1b The attached N atoms cyclize together to form a heterocyclic base ring; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl groups; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo, and cyano groups each time it appears; and p is 0 or 1.

2. The compound of claim 1, wherein Q 1 O and Q 2 It is O.

3. The compound of claim 1, wherein Q 1 O and Q 2 It is NH.

4. The compound of claim 1, wherein Q 1 For NH and Q 2 It is O.

5. The compound according to any one of claims 1-4, wherein Z is composed of... The optional substituted 5-membered ring heteroaryl group; wherein R 6 Each time it appears, it is independently selected from H or alkyl.

6. A compound represented by formula IB: Formula IB Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q 1 and Q 2 Each is independently selected from O and NH; X 1 X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from the following group: CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; The prerequisite is: when X 3 When X is N, 4 For COLE, CLE, CN(R) 4 -LE, N, or CH; The prerequisite is: when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; The prerequisite is: when X 3 When C=O, X 4 For NLE; The prerequisite is: when X 4 When C=O, X 3 For NLE; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy; The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl groups; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

7. A compound represented by formula IC: IC Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; The prerequisite is: when X 3 When X is N, 4 For COLE, CLE, CN(R) 4 -LE, N, or CH; The prerequisite is: when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; The prerequisite is: when X 3 When C=O, X 4 For NLE; The prerequisite is: when X 4 When C=O, X 3 For NLE; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from the following group: H and alkyl; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

8. A compound represented by formula ID: Formula ID Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 4 Selected from the following groups: N, CH, COLE, CLE, and CN(R) 4 )-LE; X 5 Selected from CH or N; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from the following group: CR 5 and N; The prerequisite is: X 4 and X 5 No more than one of them is N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from the following group: H and alkyl; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

9. A compound represented by the formula IE: IE Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from the following group: CR 5 and N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; and R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure.

10. The compound of claim 9, wherein R 3 It is H or a haloalkyl group.

11. A compound represented by the formula IF: Formula IF Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 8 Selected from the following groups: CH, CF, and N; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally substituted with a substituent selected from halogens and alkyl groups each time it appears; and R 5 Selected from the following group: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl.

12. A compound represented by the formula IG: IG Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally substituted with a substituent selected from halogens and alkyl groups each time it appears; and R 5 Selected from the following group: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl.

13. A compound represented by the formula IH: Formula IH Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally substituted with a substituent selected from halogens and alkyl groups each time it appears; and R 3 Selected from the following group: H, haloalkyl, alkyl, cycloalkyl, alkoxy, and amino.

14. A compound represented by formula IJ: Formula IJ Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 X 2 and X 5 Each is independently selected from CH and N; X 4 Selected from the following groups: N, CH, COLE, CLE, and CN(R) 4 )-LE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl groups; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

15. A compound represented by formula IK: Formula IK Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 X 2 and X 5 Each is independently selected from CH and N; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 and X 5 No more than one of them is N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, heterocyclic, heteroaryl, haloalkyl, and haloalkoxy. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cyano, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

16. A compound represented by the formula IL: Formula IL Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q 2 Selected from O and NH; X 1 X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; The prerequisite is: when X 3 When X is N, 4 For COLE, CLE, CN(R) 4 -LE, N, or CH; The prerequisite is: when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; The prerequisite is: when X 3 When C=O, X 4 For NLE; The prerequisite is: when X 4 When C=O, X 3 For NLE; When p is 1, R 1 Selected from the following group: H, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, heterocyclic and haloalkyl. The alkyl substituent is independently and optionally substituted by a substituent selected from the group consisting of amino, halogen, cycloalkyl, and heterocyclic groups each time it appears; The cycloalkyl group in the cycloalkyl or cycloalkylalkyl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; When p is 0, R 1 Selected from the following group: heterocyclic and heteroaryl; The heterocyclic substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; The heteroaryl substituent is independently and optionally replaced by a substituent selected from halogens and alkyl groups each time it appears; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl groups; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine, and optionally substituted heterocyclic groups, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo, and cyano groups each time it appears; and p is 0 or 1.

17. The compound of claim 16, wherein Q 2 It is O.

18. A compound represented by the formula IM: IM Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q 2 Selected from O and NH; X 1 X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; The prerequisite is: when X 3 When X is N, 4 For COLE, CLE, CN(R) 4 -LE, N, or CH; The prerequisite is: when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; The prerequisite is: when X 3 When C=O, X 4 For NLE; The prerequisite is: when X 4 When C=O, X 3 For NLE; R 1a and R 1b Independently selected from H, alkyl and cycloalkyl, or R 1a With R 1b Together with the nitrogen atoms they are attached to, they form a heterocyclic base ring with 4-7 atoms in the ring structure; R 2 Selected from the following group: alkyl, H, halogen, and alkoxy; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl groups; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

19. The compound of claim 18, wherein Q 2 It is O.

20. A compound represented by the formula IN: IN Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q 2 Selected from O and NH; X 2 and X 5 Each is independently selected from CH and N; X 3 and X 4 Each of the following groups is selected independently: N, CH, C=O, COLE, CLE, CN(R) 4 -LE and NLE; X 6 Selected from CH or N; X 7 Selected from the following groups: CH, CF, and N; X 8 and X 10 Each is independently selected from the following groups: CH, CF, and N; X 9 Selected from CR 5 and N; The prerequisite is: X 2 X 3 X 4 and X 5 No more than two of them are N; The prerequisite is: X 6 and X 7 No more than one of them is N; The prerequisite is: X 8 X 9 and X 10 No more than one of them is N; The prerequisite is: when X 3 When X is N, 4 For COLE, CLE, CN(R) 4 -LE, N, or CH; The prerequisite is: when X 4 When X is N, 3 For N, CH, COLE, CLE or CN(R) 4 )-LE; The prerequisite is: when X 3 When C=O, X 4 For NLE; The prerequisite is: when X 4 When C=O, X 3 For NLE; R 2 Selected from the following group: alkyl, alkoxy, and halogen; R 3 Selected from the group consisting of H, haloalkyl, alkyl, cycloalkyl, and amino, or R. 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 4 Selected from H and alkyl groups; R 5 Selected from the group consisting of: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl, or R. 5 With R 3 Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-6 atoms in the ring structure; R 6 Selected from H and alkyl groups; L is selected from the group consisting of: direct bonds and optionally substituted C1-C6 alkyl groups; and E is selected from the group consisting of: H, alkyl, hydroxyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, amine and optionally substituted heterocyclic group, wherein the optionally substituted substituent is independently selected from the group consisting of: alkyl, halogen, amino, hydroxyl, oxo and cyano in each occurrence.

21. The compound of claim 20, wherein Selected from the following group: .

22. The compound of claim 20 or 21, wherein Q 2 It is O.

23. The compound according to any one of claims 1-7 and 14-19, wherein X 1 For CH.

24. The compound according to any one of claims 1-7 and 14-23, wherein X 2 For CH.

25. The compound according to any one of claims 1-7 and 16-24, wherein X 3 Let N be the number of elements in the array.

26. The compound according to any one of claims 1-8, 14, and 16-25, wherein X 4 Selected from the following groups: N, CH, COLE, and CN(R) 4 )-LE.

27. The compound according to any one of claims 1-8, 14 and 16-26, wherein X 4 Selected from the following groups: N and CH.

28. The compound according to any one of claims 1-8, 14 and 16-26, wherein X 4 Selected from the following group: CO-CH(R) 4 )-CH2-OH and C-NH-CH(R 4 )-CH2-OH.

29. The compound according to any one of claims 1-8 and 14-28, wherein X 5 For CH.

30. The compound of any one of claims 1-7 and 16-23, wherein it contains X 2 X 3 X 4 and X 5 The ring is selected from the following group: Where s1 represents the relationship with Z, , , , or The connection is s2, and s2 represents the connection with X. 6 and X 7 The connection of the rings.

31. The compound according to any one of claims 1-8 and 14-30, wherein X 6 For CH.

32. The compound according to any one of claims 1-8 and 14-31, wherein X 7 For CH.

33. The compound according to any one of claims 1-11 and 14-32, wherein X 8 Let N be the number of elements in the array.

34. The compound according to any one of claims 1-10 and 14-33, wherein X 9 For CR 5 .

35. The compound according to any one of claims 1-12 and 14-34, wherein R 5 Selected from the group consisting of alkyl, cycloalkyl, and haloalkyl.

36. The compound according to any one of claims 1-10 and 14-35, wherein X 10 For CH.

37. The compound according to any one of claims 1-17 and 23-36, wherein R 1 Selected from the group consisting of: H, alkyl, (C3-C8)cycloalkyl, alkoxy, alkoxyalkyl, heterocyclic, haloalkyl, haloalkoxy, wherein the alkyl substituent is optionally substituted independently each time it appears by a substituent selected from amino, halogen and (C3-C8)cycloalkyl, wherein the heterocyclic substituent is optionally substituted independently each time it appears by a substituent selected from halogen and alkyl.

38. The compound according to any one of claims 1-17 and 23-37, wherein R 1 Selected from the group consisting of: H, alkyl, (C3-C8)cycloalkyl, alkoxy, alkoxyalkyl, heterocyclic, haloalkyl, wherein the alkyl substituent is independently and optionally substituted by a substituent selected from amino, halogen and (C3-C8)cycloalkyl each time it appears.

39. The compound according to any one of claims 1-17 and 23-38, wherein R 1 Selected from the following group: H, methyl, ethyl, methoxy, .

40. The compound according to any one of claims 16-17 and 23-36, wherein if p is 1, then R 1 Selected from the following group: H, alkyl, cycloalkyl, heterocyclic, heterocyclic alkyl, aminoalkyl, alkoxyalkyl.

41. The compound according to any one of claims 16-17 and 23-36, wherein if p is 0, then R 1 Selected from the following group: heterocyclic and heteroaryl.

42. The compound of claim 41, wherein R 1 for .

43. The compound of any one of claims 18-19 and 23-36, wherein R 1a and R 1b Independently selected from H, alkyl, cycloalkyl, or R 1a With R 1b Together with the carbon atoms they are attached to, they form a cycloalkyl or heterocyclic ring with 4-7 atoms in the ring structure.

44. The compound of any one of claims 1-43, wherein R 2 Selected from alkyl and halogens.

45. The compound of any one of claims 1-44, wherein R 2 Selected from methyl and fluorine.

46. ​​The compound according to any one of claims 1-10 and 13-45, wherein R 3 Selected from the following group: H, haloalkyl, alkyl, cycloalkyl, alkoxy, and amino.

47. The compound according to any one of claims 1-10 and 13-46, wherein R 3 Selected from the following group: H, methyl, isopropyl, cyclopropyl, trifluoromethyl, .

48. The compound of any one of claims 1-45, wherein R 3 With R 5 Together with the carbon atoms they are attached to, they form a cycloalkyl ring with 4-6 atoms in the ring structure.

49. The compound according to any one of claims 1-8, 14 and 16-49, wherein R 4 For H.

50. The compound of any one of claims 1-49, wherein R 5 Selected from the following group: haloalkyl, cycloalkyl, cyano, H, alkyl, alkoxy, amino, amide, halogen, phosphine oxide, haloalkoxy and cyanoalkyl.

51. The compound of any one of claims 1-50, wherein R 5 Selected from the following group: H, .

52. The compound of any one of claims 1-8 and 14-51, wherein L is an optionally substituted C1-C6 alkyl group.

53. The compound of any one of claims 1-8 and 14-52, wherein L is selected from the group consisting of: , where E is connected to the carbon identified by *.

54. The compound of any one of claims 1-8 and 14-53, wherein L is selected from the group consisting of: , where E is connected to the carbon identified by *.

55. The compound of any one of claims 1-8 and 14-54, wherein E is selected from the group consisting of H, methyl, and hydroxyl.

56. A compound selected from the group consisting of: And its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers.

57. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-56 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

58. A method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound as claimed in any one of claims 1-56 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition as claimed in claim 51.

59. The method of claim 58, wherein the cancer is selected from the group consisting of: melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, hematogenous cancer, acute myeloid leukemia (AML), and other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

60. The method of claim 58 or 59, wherein the cancer has a BRAF oncogenic mutation.

61. The method of any one of claims 58-60, wherein the cancer has a RAS oncogenic mutation.

62. The method of any one of claims 58-61, wherein the cancer has an NRAS oncogenic mutation.

63. The method of claim 62, wherein the NRAS oncogenic mutation is NRAS Q61R or NRAS Q61K.

64. The method of any one of claims 58-63, wherein the cancer has a KRAS oncogenic mutation.

65. The method of claim 64, wherein the KRAS oncogenic mutation is KRAS G12D, KRAS G12V, KRAS G12C, KRAS G12R or KRAS G13D.

66. The method of any one of claims 58-65, wherein the cancer has an NF1 oncogenic mutation.

67. A method of treating a patient with a condition selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, 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 1-56 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 57.

Images