Vps34 inhibitors and methods of use thereof

Abstract

The present disclosure provides, in part, compounds of Formula (I) as VPS34 inhibitors, compositions thereof, and methods of use, such as use in methods of treating cancer, diabetes, inflammatory diseases, neurodegenerative disorders, cardiovascular disorders, autoimmune diseases, and viral infections: Formula (I).

Description

Cross-reference

[0001] This application claims priority to U.S. Provisional Application No. 63 / 609,562, filed December 13, 2023, and U.S. Provisional Application No. 63 / 622,680, filed January 19, 2024, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Autophagy is a cellular process that recycles cytoplasmic components by forming two-membrane vesicles called autophagosomes. In addition to autophagy-mediated vesicle transport, endosome vesicle transport also enables the separation and destruction / recycling of cellular components. Due to its cytoprotective role, defective autophagy has been involved in several human diseases, including cancer. Cancer cells have been shown to upregulate autophagy in response to stressors present in the tumor microenvironment (TME), such as hypoxia, nutrient deprivation, and resistance mechanisms to anticancer therapies. In recent years, it has been known that autophagy and / or endosome pathways can be upregulated in various cancers to degrade proteins that can trigger beneficial antitumor immune responses. Therefore, blocking the immunosuppressive effects of autophagy and endosome transport in the tumor environment is needed as a potential therapeutic strategy for improving cancer immunotherapy.

[0003] Recent studies have confirmed that activation of the STING pathway in the congenital tumor setting is necessary for inducing beneficial CD8+ T cell responses against tumor-derived antigens in vivo. STING, a transmembrane protein confined to the endoplasmic reticulum, is activated in response to the binding of cyclic dinucleotides (CDNs), triggering a downstream signaling cascade including TBK1 kinase activation, IRF-3 phosphorylation, and the production of IFN-β and other cytokines. IFN-β is a major cytokine induced by the binding of exogenous CDNs generated through bacterial infection or structurally different endogenous CDNs produced by the host cyclic GMPAMP synthase (cGAS) in response to STING activation. These observations suggest that direct activation of the STING pathway in the tumor setting via specific agonists could be an effective therapeutic strategy to promote broad-based tumor-induced T cell activation against individual tumor antigen gene profiles. Exogenously administered STING agonists are being developed as vaccine adjuvants and for direct-acting antitumor therapies. In addition to the administration of exogenous STING agonists, alternative pathways that modulate and upregulate endogenous STING signaling in the tumor environment may be a better treatment option.

[0004] Lipid kinase vacuole protein sorting 34 (VPS34) is a target for immunosuppression mediated by blocking autophagy or endosome pathways. Also known as grade III phosphoinositol 3-kinase (PIK3C3), VPS34 regulates autophagy initiation and other vesicle transport processes, including playing a key role in endosome transport. VPS34 phosphorylates phosphatidylinositol (PI) to phosphatidylinositol-3-phosphate (PI3P), which is essential for proteins to form complexes via the FYVE domain of client proteins recruited to vesicles. PI3P is present in early and late endosomes and is essential for autophagosome formation. Inhibition of VPS34, and thus disruption of P3IP production, leads to suppression of the autophagy pathway. VPS34 is also associated with delayed degradation of STING transported through endosomes in murine cells, resulting in prolonged activity of activated STING.

[0005] VPS34 inhibitors have demonstrated in vitro antiproliferative activity as single agents and in combination with other anticancer therapies, including anti-PD1 immunotherapy and STING agonists. However, the development of VPS34 inhibitors as anticancer therapeutics is limited by the high conservation of residues in their active sites compared to other PI3K family members, and by the clinically proven reduced toxicity of isoselective PI3K inhibitors compared to van-PI3K or dual PI3K / mTOR inhibitors. Therefore, providing novel and potent VPS34 inhibitors with high selectivity compared to other PI3K family members is advantageous. Invention Overview This disclosure provides in part compounds, compositions and methods of using as VPS34 inhibitors, such as in methods of treating cancer, diabetes, inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases and viral infections.

[0007] In some embodiments, compounds of formula (I) are provided herein: Formula (I), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0008] In some embodiments, pharmaceutical compositions are also described herein that comprise compounds described herein (e.g., compounds disclosed herein) or pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers thereof, and pharmaceutically acceptable carriers or excipients.

[0009] In some embodiments, this document provides a method of treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound disclosed herein as described herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound disclosed herein as described herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof).

[0010] In some embodiments, this document provides a method for treating type 2 diabetes in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound disclosed herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof).

[0011] In some embodiments, this document provides a method for treating a patient in need of a disease selected from inflammatory diseases, neurodegenerative diseases, autoimmune diseases, and viral infections, the method comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound disclosed herein) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof). Invention Details Features and other details of this disclosure will now be described more precisely. Specific terms used in this specification, embodiments, and appended claims are collectively brought together herein. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0013] definition The definitions set forth in this application are intended to clarify the terminology used throughout this application.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains. Unless otherwise stated, the following terms have the meanings assigned to facilitate understanding of the invention as used in the specification and appended claims.

[0015] When a bond to a substituent is shown to cross the bonds of two atoms in the linking ring, such a substituent may bond to any atom in that ring. If the listed substituents do not indicate that such substituents are bonded to atoms in the remainder of the compound specified, such substituents may bond via any atom of such substituents. Such combinations are permitted only if the combination of substituents, substituent positions, and / or variables produces a stable compound.

[0016] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” cover a plural referent.

[0017] As used herein, the term "this document" refers to the entire application.

[0018] As used herein, the terms "optional" or "optionally" mean that an event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not. For example, "optionally substituted alkyl" means both the possibility that the alkyl group may be substituted and the possibility that the alkyl group is not substituted.

[0019] It should be understood that those skilled in the art can select the substituents and substitution modes of the compounds disclosed herein to produce chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods set forth below. If a substituent is itself replaced by more than one group, it should be understood that these multiple groups may be on the same carbon or different carbons, as long as a stable structure is produced.

[0020] As used herein, the term "optionally substituted" means that 1-6 hydrogen atoms in a given structure are replaced by a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH2-O alkyl. Preferably, "optionally substituted" means that 1-4 hydrogen atoms in a given structure are replaced by the substituents mentioned above. More preferably, 1-3 hydrogen atoms are replaced by the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0021] As used herein, the term “substituted” refers to a portion of one or more carbons in the main chain that has a substituent replacing hydrogen. It should be understood that “substitution” or “substituted” includes implicit limitations, namely that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is used to encompass all permissible substituents in organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in organic compounds that satisfy the heteroatom valences described herein.

[0022] Substituents may include any substituents described herein, such as, unless otherwise specified, halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, phosphonites, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate esters, sulfonates, aminesulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, heteroaryl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the substituents themselves may be substituted where appropriate. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, azide, imino, amide, phosphoryl (including phosphonates and phosphonites), sulfonyl (including sulfates, sulfonamides, aminesulfonyls, and sulfonates), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylic acids, and esters), -CF3, -CN, and similar groups. Unless specifically stated as "unsubstituted," references to the chemical term herein should be understood to include substituted variants. For example, references to the "aryl" group may implicitly include both substituted and unsubstituted variants.

[0023] As used herein, the term "alkyl" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10, and may be, for example, C1-C2. 10 Alkyl groups or, for example, C1-C6 alkyl groups. Examples of straight-chain and branched alkyl groups include (but are not limited to): methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl and similar groups. Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent replacing one or more hydrogen atoms on the hydrocarbon backbone. "Alkyl" may optionally be substituted.

[0024] Term "C" x -C y When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it is intended to include groups containing x to y carbons in the chain. For example, the term "C x -C y "" refers to substituted or unsubstituted saturated hydrocarbon groups containing x to y carbons in the chain, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl indicates hydrogen when the group is at the end position, and a single bond when it is inside.

[0025] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms, which does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and a major carbon backbone, but may optionally include heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on its connecting carbon) and ethoxy (which is linked by oxygen rather than carbon) are not. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof. The "hydrocarbon group" may optionally be substituted.

[0026] As used herein, the term "alkoxy" refers to a straight-chain or branched, saturated aliphatic (alkyl) hydrocarbon group bonded to an oxygen atom attached to a core structure. Preferably, the alkoxy group has 1-6 carbon atoms, i.e., a C1-C6 alkoxy group. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and similar groups. "Alkoxy" may optionally be substituted.

[0027] As used herein, the term "alkoxyalkyl" refers to an alkoxy-substituted alkyl group (as defined above) and may be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethylidene and ethyl-O-ethylidene. "Alkoxyalkyl" may optionally be substituted.

[0028] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogens. For example, a monohaloalkyl group may have chlorine, bromine, iodine, or fluorine atoms. Dihaloalkyl and polyhaloalkyl groups may have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to: chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and similar groups. "Haloalkyl" may optionally be substituted.

[0029] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3). "Haloalkoxy" may optionally be substituted.

[0030] As used herein, the term "haloalkoxyalkyl" refers to an alkyl group substituted with a haloalkoxy group (as defined above) and can be represented by the general formula alkyl-O-haloalkyl. Examples of haloalkoxyalkyl groups include, but are not limited to, methyl-O-difluoroethylene- and ethyl-O-difluoroethylene-. "Haloalkoxyalkyl" may optionally be substituted.

[0031] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon atom. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (fused rings), at least one of which is aromatic; for example, the other ring may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. The term "fused" refers to the connection or formation of a second ring by sharing two adjacent atoms with a first ring. The term "fused" is equivalent to the term "condensation." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrene, phenol, aniline, or dihydroindenyl and similar groups. Unless otherwise specified, all aryl groups described herein may optionally be substituted.

[0032] As used herein, the terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) in which one or more atoms are shared by two adjacent rings, such as "fused rings." Each ring in a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring in a polycyclic compound contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0033] As used herein, the term "arylalkyl" refers to an alkyl group that has been substituted with an aryl group. The aryl and / or alkyl groups of an arylalkyl group may be further substituted as defined above with respect to aryl and alkyl groups, respectively.

[0034] As used herein, the term "acyl" refers to the group -C(=O)-R. w , where R w Alkyl groups that are optionally substituted. Examples of "acyl" include, but are not limited to: wherein R w For C1-C 10 Alkyl (C1-C) 10 Acyl) or C1-C 6- In the case of alkyl (C1-C6 acyl) groups, in some embodiments, the optionally substituted substituents are selected independently each time they appear: H, OH, alkoxy, cyano, F, and amino. Additional examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3)2.

[0035] As used herein, the term "carbamoyl" refers to a group represented by the following: Where R z Independently representing hydrogen or optionally substituted hydrocarbon groups, or R z The group, together with the -NC(=O)-O- part to which it is attached, forms a heterocycle with 5-8 atoms in the ring structure, which may optionally be substituted.

[0036] As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and their salts, for example, as can be represented by the following portions: or , Where R z Independently representing hydrogen or optionally substituted hydrocarbon groups, or R z The group, together with the N atom it is attached to, forms a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0037] As used herein, the terms "amide" and "amide group" each refer to a group represented by the following: or , Where R x R y and R z Each independently represents hydrogen or an optionally substituted hydrocarbon group, or R y and R z The group, together with the N atom it is attached to, forms a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0038] As used herein, the term "sulfonamide" is represented by the following: or , Where R x R y and R z Each time it appears, it independently represents hydrogen, an optionally substituted hydrocarbon group, or R. z The group, together with the N atom it is attached to, forms a heterocycle with 4-8 atoms in the ring structure, which may optionally be substituted.

[0039] As used herein, the term "sulfone" refers to the group -S(O)2-R. U , where R U This indicates a hydrocarbon group that is optionally substituted.

[0040] As used herein, the term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group.

[0041] As used herein, the term "amide-alkyl" refers to an alkyl group that has been substituted with an amide group.

[0042] As used herein, the term "cycloalkyl," alone or in combination with other terms, refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic hydrocarbons. Typically, unless otherwise defined, monocyclic cycloalkyl groups have 3 to approximately 10 carbon atoms, more commonly 3–8 carbon atoms (e.g., C3–C4). 10 cycloalkyl or, for example, C 3- C6 cycloalkyl. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similar groups. The second or third ring of a bicyclic or tricyclic cycloalkyl group may be self-saturated, unsaturated, or aromatic. Cycloalkyl groups include bicyclic and tricyclic molecules in which the two rings share one, two, three, or more atoms. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl group in which each ring shares two adjacent atoms with the other ring. The second or third ring of a fused bicyclic or tricyclic cycloalkyl group may be self-saturated, unsaturated, or aromatic. "Cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and similar groups. Cycloalkyl groups may alternatively be polycyclic with more than two rings. Examples of polycyclic cycloalkyl groups include bridged, fused, and spirocyclic carbocyclic groups.

[0043] As used herein, the term "carbocyclic" or "of a carbocyclic" includes bicyclic molecules in which the two rings share one, two, three, or more atoms. The term "fused carbocyclic" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. The rings of a fused carbocyclic ring may be self-saturated, unsaturated, or aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring where valence permits. Exemplary "carbocyclic" includes cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decahydronaphthalene, 4,5-naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, and 4,5,6,7-tetrahydro-1 H -Indene and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” can be substituted at any one or more positions capable of carrying hydrogen atoms.

[0044] As used interchangeably in this document, the terms "cycloalkylalkyl" or "carbocycloalkyl" refer to alkyl groups substituted with cycloalkyl groups. The carbocyclo group and / or alkyl group of a carbocycloalkyl group may be further substituted as defined above with respect to cycloalkyl and alkyl groups, respectively.

[0045] As used in this article, the term "cyano" refers to the -CN group.

[0046] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0047] As used herein, the term "cyanoalkyl" refers to an alkyl group that has been substituted with a cyano group.

[0048] As used herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0049] As used herein, the terms “halide,” “halo,” or “halogen,” alone or in combination with one or more other terms, refer to chlorine, fluorine, bromine, and iodine.

[0050] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0051] As used herein, the terms “heterocyclic,” “heterocyclic alkyl,” “heterocycle,” and “heterocyclic” refer to a non-aromatic, saturated, or partially saturated ring system having 3 to 15 members, including monocyclic, polycyclic (e.g., bicyclic, tricyclic) bridged or fused rings, wherein the members have at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclic groups" include, but are not limited to: azacyclic butyl, oxacyclic butyl, imidazoalkyl, pyrrolyl, oxazolyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl, indololinyl, indololinylmethyl, 2-azabicyclo[2.2.2]octyl, acrylyl, chromyl, oxanthyl and their N-oxides. The connection of heterocyclic alkyl substituents can occur via carbon atoms or via heteroatoms. Heterocyclic alkyl groups may optionally be substituted by one or more of the aforementioned groups via one or more suitable groups. Preferably, "heterocyclic group" refers to a 4-6 membered ring selected from the following: imidazoalkyl, pyrrolalkyl, oxazolalkyl, thiazoalkyl, pyrazolalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxane and their N-oxides. More preferably, "heterocyclic alkyl" includes azacyclic butyl, pyrrolalkyl, morpholinyl and piperidinyl. All heterocyclic alkyl groups are optionally substituted with one or more of the aforementioned groups.

[0052] As used herein, “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally attached to an alkyl group at the nitrogen atom. The heterocyclic group and / or alkyl group of a heterocyclic alkyl group may be further substituted as defined above with respect to heterocyclic groups and alkyl groups, respectively.

[0053] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic structure, preferably a 5-7 membered ring, more preferably a 5-6 membered ring, whose ring structure includes at least one heteroatom, preferably 1-4 heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), containing 8-20 ring atoms, suitably 5-10 ring atoms, which may be covalently linked or fused, wherein two or more atoms are shared by two adjacent rings, wherein at least one of these rings is heteroaromatic, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. These rings may contain N or S atoms, wherein the N or S atom is optionally oxidized, or the N atom is optionally quaternized. All heteroaryl groups are optionally substituted. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryl groups include, but are not limited to: furanyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazoleyl, oxazolyl, cenylyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothiopheneyl, benzotriazinyl, phthalazinyl, thiaanthracene, dibenzofuranyl, dibenzothiopheneyl, benzimidazolyl, indoleyl, isoindoleyl, indazoleyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purineyl, pteridinyl, 9 H -Carbazolyl, α-carbazoline, indoleazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanopyridyl, purinel, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothiadiazolyl, 7-azaindolyl, 7-azaindolyl, pyrrolopyridyl, pyrrolopyrimidinyl, oxazolinone pyridyl, oxazolinone pyrimidinyl, imidazolinone pyridyl, imidazolinone pyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, tetrahydronaphridyl, tetrahydropyridinephenol pyrimidinyl, dihydronaphridinone, naphridinone, oxazinone pyridyl, oxazinone pyrimidinyl, carbazolyl, dibenzothiaphenyl, acridinel and similar groups.

[0054] As used herein, “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The heteroaryl group and / or alkyl group of a heteroarylalkyl group may be further substituted as defined above with respect to heteroaryl and alkyl groups, respectively.

[0055] The compounds disclosed herein may contain one or more chiral centers and thus exist in stereoisomer form. The term "stereoisomer," as used herein, comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereoforming carbon atom, these compounds may be designated by the symbol "R" or "S," but those skilled in the art will recognize that the structure may implicitly represent the chiral center. These compounds may also be designated by "(+)" and "(-)" based on their optical rotational properties. The compounds described in this invention encompass various stereoisomers of these compounds and mixtures thereof. Enantiomers or mixtures of diastereomers may be designated by the symbol "(±)" in the nomenclature, but those skilled in the art will recognize that the structure may implicitly represent the chiral center.

[0056] Individual enantiomers and diastereomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by analytical methods well known to those skilled in the art. These analytical methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, with the auxiliary agent releasing an optically pure product; (2) forming a salt using an optically active analytical agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) performing kinetic analysis using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved to their constituent enantiomers by well-known methods such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis of unequal mixtures of stereoisomers formed by chemical or enzymatic reactions during the generation of new stereocenters or during the transformation of pre-existing stereocenters is well known in the art. Stereoselective synthesis encompasses both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno. Classics in Stereoselective Synthesis , Wiley-VCH: Weinheim, 2009.

[0057] This invention also covers isotopically labeled compounds consistent with those described herein, except that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P,32 P, 35 S, 18 F and 36 Cl. For example, compounds disclosed herein may have one or more deuterated H atoms.

[0058] "Combination therapy" refers to treatment that involves administering two or more therapeutic agents, such as the compounds disclosed herein and STING agonists, to a patient in need.

[0059] The terms “disease,” “symptom,” and “condition” can be used interchangeably in this article.

[0060] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds described herein can be applied not only to mammals such as humans but also to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, and similar animals), agricultural animals (e.g., cows, sheep, pigs, horses, and similar animals), and laboratory animals (e.g., rats, mice, guinea pigs, and similar animals).

[0061] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that, when properly administered to animals or humans, do not produce adverse, allergic, or other undesirable reactions. For human use, formulations should meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA Office of Biologics Standards.

[0062] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutical acceptable excipient” refer to any and all solvents, dispersion media, coatings, isotonics, absorption delay agents, and the like that compatible with drug administration. The use of these media and agents for the active pharmaceutical ingredient is well known in the art. Compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0063] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0064] As used herein, the term "pharmaceutically acceptable salt" refers to a salt having acidic or basic groups that may be present in the compounds used in the composition. The compounds included in the compositions of this invention, which are inherently basic, are capable of forming a wide variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to: malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronide, glucosidate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate). The compounds included in the compositions of this invention, which are inherently acidic, are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. The compounds included in the compositions of this invention, including basic or acidic portions, can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or basic salts.

[0065] In this specification, the term "therapeuticly effective amount" refers to the amount of the compound of the invention that researchers, veterinarians, medical professionals, or other clinicians are seeking to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human). The compounds described herein are administered in therapeutically effective amounts to treat a condition.

[0066] "Treatment" includes any action that causes improvement in a condition, disease, symptom, etc., such as reducing, decreasing, regulating, or eliminating it.

[0067] As used herein, “prophylaxis” encompasses any action that occurs before a subject begins to suffer from a specified condition, disease, symptom, or similar condition, and includes preventing the condition, disease, symptom, or one or more symptoms associated with the condition, disease, or symptom, or preventing its recurrence.

[0068] compound In some embodiments, a compound of formula (I) is described herein: Formula (I), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0069] In some implementations, a compound of formula (IA) is described herein: Formula (IA), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is a heterocyclic group; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0070] In some implementations, Q is selected from: -NHR 2 and -NHC(O)LR 4 .

[0071] In some implementations, a compound of formula (IB) is described herein: Formula (IB), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is a heteroaryl group; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0072] In some implementations, Q is selected from: -NHR2 and -NHC(O)LR 4 .

[0073] In some implementations, a compound of formula (IC) is described herein: Formula (IC), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is -NHR 2 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; and R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0074] In some implementations, this document describes a compound of formula (ID): Formula (ID), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 4Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0075] In some implementations, this document describes a compound of formula (IE): Formula (IE), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: A is a heterocyclic group; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; L is selected from: bonds and alkyl groups; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; and R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl and NH-heteroaryl. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0076] In some implementations, this document describes a compound of formula (IF): Formula (IF), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Y 1 and Y3 Selected from: CH and N; Y 2 Selected from: CR 6 and N; Its constraint is Y 1 Y 2 and Y 3 No more than one of them is N; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; L is selected from: bonds and alkyl groups; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl and NH-heteroaryl; R 5 Selected from: alkyl, cycloalkyl, haloalkyl and halogens; R 6 Selected from: NHS(O)2R 7 and NHC(O)R 8 ; R 7 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and R 8 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0077] In some implementations, a compound of formula (IG) is described herein: Formula (IG), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Z is selected from: CH2 and NR 9 ; Q is selected from: H, -NHR2 and -NHC(O)LR 4 ; L is selected from: bonds and alkyl groups; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl and NH-heteroaryl; R 9 Selected from: S(O)2R 31 and C(O)R 32 ; R 10 Selected from: H, alkyl, cycloalkyl, and haloalkyl; or R appearing twice. 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C5 cycloalkyl ring; R 31 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and R 32 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and m is 1 or 2 The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0078] In some embodiments, a compound of formula (IH) is described herein: Formula (IH), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Z is selected from: CH2 and NR 9 ; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; L is selected from: bonds and alkyl groups; R 1Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl and NH-heteroaryl; R 9 Selected from: S(O)2R 31 and C(O)R 32 ; R 10 Selected from: H, alkyl, cycloalkyl, and haloalkyl; or R appearing twice. 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C5 cycloalkyl ring; R 31 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and R 32 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and m is 1 or 2 The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0079] In some embodiments, a compound of formula (II) is described herein: Equation (II), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Z is selected from: CH2 and NR 9 ; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; L is selected from: bonds and alkyl groups; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl and NH-heteroaryl; R 9 Selected from: S(O)2R 31 and C(O)R 32 ; R 10 Selected from: H, alkyl, cycloalkyl, and haloalkyl; or R appearing twice in any of these groups. 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C5 cycloalkyl ring; R 31 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and R 32 Selected from: alkyl, amino, cycloalkyl, heterocyclic, alkylamino, aryl, and heteroaryl; and m is 1 or 2 The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0080] In some embodiments, a compound of formula (IJ) is described herein: Formula (IJ), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; L is selected from: bonds and alkyl groups; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; and R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl and NH-heteroaryl. The cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more of the following groups that appear independently each time it appears: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

[0081] In some implementation schemes, X 1 For CH. In other implementations, X 1 Let N be the number of elements in the array.

[0082] In some implementation schemes, R 1 Selected from: alkyl, halogenated, and amino groups. For example, in some embodiments, R 1 It can be CH3, -NH2, F, or Cl. In some implementations, R 1 For CH3. In some implementations, R 1 For -NH2. In some implementations, R 1 Selected from: F and Cl.

[0083] In some implementations, Q is -NHR 2 .

[0084] In some implementation schemes, R 2 It is a heteroaryl group. For example, in some embodiments, R 2 for ;in It can be a single or double bond; X 11 Selected from: N, CR 11 NR 21 S and O; X 12 Selected from: N, CR 12 NR 22 S and O; X 13 Selected from: N, CR 13 NR 23 S and O; X 14 Selected from: N, CR 14 NR 24 S and O; and R among them 11 R 12 R 13 R 14 R 21 R 22 R 23 and R 24 Each is independently selected from: H, amino, halogen, cyano, alkyl, cycloalkyl, and alkylamino. In some embodiments, R 11 R12 R 13 and R 14 Each is independently selected from: H, C1-C6 alkyl, and C1-C6 alkylamino. In some embodiments, R 11 R 12 R 13 and R 14 Each is independently selected from: H, CH3, and -(CH2)2N(CH3)2. In some embodiments, R 21 R 22 R 23 and R 24 Each is independently selected from: H, C1-C6 alkyl, and C1-C6 alkylamino. In some embodiments, R 21 R 22 R 23 and R 24 Each is independently selected from: H, CH3 and -(CH2)2N(CH3)2.

[0085] In some implementation schemes, R 2 Selected from: and .

[0086] In some implementation schemes, R 2 for ;X 5 Selected from: N and CR 15 ;X 6 Selected from: N and CR 16 ;X 7 Selected from: N and CR 17 ;X 8 Selected from: N and CR 18 ;X 9 Selected from: N and CR 19 ;where X 5 X 6 X 7 X 8 and X 9 No more than three of them are nitrogen; and R 15 R 16 R 17 R 18 and R 19 Each is independently selected from: H, amino, halogen, cyano, alkyl, cycloalkyl, and alkylamino. In some embodiments, R 15 R 16 R 17 R 18 and R 19Each group is independently selected from: H, amino, halogen, and cyano. In some embodiments, R 15 R 16 R 17 R 18 and R 19 Each is independently selected from: H and C1-C6 alkyl groups. In some embodiments, R 15 R 16 R 17 R 18 and R 19 Each is independently selected from: H and CH3.

[0087] In some implementation schemes, R 2 Selected from: and .

[0088] In some implementation schemes, R 2 Selected from: and .

[0089] In some embodiments, L is selected from: bonds and alkyl groups. In some embodiments, L is selected from: bonds and C1-C6 alkyl groups. In some embodiments, L is selected from: bonds and C1-C4 alkyl groups.

[0090] In some implementations, Q is NHC(O)LR 4 .

[0091] In some implementations, L stands for key.

[0092] In some implementation schemes, R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl. In some embodiments, the cycloalkyl, heterocyclic, aryl, heteroaryl, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, or NH-heteroaryl are each optionally substituted by one or more substituents independently selected from alkyl and halogen groups. In some embodiments, R 4Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, NH-cycloalkyl, NH-heterocyclic, and NH-heteroaryl. In some embodiments, the cycloalkyl, heterocyclic, aryl, heteroaryl, O-cycloalkyl, O-heterocyclic, NH-cycloalkyl, NH-heterocyclic, or NH-heteroaryl group is optionally substituted by one or more substituents independently selected from alkyl and halogen groups. In some embodiments, R... 4 Selected from: alkyl, alkoxy, amino, alkylamino, cycloalkyl, heterocyclic, aryl, heteroaryl, O-cycloalkyl, and O-heterocyclic. In some embodiments, the heterocyclic, heteroaryl, O-cycloalkyl, or O-heterocyclic group is optionally substituted by one or more substituents independently selected from alkyl and halogen groups. In some embodiments, R 4 Selected from: alkyl, alkoxy, amino, cycloalkyl, heterocyclic, heteroaryl, O-cycloalkyl, and O-heterocyclic. In some embodiments, the heterocyclic, heteroaryl, O-cycloalkyl, or O-heterocyclic group is optionally substituted by one or more substituents independently selected from alkyl and halogen groups. In some embodiments, R 4 Selected from: alkyl, alkoxy, amino, alkylamino, cycloalkyl, heterocyclic, aryl, heteroaryl, and O-heterocyclic. In some embodiments, the heterocyclic, heteroaryl, and O-heterocyclic groups are each optionally substituted by one or more substituents independently selected from alkyl and halogen groups. In some embodiments, R 4 Selected from: alkyl, alkoxy, amino, cycloalkyl, heterocyclic, heteroaryl, and O-heterocyclic. In some embodiments, the heterocyclic, heteroaryl, and O-heterocyclic groups are each optionally substituted by one or more substituents independently selected from alkyl and halogen groups.

[0093] In some implementation schemes, LR 4 Selected from: methyl, methoxy, -N(H)CH3, and .

[0094] In some implementation schemes, LR 4 Selected from: methyl, methoxy and .

[0095] In some implementations, L is an alkyl group.

[0096] In some implementation schemes, R 4 Selected from: alkoxy, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from alkyl and halogen groups. In some embodiments, R 4Selected from: amino and heterocyclic groups. In some embodiments, LR 4 Selected from: and .

[0097] In some embodiments, A is selected from: aryl, heteroaryl, heterocyclic and -NHSO2R 3 .

[0098] In some implementations, A is -NHSO2R 3 And R 3 For optional use by R, which appears one or more times 33 Substituted phenyl, wherein R 33 Each time it appears, it is independently selected from: H, amino, halogen, cyano, alkyl, cycloalkyl, and alkylamino. In some embodiments, A is -NHSO2R. 3 And R 3 For optional use by R, which appears one or more times 33 Substituted phenyl, wherein R 33 Each time it appears, it is independently selected from: H, amino, and halogen.

[0099] In some implementations, A is selected from aryl and heteroaryl groups.

[0100] In some implementation schemes, A is Where n is 0, 1, 2 or 3; and R 22 Each time it appears, it is independently selected from: alkyl, haloalkyl, cycloalkyl, and sulfonamide. In some embodiments, A is... .

[0101] In some implementation schemes, A is selected from: and Where n is 0, 1, 2 or 3; and R 23 Each time it appears, it is independently selected from: alkyl, haloalkyl, and cycloalkyl.

[0102] In some implementation schemes, A is selected from: and .

[0103] In some implementation schemes, A is selected from: and .

[0104] In some embodiments, A is a heterocyclic group. In some embodiments, A is selected from: and Where n is 0, 1, 2, or 3; R 24Each time it appears, it is independently selected from: alkyl, haloalkyl, and cycloalkyl; R 25 Selected from: alkyl, cycloalkyl, C(O)-R 26 SO2-R 27 ;R 26 Selected from: alkyl, cycloalkyl, aryl, and heteroaryl; and R 27 Selected from: alkyl, cycloalkyl, aryl and heteroaryl.

[0105] In some implementation schemes, A is selected from: and .

[0106] In some implementation schemes, A is selected from: and .

[0107] In some implementation schemes, A is selected from: and .

[0108] In some embodiments, this document provides a compound selected from the group consisting of:

[0109] And its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers.

[0110] Pharmaceutical Compositions and Kits Another aspect of this disclosure provides pharmaceutical compositions comprising a compound as disclosed herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, formulated with a pharmaceutically acceptable carrier. Specifically, the invention provides pharmaceutical compositions comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, non-intestinal (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or nebulized administration; however, in any given case, the most suitable form of administration will depend on the extent and severity of the condition being treated and on the nature of the particular compound used. For example, the compositions of this disclosure may be formulated in unit dose form and / or may be formulated for oral or subcutaneous administration.

[0111] Exemplary pharmaceutical compositions may be used in pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more of the compounds described herein as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or non-enterogonal administration. The active ingredient may be formulated, for example, with a commonly used, non-toxic, pharmaceutically acceptable carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form of use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0112] For the preparation of solid compositions such as lozenges, the main active ingredient may be mixed with a drug carrier, such as conventional lozenge components (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 further divided into equally effective unit dosage forms, such as lozenges, pills, and capsules.

[0113] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, and the like) intended for oral administration, the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any one of the following substances: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) (3) Humectants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption enhancers, such as quaternary ammonium compounds; (7) Wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) Colorants. In the case of capsules, tablets and pills, the composition may also contain buffers. Excipients such as lactose and high molecular weight polyethylene glycol and the like may also be used as fillers in soft-filled and hard-filled gelatin capsules.

[0114] Tablets can be manufactured by compression or molding, optionally together with one or more auxiliary components. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be manufactured by molding a mixture of the compositions of the invention moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules can optionally be scored or coated and shelled with coatings such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0115] 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, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof. 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 ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragacanth gum and mixtures thereof as suspending agents.

[0116] 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.

[0117] Dosage forms for transdermal application of the compositions of the present invention include: powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredients may be mixed under aseptic conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required.

[0118] In addition to the compositions of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, polysilicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0119] In addition to the compositions of the present 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 further contain common propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0120] The compositions and compounds of the present invention can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Acoustic nebulizers can be used because they minimize the exposure of the agent to shear forces that could lead to degradation of the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are manufactured by formulating an aqueous solution or suspension of the compositions of the present invention with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the specific composition of the present invention, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol); harmless proteins such as serum albumin; dehydrated sorbitol esters; oleic acid; lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0121] The pharmaceutical compositions of the present invention suitable for non-enteral administration comprise the composition of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use. These sterile powders may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0122] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include: water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate), and cyclodextrins. Appropriate flowability can be achieved, for example, by using a coating material such as lecithin, and by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0123] In another embodiment, an enteric pharmaceutical formulation is provided, comprising the compounds of this disclosure, an enteric-coating material, and a pharmaceutically acceptable carrier or excipient thereof. An enteric-coating material is a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5.

[0124] Therefore, the enteric material is insoluble, for example up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include: cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose succinate (HPMCAS); cellulose trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose hexahydrophthalate; cellulose propionate; cellulose maleate; cellulose acetate butyrate; cellulose propionate; copolymers of methyl methacrylate and methyl methacrylate; methyl acrylate, methyl methacrylate and methacrylate copolymers; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers; natural resins such as corn gluten, shellac and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit...). FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be readily determined in vitro. The foregoing materials are a list of possible materials, but those skilled in the art will recognize that this list is incomplete and that other enteric-coated materials exist that satisfy the objectives described herein.

[0125] Advantageously, this document provides kits for use by consumers, for example, those requiring cancer treatment. These kits include suitable dosage forms such as those described above; and instructions describing methods of using the dosage form to mediate, reduce, or prevent inflammation. The instructions will guide the consumer or medical professional to administer the dosage form according to administration methods known to those skilled in the art. These kits can advantageously be packaged and sold as single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging drug unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a relatively rigid material sheet covered with a foil, preferably of a transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the relatively rigid material sheet is sealed against the plastic foil at the foil side opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet is strong enough that pressure can be manually applied to the groove to create an opening in the sheet at the groove location, allowing removal of the tablet or capsule from the blister pack. The tablet or capsule can then be removed through this opening.

[0126] Memory aids may need to be provided on the kit, for example, in the form of numbers immediately preceding the tablets or capsules, corresponding to the number of days in the regimen for which the prescribed tablets or capsules should be taken. Another example of such memory aids is a schedule printed on a card, such as "Week 1, Monday, Tuesday, ... etc.; Week 2, Monday, Tuesday, ... etc." Other variations of memory aids are self-evident. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a specified date. Furthermore, the first compound of the daily dose may consist of one tablet or capsule, while the second compound of the daily dose may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0127] Combination therapy The compounds described herein (e.g., compounds of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein) may be administered in combination with one or more additional therapeutic agents (e.g., one or more additional therapeutic agents described herein) to treat the conditions described herein, such as cancers described herein. For example, this disclosure provides a pharmaceutical composition comprising the compounds described herein (e.g., compounds of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein), one or more additional therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, a compound of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein and an additional therapeutic agent are administered. In some embodiments, a compound of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein, and two additional therapeutic agents are administered. In some embodiments, a compound of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein, and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each formulated and administered separately. For example, a compound of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein, and additional therapeutic agents can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents as a single formulation, such as a pharmaceutical composition comprising, for example, a compound of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as a therapeutic agent and one or more additional therapeutic agents (such as antibiotics, viral protease inhibitors, or antiviral nucleoside antimetabolites). For example, a compound of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ as defined herein, and an additional therapeutic agent, 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 always the case. For example, the administration of the first agent (or combination of agents) may be minutes, hours, days, or weeks earlier than the administration of the second agent (or combination of agents).Therefore, the administration of two or more drugs can occur within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks or several weeks. In some cases, even longer time intervals are possible. Although 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.

[0128] Combination therapy may also include administering one or more of the component drugs two or more times in different sequences. For example, if drugs X and Y are used together, they can be administered one or more times in any combination sequence, such as XYX, XXY, YXY, YYX, XXYY, etc.

[0129] Examples of additional therapeutic agents that can be used in combination with VPS34 inhibitors (such as compounds of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, or IJ) include, but are not limited to: anti-STING agonists (e.g., DMXAA, ADU-S100, or pharmaceutically acceptable salts thereof), anti-PD-1 therapeutics, anti-PD-L1 therapeutics, or CTLA4 inhibitors.

[0130] How to use In some embodiments, this document provides a method of treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0131] In some implementation schemes, the cancer is selected from: breast cancer (such as triple-negative breast cancer), bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, gastrointestinal stromal tumor, esophageal cancer, gastric cancer, glioma, glioblastoma, ovarian cancer, head cancer, neck cancer, urothelial carcinoma, uterine cancer, prostate cancer, hepatic cancer, osteosarcoma, sarcoma, multiple myeloma, metastatic bone cancer and papillary thyroid carcinoma, as well as hypoxic tumors.

[0132] In some implementations, the method also includes radiotherapy.

[0133] In some embodiments, this document also provides a method for treating type 2 diabetes in patients in need, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0134] In some embodiments, this document provides a method for treating a disease selected from inflammatory diseases, neurodegenerative diseases, autoimmune diseases, and viral infections, the method comprising administering to a patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0135] In some embodiments, this document provides a method for treating a viral infection, the method comprising administering to a patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0136] In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronaviruses, rhinoviruses, and flaviviruses. In some embodiments, the viral infection is caused by a rhinovirus. In some embodiments, the viral infection is caused by a flavivirus.

[0137] In some embodiments, the viral infection is caused by coronaviruses selected from the group consisting of: 229E α coronavirus, NL63 α coronavirus, OC43 β coronavirus, HKU1 β coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2. In some embodiments, the viral infection is caused by SARS. In some embodiments, the viral infection is caused by SARS-CoV. In some embodiments, the viral infection is caused by SARS-CoV-2. In some embodiments, the viral infection is caused by MERS-CoV. In some embodiments, the viral infection is caused by COVID-19.

[0138] In some embodiments, the viral infection is caused by a positive-sense RNA virus. In some embodiments, the virus is a positive-sense RNA virus. In some embodiments, the virus is a sense RNA virus. In some embodiments, the virus is a sense-strand RNA virus. In some embodiments, the virus is a positive-sense RNA virus. In some embodiments, the virus is a positive (+) RNA virus. In some embodiments, the virus is a positive-sense single-sense RNA virus. In some embodiments, the positive-sense RNA virus is selected from: coronaviruses, flaviviruses, and microRNAviruses. In some embodiments, the positive-sense RNA virus is selected from: rhinoviruses, flaviviruses, microRNAviruses, and coronaviruses. In some embodiments, the positive-sense RNA virus is a microRNA virus. In some embodiments, the positive-sense RNA virus is a rhinovirus. In some embodiments, the positive-sense RNA virus is a human rhinovirus. In some embodiments, the positive-sense RNA virus is a flavivirus. In some embodiments, the positive-sense RNA virus is a coronavirus. In some embodiments, the positive-sense RNA virus is selected from: SARS CoV-1, SARS CoV-2, MERS, hepatitis C (HCV), rhinovirus, dengue virus, Zika virus, and West Nile virus. In some embodiments, the positive-sense RNA virus is a coronavirus. In some embodiments, the coronavirus is selected from: SARS CoV-1, SARS CoV-2, and MERS. In some embodiments, the coronavirus is SARS CoV-1. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the positive-sense RNA virus (e.g., coronavirus) has any variant resulting from mutation or a novel variant arising from other species (e.g., mammalian species, such as mink). In some embodiments, the positive-sense RNA virus is MERS. In some embodiments, the positive-sense RNA virus is hepatitis C. In some embodiments, the positive-sense RNA virus is Zika virus. In some embodiments, the positive-sense RNA virus is dengue virus. In some embodiments, the positive-sense RNA virus is West Nile virus.

[0139] In some implementations, the viral infection is a respiratory viral infection. In some implementations, the viral infection is an upper respiratory tract viral infection or a lower respiratory tract viral infection.

[0140] In some embodiments, the method further includes administering a therapeutically effective amount of one or more other agents or compositions to the patient.

[0141] In some implementations, the one or more additional agents are selected from: ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.

[0142] In some embodiments, the one or more additional agents are selected from: protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitors, acyclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, compivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ib... acitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitors, interferon, lopinavir, loviride, moroxydine, nexavir, nucleoside analogs, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.

[0143] In some embodiments, the one or more additional agents are selected from: lamivudine, interferon-alpha, VAP anti-idiotype antibody, enfvirdi, amantadine, rimantadine, proconalide, acyclovir, zidovudine, formivir, protease inhibitors, double-stranded RNA activated apoptosis protease oligomer (DRACO), rifampicin, zanamivir, oseltamivir, danopvir, ritonavir, and remdesivir.

[0144] In some embodiments, the one or more additional agents are selected from: quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives, doxycycline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflornithine, nitazoxanide, ornidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), sulfonamides, tafenoquine, tinidazole, and PPT1 inhibitors.

[0145] In some embodiments, the one or more additional agents are RNA polymerase inhibitors. In some embodiments, the RNA polymerase inhibitor is selected from: remdesivir, sofosbuvir, 7-dezo-2-CMA, galidesvir, and AT-527. In some embodiments, the RNA polymerase inhibitor is remdesivir.

[0146] In some embodiments, the one or more additional agents are selected from: TMPRSS protease inhibitors, lysosomal blockers (e.g., hydroxychloroquine), PIKfyve inhibitors (e.g., apilimod), anti-SARS-CoV-2 antibodies, mixtures of anti-SARS-CoV-2 antibodies, anti-inflammatory agents, anti-TNF agents (e.g., adalimumab, infliximab, etanercept, golimumab, or certolizumab), histamine H1 / H2 blockers (e.g., famotidine, nizatidine, ranitidine, and cimetidine), steroids, anticoagulants, complement-targeting agents, statins, and ACE inhibitors. In some embodiments, the TMPRSS protease inhibitor is selected from: TMPRSS4 inhibitors, TMPRSS11A inhibitors, TMPRSS11D inhibitors, TMPRSS11E1 inhibitors, and TMPRSS2 inhibitors. In some embodiments, the TMPRSS protease inhibitor is a TMRSS2 protease inhibitor. In some embodiments, the TMRSS-2 protease inhibitor is selected from: carmostat and nafamostat. In some embodiments, the anti-SARS-CoV-2 antibody is selected from: LY-CoV555 (bamlanivimab) and LY-CoV016 (etesevimab). In some embodiments, the mixture of anti-SARS-CoV-2 antibodies is REGN-COV2. In some embodiments, the anti-inflammatory agent is an IL-6 antagonist (e.g., siltuximab, sarilumab, olokizumab, BMS-945429, sirukumab, and clazakizumab). In some embodiments, the steroid is dexamethasone. In some embodiments, the anticoagulant is low molecular weight heparin. In some embodiments, the complement target is eculizumab. In some embodiments, the statin is selected from atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0147] In some implementation schemes, the ACE inhibitor is selected from: benazepril, captopril, enalapril / enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, and ramipril.

[0148] In some implementations, the one or more additional agents are selected from: remdesivir, carmostat, naprost, hydroxychloroquine, chloroquine, apimod, LY-CoV555 (barnivir), LY-CoV016 (Etesvirumab), REGN-COV2, tocilizumab, statoximab, sarrizumab, olozazumab, BMS-945429, cilukumab, clazazumab, adalimumab, infliximab, etanercept, golimumab, sertoximab, famotidine, nisatidine, ranitidine, cimetidine, dexamethasone, low molecular weight heparin, eculizumab, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, russovastatin, simvastatin, benazepril, captopril, enalapril / enalapril, fosinopril, lisinopril, moxipril, perindopril, quinapril, and ramipril.

[0149] In some embodiments, the method includes administering one or more additional agents selected from the group consisting of: remdesivir, sofosbuvir, 7-dezo-2-CMA, galilisvir, AT-527, temoporfin, novobiocin, curcumin, voxilaprevir, grazopevir, glecaprevir, carmostat, naftomostat, hydroxychloroquine, chloroquine, apimod, imatinib, dasatinib, ponatinib, velpatasvir, ledipasvir, elbasivir, pibrentasvir, NITD008, LY-CoV555 (barnivir monoclonal antibody), and LY-CoV016. (Etessermab), REGN-COV2, Tocilizumab, Sestoximab, Salrelumarab, Olozumab, BMS-945429, Cilukumab, Crazazumab, Adalimumab, Infliximab, Etanercept, Golimumab, Sertoximab, Famotidine, Nisatidine, Ranitidine, Cimetidine, Dexamethasone, Low Molecular Weight Heparin, Eculizumab, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Benazepril, Captopril, Enalapril / Enalapril, Fosinopril, Lisinopril, Moxipril, Perindopril, Quinapril, Ramipril, and Adoptive NK Cell Therapy.

[0150] In some implementations, one or more additional agents are selected from ABL inhibitors and JAK inhibitors.

[0151] In some embodiments, one or more additional agents are ABL inhibitors (e.g., imatinib, dasatinib, or ponatinib). In some embodiments, the ABL inhibitor is selected from imatinib, dasatinib, and ponatinib. In some embodiments, the ABL inhibitor is imatinib. In some embodiments, the ABL inhibitor is dasatinib. In some embodiments, the ABL inhibitor is ponatinib.

[0152] In some embodiments, one or more additional agents are JAK inhibitors. In some embodiments, the JAK inhibitor is selected from baricitinib, ruxolitinib, tofacitinib, and upadacitinib. In some embodiments, the JAK inhibitor is baricitinib. In some embodiments, the JAK inhibitor is ruxolitinib. In some embodiments, the JAK inhibitor is tofacitinib. In some embodiments, the JAK inhibitor is upadacitinib.

[0153] In some embodiments, one or more additional agents are protease inhibitors. In some embodiments, the protease inhibitor is selected from: temopofol, neomycin, curcumin, voxiprevir, gzopivir, and gcapipvir.

[0154] In some embodiments, one or more additional agents are NS5A inhibitors. In some embodiments, the NS5A inhibitor is selected from velpatasvir, ledipasvir, ibasvir, and pirentavir.

[0155] In some embodiments, one or more additional agents are pyrimidine synthesis inhibitors. In some embodiments, the pyrimidine synthesis inhibitor is NITD008.

[0156] In some embodiments, one or more additional agents are adoptive natural killer (NK) cell therapy. In some embodiments, the additional therapeutic agent is a vaccine. In some embodiments, the vaccine is a coronavirus vaccine. In some embodiments, the vaccine is selected from BNT162b2, mRNA-1273, AZD1222, and Ad26.COV2.S. In some embodiments, the vaccine is a protein-based vaccine. In some embodiments, the vaccine is an RNA-based vaccine. In some embodiments, the vaccine is an attenuated viral vaccine. In some embodiments, the vaccine is an inactivated viral vaccine. In some embodiments, the vaccine is a non-replicating viral vector vaccine.

[0157] In some embodiments, the compounds described herein are administered orally to a patient. In some embodiments, the compounds described herein are administered non-enterally to a patient.

[0158] In some embodiments, this document provides a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein, for the treatment or prevention of disease.

[0159] In some embodiments, this document provides a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein, for the treatment of cancer.

[0160] In some implementation schemes, the cancer is selected from: breast cancer (such as triple-negative breast cancer), bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, gastrointestinal stromal tumor, esophageal cancer, gastric cancer, glioma, glioblastoma, ovarian cancer, head cancer, neck cancer, urothelial carcinoma, uterine cancer, prostate cancer, hepatic cancer, osteosarcoma, sarcoma, multiple myeloma, metastatic bone cancer and papillary thyroid carcinoma, as well as hypoxic tumors.

[0161] In some embodiments, this document also provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, an enantiomer, a stereoisomer or a tautomer thereof, or a pharmaceutical composition disclosed herein for the treatment of cancer, wherein the cancer treatment further includes radiotherapy.

[0162] In some embodiments, this document also provides a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein, for the treatment of type II diabetes.

[0163] In some embodiments, this document provides a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein, for the treatment of a disease selected from inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and viral infections.

[0164] In some embodiments, this document provides a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition disclosed herein, for the treatment of viral infections.

[0165] In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronaviruses, rhinoviruses, and flaviviruses. In some embodiments, the viral infection is caused by a rhinovirus. In some embodiments, the viral infection is caused by a flavivirus.

[0166] In some embodiments, the viral infection is caused by coronaviruses selected from the group consisting of: 229E α coronavirus, NL63 α coronavirus, OC43 β coronavirus, HKU1 β coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2. In some embodiments, the viral infection is caused by SARS. In some embodiments, the viral infection is caused by SARS-CoV. In some embodiments, the viral infection is caused by SARS-CoV-2. In some embodiments, the viral infection is caused by MERS-CoV. In some embodiments, the viral infection is caused by COVID-19.

[0167] In some embodiments, the viral infection is caused by a positive-sense RNA virus. In some embodiments, the virus is a positive-sense RNA virus. In some embodiments, the virus is a sense RNA virus. In some embodiments, the virus is a sense-strand RNA virus. In some embodiments, the virus is a positive-sense RNA virus. In some embodiments, the virus is a positive (+) RNA virus. In some embodiments, the virus is a positive-sense single-sense RNA virus. In some embodiments, the positive-sense RNA virus is selected from: coronaviruses, flaviviruses, and microRNAviruses. In some embodiments, the positive-sense RNA virus is selected from: rhinoviruses, flaviviruses, microRNAviruses, and coronaviruses. In some embodiments, the positive-sense RNA virus is a microRNA virus. In some embodiments, the positive-sense RNA virus is a rhinovirus. In some embodiments, the positive-sense RNA virus is a human rhinovirus. In some embodiments, the positive-sense RNA virus is a flavivirus. In some embodiments, the positive-sense RNA virus is a coronavirus. In some embodiments, the positive-sense RNA virus is selected from: SARS CoV-1, SARS CoV-2, MERS, hepatitis C (HCV), rhinovirus, dengue virus, Zika virus, and West Nile virus. In some embodiments, the positive-sense RNA virus is a coronavirus. In some embodiments, the coronavirus is selected from: SARS CoV-1, SARS CoV-2, and MERS. In some embodiments, the coronavirus is SARS CoV-1. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the positive-sense RNA virus (e.g., coronavirus) has any variant resulting from mutation or a novel variant arising from other species (e.g., mammalian species, such as mink). In some embodiments, the positive-sense RNA virus is MERS. In some embodiments, the positive-sense RNA virus is hepatitis C. In some embodiments, the positive-sense RNA virus is Zika virus. In some embodiments, the positive-sense RNA virus is dengue virus. In some embodiments, the positive-sense RNA virus is West Nile virus.

[0168] In some implementations, the viral infection is a respiratory viral infection. In some implementations, the viral infection is an upper respiratory tract viral infection or a lower respiratory tract viral infection.

[0169] In some embodiments, the use also includes administering a therapeutically effective amount of one or more other pharmaceutical agents or compositions to a patient.

[0170] In some implementations, the one or more additional agents are selected from: ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danopvir, ritonavir, and remdesivir.

[0171] In some embodiments, the one or more additional agents are selected from: protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitors, acyclovir, aclovir, protease inhibitors, arbidol, atazanavir, atrazal, boprevir, cidofovir, cobivir, darunavir, didocidol, edulouridine, entry inhibitors, entecavir, and famciclovir. Lovir, fomivirex, fosanavir, phosphonoformic acid, phosphonoethanol, ganciclovir, ibatabin, imnovivir, idoxuridine, imiquimod, inosine, integrase inhibitors, interferon, lopinavir, cloviramide, morpholineguanidine, nesavir, nucleoside analogs, penciclovir, proconavir, podophyllotoxin, ribavirin, telanavir, trifluuridine, triamantadine, tremadiolone, truvada, valacyclovir, valganciclovir, velivirol, vidarabine, veramidine, and zoldovudine.

[0172] In some embodiments, the one or more additional agents are selected from: lamivudine, interferon-alpha, VAP anti-idiotype antibody, enfvirdi, amantadine, amantadine ethylamine, proconalide, acyclovir, zidovudine, formivir, protease inhibitors, double-stranded RNA activated apoptosis protease oligomers (DRACO), rifampin, zanamivir, oseltamivir, danopvir, ritonavir, and remdesivir.

[0173] In some embodiments, the one or more additional agents are selected from: quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives, doxycycline, pyrimethamine, mefloquine, halofantroline, hydroxychloroquine, efornithine, nitrozonide, ornidazole, paromomycin, pentanemidine, primaquine, pyrimethamine, chloroguanidine (optionally in combination with atovaquinone), sulfonamide, tafenoxanone, sulfomethylnitroimidazole, and PPT1 inhibitors.

[0174] In some embodiments, the one or more additional agents are RNA polymerase inhibitors. In some embodiments, the RNA polymerase inhibitor is selected from: remdesivir, sofosbuvir, 7-dezo-2-CMA, galisvir, and AT-527. In some embodiments, the RNA polymerase inhibitor is remdesivir.

[0175] In some embodiments, the one or more additional agents are selected from: TMPRSS protease inhibitors, lysosomal blockers (e.g., hydroxychloroquine), PIKfyve inhibitors (e.g., apimod), anti-SARS-CoV-2 antibodies, mixtures of anti-SARS-CoV-2 antibodies, anti-inflammatory agents, anti-TNF agents (e.g., adalimumab, infliximab, etanercept, golimumab, or cetuzumab), histamine H1 / H2 blockers (e.g., famotidine, nisatidine, ranitidine, and cimetidine), steroids, anticoagulants, complement-targeting agents, statins, and ACE inhibitors. In some embodiments, the TMPRSS protease inhibitor is selected from: TMPRSS4 inhibitors, TMPRSS11A inhibitors, TMPRSS11D inhibitors, TMPRSS11E1 inhibitors, and TMPRSS2 inhibitors. In some embodiments, the TMPRSS protease inhibitor is a TMRSS2 protease inhibitor. In some embodiments, the TMRSS-2 protease inhibitor is selected from: carmostat and naftomostat. In some embodiments, the anti-SARS-CoV-2 antibody is selected from LY-CoV555 (barnivirumab) and LY-CoV016 (etesvirumab). In some embodiments, the mixture of anti-SARS-CoV-2 antibodies is REGN-COV2. In some embodiments, the anti-inflammatory agent is an IL-6 antagonist (e.g., staxicumab, sarerucumab, olozazumab, BMS-945429, cilukumab, and clazazumab). In some embodiments, the steroid is dexamethasone. In some embodiments, the anticoagulant is low molecular weight heparin. In some embodiments, the complement target is eculizumab. In some embodiments, the statin is selected from atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, ruslavovastatin, and simvastatin.

[0176] In some implementation schemes, the ACE inhibitor is selected from: benazepril, captopril, enalapril / enalapril, fosinopril, lisinopril, moxipril, perindopril, quinapril, and ramipril.

[0177] In some implementations, the one or more additional agents are selected from: remdesivir, carmostat, naprost, hydroxychloroquine, chloroquine, apimod, LY-CoV555 (barnivir), LY-CoV016 (Etesvirumab), REGN-COV2, Tocilizumab, Sestoxicumab, Saliruzumab, Olozumab, BMS-945429, Cilukumab, Crazazumab, Adalimumab, Infliximab, Etanercept, Golimumab, Sertoxicumab, Famotidine, Nisatidine, Ranitidine, Cimetidine, Dexamethasone, Low Molecular Weight Heparin, Eculizumab, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Russellvastatin, Simvastatin, Benazepril, Captopril, Enalapril / Enalapril, Fosinopril, Lisinopril, Moxipril, Perindopril, Quinapril, and Ramipril.

[0178] In some embodiments, the use includes administration of one or more additional agents selected from the group consisting of: remdesivir, sofosbuvir, 7-dezo-2-CMA, galilisvir, AT-527, temopofol, neomycin, curcumin, voxiprevir, gzopiclone, gcapiprvir, carmostat, namastat, hydroxychloroquine, chloroquine, apimod, imatinib, dasatinib, ponatinib, velpatasvir, ledipasvir, ibasimir, pirentavir, NITD008, LY-CoV555 (barnivir monoclonal antibody), LY-CoV016 (Etessermab), REGN-COV2, Tocilizumab, Sestoximab, Salrelumarab, Olozumab, BMS-945429, Cilukumab, Crazazumab, Adalimumab, Infliximab, Etanercept, Golimumab, Sertoximab, Famotidine, Nisatidine, Ranitidine, Cimetidine, Dexamethasone, Low Molecular Weight Heparin, Eculizumab, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Benazepril, Captopril, Enalapril / Enalapril, Fosinopril, Lisinopril, Moxipril, Perindopril, Quinapril, Ramipril, and Adoptive NK Cell Therapy.

[0179] In some implementations, one or more additional agents are selected from ABL inhibitors and JAK inhibitors.

[0180] In some embodiments, one or more additional agents are ABL inhibitors (e.g., imatinib, dasatinib, or ponatinib). In some embodiments, the ABL inhibitor is selected from imatinib, dasatinib, and ponatinib. In some embodiments, the ABL inhibitor is imatinib. In some embodiments, the ABL inhibitor is dasatinib. In some embodiments, the ABL inhibitor is ponatinib.

[0181] In some embodiments, one or more additional agents are JAK inhibitors. In some embodiments, the JAK inhibitor is selected from baricitinib, ruxolitinib, tofacitinib, and uropatinib. In some embodiments, the JAK inhibitor is baricitinib. In some embodiments, the JAK inhibitor is ruxolitinib. In some embodiments, the JAK inhibitor is tofacitinib. In some embodiments, the JAK inhibitor is uropatinib.

[0182] In some embodiments, one or more additional agents are protease inhibitors. In some embodiments, the protease inhibitor is selected from: temopofol, neomycin, curcumin, voxiprevir, gzopivir, and gcapipvir.

[0183] In some embodiments, one or more additional agents are NS5A inhibitors. In some embodiments, the NS5A inhibitor is selected from velpatasvir, ledipasvir, ibasvir, and pirentavir.

[0184] In some embodiments, one or more additional agents are pyrimidine synthesis inhibitors. In some embodiments, the pyrimidine synthesis inhibitor is NITD008.

[0185] In some embodiments, one or more additional agents are adoptive natural killer (NK) cell therapy. In some embodiments, the additional therapeutic agent is a vaccine. In some embodiments, the vaccine is a coronavirus vaccine. In some embodiments, the vaccine is selected from BNT162b2, mRNA-1273, AZD1222, and Ad26.COV2.S. In some embodiments, the vaccine is a protein-based vaccine. In some embodiments, the vaccine is an RNA-based vaccine. In some embodiments, the vaccine is an attenuated viral vaccine. In some embodiments, the vaccine is an inactivated viral vaccine. In some embodiments, the vaccine is a non-replicating viral vector vaccine.

[0186] In some embodiments, the compounds described herein are administered orally to a patient. In some embodiments, the compounds described herein are administered non-enterally to a patient.

[0187] In some embodiments, this document provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for treating cancer.

[0188] In some implementation schemes, the cancer is selected from: breast cancer (such as triple-negative breast cancer), bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, gastrointestinal stromal tumor, esophageal cancer, gastric cancer, glioma, glioblastoma, ovarian cancer, head cancer, neck cancer, urothelial carcinoma, uterine cancer, prostate cancer, hepatic cancer, osteosarcoma, sarcoma, multiple myeloma, metastatic bone cancer and papillary thyroid carcinoma, as well as hypoxic tumors.

[0189] In some implementations, the use also includes administering radiation therapy.

[0190] In some embodiments, this document provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for the treatment of type II diabetes.

[0191] In some embodiments, this document also provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for treating a disease selected from inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and viral infections.

[0192] In some embodiments, this document provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for treating viral infections.

[0193] In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronaviruses, rhinoviruses, and flaviviruses. In some embodiments, the viral infection is caused by a rhinovirus. In some embodiments, the viral infection is caused by a flavivirus.

[0194] In some embodiments, the viral infection is caused by coronaviruses selected from the group consisting of: 229E α coronavirus, NL63 α coronavirus, OC43 β coronavirus, HKU1 β coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2. In some embodiments, the viral infection is caused by SARS. In some embodiments, the viral infection is caused by SARS-CoV. In some embodiments, the viral infection is caused by SARS-CoV-2. In some embodiments, the viral infection is caused by MERS-CoV. In some embodiments, the viral infection is caused by COVID-19.

[0195] In some embodiments, the viral infection is caused by a positive-sense RNA virus. In some embodiments, the virus is a positive-sense RNA virus. In some embodiments, the virus is a sense RNA virus. In some embodiments, the virus is a sense-strand RNA virus. In some embodiments, the virus is a positive-sense RNA virus. In some embodiments, the virus is a positive (+) RNA virus. In some embodiments, the virus is a positive-sense single-sense RNA virus. In some embodiments, the positive-sense RNA virus is selected from: coronaviruses, flaviviruses, and microRNAviruses. In some embodiments, the positive-sense RNA virus is selected from: rhinoviruses, flaviviruses, microRNAviruses, and coronaviruses. In some embodiments, the positive-sense RNA virus is a microRNA virus. In some embodiments, the positive-sense RNA virus is a rhinovirus. In some embodiments, the positive-sense RNA virus is a human rhinovirus. In some embodiments, the positive-sense RNA virus is a flavivirus. In some embodiments, the positive-sense RNA virus is a coronavirus. In some embodiments, the positive-sense RNA virus is selected from: SARS CoV-1, SARS CoV-2, MERS, hepatitis C (HCV), rhinovirus, dengue virus, Zika virus, and West Nile virus. In some embodiments, the positive-sense RNA virus is a coronavirus. In some embodiments, the coronavirus is selected from: SARS CoV-1, SARS CoV-2, and MERS. In some embodiments, the coronavirus is SARS CoV-1. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the positive-sense RNA virus (e.g., coronavirus) has any variant resulting from mutation or a novel variant arising from other species (e.g., mammalian species, such as mink). In some embodiments, the positive-sense RNA virus is MERS. In some embodiments, the positive-sense RNA virus is hepatitis C. In some embodiments, the positive-sense RNA virus is Zika virus. In some embodiments, the positive-sense RNA virus is dengue virus. In some embodiments, the positive-sense RNA virus is West Nile virus.

[0196] In some implementations, the viral infection is a respiratory viral infection. In some implementations, the viral infection is an upper respiratory tract viral infection or a lower respiratory tract viral infection.

[0197] In some embodiments, the use also includes administering a therapeutically effective amount of one or more other pharmaceutical agents or compositions to a patient.

[0198] In some implementations, the one or more additional agents are selected from: ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danopvir, ritonavir, and remdesivir.

[0199] In some embodiments, the one or more additional agents are selected from: protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitors, acyclovir, aclovir, protease inhibitors, arbidol, atazanavir, atrazal, boprevir, cidofovir, cobivir, darunavir, didocidol, edulouridine, entry inhibitors, entecavir, and famciclovir. Lovir, fomivirex, fosanavir, phosphonoformic acid, phosphonoethanol, ganciclovir, ibatabin, imnovivir, idoxuridine, imiquimod, inosine, integrase inhibitors, interferon, lopinavir, cloviramide, morpholineguanidine, nesavir, nucleoside analogs, penciclovir, proconavir, podophyllotoxin, ribavirin, telanavir, trifluuridine, triamantadine, tremadiolone, truvada, valacyclovir, valganciclovir, velivirol, vidarabine, veramidine, and zoldovudine.

[0200] In some embodiments, the one or more additional agents are selected from: lamivudine, interferon-alpha, VAP anti-idiotype antibody, enfvirdi, amantadine, amantadine ethylamine, proconalide, acyclovir, zidovudine, formivir, protease inhibitors, double-stranded RNA activated apoptosis protease oligomers (DRACO), rifampin, zanamivir, oseltamivir, danopvir, ritonavir, and remdesivir.

[0201] In some embodiments, the one or more additional agents are selected from: quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives, doxycycline, pyrimethamine, mefloquine, halofantroline, hydroxychloroquine, efornithine, nitrozonide, ornidazole, paromomycin, pentanemidine, primaquine, pyrimethamine, chloroguanidine (optionally in combination with atovaquinone), sulfonamide, tafenoxanone, sulfomethylnitroimidazole, and PPT1 inhibitors.

[0202] In some embodiments, the one or more additional agents are RNA polymerase inhibitors. In some embodiments, the RNA polymerase inhibitor is selected from: remdesivir, sofosbuvir, 7-dezo-2-CMA, galisvir, and AT-527. In some embodiments, the RNA polymerase inhibitor is remdesivir.

[0203] In some embodiments, the one or more additional agents are selected from: TMPRSS protease inhibitors, lysosomal blockers (e.g., hydroxychloroquine), PIKfyve inhibitors (e.g., apimod), anti-SARS-CoV-2 antibodies, mixtures of anti-SARS-CoV-2 antibodies, anti-inflammatory agents, anti-TNF agents (e.g., adalimumab, infliximab, etanercept, golimumab, or cetuzumab), histamine H1 / H2 blockers (e.g., famotidine, nisatidine, ranitidine, and cimetidine), steroids, anticoagulants, complement-targeting agents, statins, and ACE inhibitors. In some embodiments, the TMPRSS protease inhibitor is selected from: TMPRSS4 inhibitors, TMPRSS11A inhibitors, TMPRSS11D inhibitors, TMPRSS11E1 inhibitors, and TMPRSS2 inhibitors. In some embodiments, the TMPRSS protease inhibitor is a TMRSS2 protease inhibitor. In some embodiments, the TMRSS-2 protease inhibitor is selected from: carmostat and naftomostat. In some embodiments, the anti-SARS-CoV-2 antibody is selected from LY-CoV555 (barnivirumab) and LY-CoV016 (etesvirumab). In some embodiments, the mixture of anti-SARS-CoV-2 antibodies is REGN-COV2. In some embodiments, the anti-inflammatory agent is an IL-6 antagonist (e.g., staxicumab, sarerucumab, olozazumab, BMS-945429, cilukumab, and clazazumab). In some embodiments, the steroid is dexamethasone. In some embodiments, the anticoagulant is low molecular weight heparin. In some embodiments, the complement target is eculizumab. In some embodiments, the statin is selected from atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, ruslavovastatin, and simvastatin.

[0204] In some implementation schemes, the ACE inhibitor is selected from: benazepril, captopril, enalapril / enalapril, fosinopril, lisinopril, moxipril, perindopril, quinapril, and ramipril.

[0205] In some implementations, the one or more additional agents are selected from: remdesivir, carmostat, naprost, hydroxychloroquine, chloroquine, apimod, LY-CoV555 (barnivir), LY-CoV016 (Etesvirumab), REGN-COV2, Tocilizumab, Sestoxicumab, Saliruzumab, Olozumab, BMS-945429, Cilukumab, Crazazumab, Adalimumab, Infliximab, Etanercept, Golimumab, Sertoxicumab, Famotidine, Nisatidine, Ranitidine, Cimetidine, Dexamethasone, Low Molecular Weight Heparin, Eculizumab, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Russellvastatin, Simvastatin, Benazepril, Captopril, Enalapril / Enalapril, Fosinopril, Lisinopril, Moxipril, Perindopril, Quinapril, and Ramipril.

[0206] In some embodiments, the use includes administration of one or more additional agents selected from the group consisting of: remdesivir, sofosbuvir, 7-dezo-2-CMA, galilisvir, AT-527, temopofol, neomycin, curcumin, voxiprevir, gzopiclone, gcapiprvir, carmostat, namastat, hydroxychloroquine, chloroquine, apimod, imatinib, dasatinib, ponatinib, velpatasvir, ledipasvir, ibasimir, pirentavir, NITD008, LY-CoV555 (barnivir monoclonal antibody), LY-CoV016 (Etessermab), REGN-COV2, Tocilizumab, Sestoximab, Salrelumarab, Olozumab, BMS-945429, Cilukumab, Crazazumab, Adalimumab, Infliximab, Etanercept, Golimumab, Sertoximab, Famotidine, Nisatidine, Ranitidine, Cimetidine, Dexamethasone, Low Molecular Weight Heparin, Eculizumab, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Benazepril, Captopril, Enalapril / Enalapril, Fosinopril, Lisinopril, Moxipril, Perindopril, Quinapril, Ramipril, and Adoptive NK Cell Therapy.

[0207] In some implementations, one or more additional agents are selected from ABL inhibitors and JAK inhibitors.

[0208] In some embodiments, one or more additional agents are ABL inhibitors (e.g., imatinib, dasatinib, or ponatinib). In some embodiments, the ABL inhibitor is selected from imatinib, dasatinib, and ponatinib. In some embodiments, the ABL inhibitor is imatinib. In some embodiments, the ABL inhibitor is dasatinib. In some embodiments, the ABL inhibitor is ponatinib.

[0209] In some embodiments, one or more additional agents are JAK inhibitors. In some embodiments, the JAK inhibitor is selected from baricitinib, ruxolitinib, tofacitinib, and uropatinib. In some embodiments, the JAK inhibitor is baricitinib. In some embodiments, the JAK inhibitor is ruxolitinib. In some embodiments, the JAK inhibitor is tofacitinib. In some embodiments, the JAK inhibitor is uropatinib.

[0210] In some embodiments, one or more additional agents are protease inhibitors. In some embodiments, the protease inhibitor is selected from: temopofol, neomycin, curcumin, voxiprevir, gzopivir, and gcapipvir.

[0211] In some embodiments, one or more additional agents are NS5A inhibitors. In some embodiments, the NS5A inhibitor is selected from velpatasvir, ledipasvir, ibasvir, and pirentavir.

[0212] In some embodiments, one or more additional agents are pyrimidine synthesis inhibitors. In some embodiments, the pyrimidine synthesis inhibitor is NITD008.

[0213] In some embodiments, one or more additional agents are adoptive natural killer (NK) cell therapy. In some embodiments, the additional therapeutic agent is a vaccine. In some embodiments, the vaccine is a coronavirus vaccine. In some embodiments, the vaccine is selected from BNT162b2, mRNA-1273, AZD1222, and Ad26.COV2.S. In some embodiments, the vaccine is a protein-based vaccine. In some embodiments, the vaccine is an RNA-based vaccine. In some embodiments, the vaccine is an attenuated viral vaccine. In some embodiments, the vaccine is an inactivated viral vaccine. In some embodiments, the vaccine is a non-replicating viral vector vaccine.

[0214] In some embodiments, the compounds described herein are administered orally to a patient. In some embodiments, the compounds described herein are administered non-enterally to a patient.

[0215] In some embodiments, this document provides a method for treating cancer in a patient in need, the method comprising (i) administering to the patient a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein, compared to any increase in the expression of at least one chemokine caused by administering the compound alone to the patient, the administration of the therapeutically effective amount of the STING agonist and the compound causes an increase in the expression of at least one chemokine in the patient.

[0216] In some embodiments, this document provides a method for upregulating at least one chemokine in cells, the method comprising contacting a cell sample with: (i) a compound disclosed herein or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; and (ii) a STING agonist, said substance in an amount sufficient to increase the expression of at least one chemokine in cells.

[0217] In some implementation schemes, the cancer is selected from: gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, head cancer, cervical cancer, urethral cancer, uterine cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, osteosarcoma, sarcoma, multiple myeloma, cervical cancer, bone metastatic cancer, papillary thyroid carcinoma, non-small cell lung cancer, lymphoma, leukemia, and colorectal cancer.

[0218] In some implementations, the STING agonist is selected from: 5,6-dimethyldibenzopyranone-4-acetic acid (DMXAA), ADU-S100, MK-1454, MK-2118, BMS-986301, GSK3745417, SB-11285, BI1387446 (BI-STING), E7766, TAK-676, SNX281, SYNB1891, JNJ-67544412, JNJ-'6196, GSK532, TTI-10001, ALG-031048, MSA-1, MSA-2, CRD-5500, MV-626, SR-8314, SR-8291, SR8541A, SR-717, STING antibody-drug conjugate (ADC), and IMSA-101, and pharmaceutically acceptable salts thereof.

[0219] In some implementations, the STING agonist is selected from: ADU-S100, MK-1454, MK-2118, BMS-986301, GSK3745417, SB-11285, BI1387446 (BI-STING), E7766, TAK-676, SNX281, SYNB1891, and IMSA-101, and pharmaceutically acceptable salts thereof.

[0220] In some implementations, the STING agonist is selected from ADU-S100 and MSA-2, and their pharmaceutically acceptable salts.

[0221] Example The compounds described herein can be prepared in various ways based on the teachings contained herein and synthetic procedures known in the art. In the following description of the synthetic methods, it should be understood that, unless otherwise stated, all reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) presented 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 provided 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.

[0222] The following abbreviations are used in this invention and have the following definitions: "ADP" is adenosine diphosphate, "aq" is aqueous solution, "ATP" is adenosine triphosphate, "Ar" is argon, "Bn" is benzyl, "BPD" is bis(pinacolyl)diboron, "Boc" is tert-butyl carbonate, and "BSA" is bovine serum albumin. tert "-BuOK" stands for potassium tert-butoxide. tert "-BuONa" is sodium tert-butoxide, "conc" is concentrated, "CaCl2" is calcium chloride, "CDCl3" is chloroform-deuterium, "Cs2CO3" is cesium carbonate, "DAST" is diethylaminosulfur trifluoride, "DCM" is dichloromethane, and "DIEA" is... N , N -Diisopropylethylamine, "DMB" is dimethylanisole, "DMF" is dimethylanisole. N , N -Dimethylformamide, "dppf" represents 1,1′-bis(diphenylphosphino)ferrocene, "DMSO-d6" represents dimethyl sulfoxide-deuterium, and "DSC" represents... N , N ′-Disuccinimino carbonate, “DTT” for dithiothreitol, “EDC” for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, “ESI” for electrospray ionization, “EtOAc” for ethyl acetate, “EtOH” for ethanol, “GST” for glutathione S-transferase, “h” for one hour or several hours, “HATU” for azirmonatriazole tetramethylureonium hexafluorophosphate, “H2” for hydrogen, “HCl” for hydrochloric acid, “H2O” for water, “IC” for water, “DTT” for dithiothreitol, “EtOH” for glutathione S-transferase, “h” for one hour or several hours, “HATU” for azirmonatriazole tetramethylureonium hexafluorophosphate, “H2” for hydrogen, “HCl” for hydrochloric acid, “H2O” for water, “IC” for water, “H2O ... 50"LDA" is lithium diisopropylamino, "LiHMDS" is lithium hexamethyldisilamino, "MeCN" is acetonitrile, "MeOD" is methanol-deuterium, "MeOH" is methanol, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is one minute or several minutes, "MS" is mass spectrometry, "MTBE" is methyl tert-butyl ether, "m / z" is mass / charge number, "NaCN" is sodium cyanide, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, "NaHCO3" is sodium bicarbonate, "Na2SO4" is sodium sulfate, "NMI" is... N -Methylimidazole, "NMR" is nuclear magnetic resonance, "PBS" is phosphate-buffered saline, "Pd" is palladium, "Pd / C" is palladium / carbon, "Pd(dppf)Cl2" is "bis(diphenylphosphino)ferrocene palladium(II) chloride", "Pd(PPh3)4" is palladium-tetra(triphenylphosphine), "PEPPSI-IPr" is [1,3-bis(2,6-diisopropylphenyl)imidazolium-2-yl](3-chloropyridinyl)palladium(II)(II) chloride, "pet-ether" is petroleum ether, "PMB" is p-methoxybenzyl, "RLU" is relative emission unit, and "rt" is room temperature, also known as "ambient temperature", which will be understood as the temperature range of 15-25°C. o A series of normal laboratory temperature compositions within the C range, "sat'd" indicates saturation, "SFC" indicates supercritical fluid chromatography, "SM" indicates starting material, and "S" indicates... N "Ar" indicates nucleophilic aromatic substitution, "T3P" indicates 1-propanephosphonic anhydride, "TBAF" indicates tetrabutylammonium fluoride, "TBDMS" indicates tert-butyldimethylsilyl, and "TCFH" indicates chloro- N , N , N ', N '-Tetramethylchloromethanediamine hexafluorophosphate, where "TEA" stands for triethylamine, "TFA" for trifluoroacetic acid, "Tf2O" for trifluoromethanesulfonic anhydride, "THF" for tetrahydrofuran, "tris" for tri(hydroxymethyl)aminomethane, and "TMS" for trimethylsilyl.

[0223] General chemical reactions The exemplary compounds described herein can be obtained through the following schemes, intermediate preparations, and general synthetic methods illustrated in the accompanying examples.

[0224] Synthesis scheme Option 1 Scheme 1 describes an exemplary preparation of intermediates 1-3, 1-5, 1-6, and 1-8. Amine 1-1 (commercially available or synthesized by those skilled in the art) is prepared at ambient or high temperature in a base (such as pyridine, TEA, and...) tert In the presence of -BuOK), through acylation with R 4 The reaction with COCl (commercially available or synthesized by those skilled in the art) yields intermediates 1-3. In another embodiment, amine 1-1 is reacted with R via a typical amide coupling reaction in the presence of a coupling agent (such as HATU, T3P, or TCFH). 4 The reaction of COOH (commercially available or synthesized by those skilled in the art) yields intermediates 1-3. Alternatively, intermediates 1-3 can be prepared by reacting 1-2 (commercially available or synthesized by those skilled in the art) with R in the presence of a base (such as LDA or Cs2CO3). 2 -NH2 through S N Prepared by Ar reaction. Compounds 1-3 (when R 1 = I) can be converted into 1-5 and 1-6: (1) Stille coupling reaction with SnBu3CH2OH followed by fluorination reaction with DAST, and (2) Suzuki reaction with cyclopropylboronic acid. In another embodiment, compound 1-3 (when R) can be converted into 1-5 and 1-6: (1) Stille coupling reaction with SnBu3CH2OH followed by fluorination reaction with DAST, and (2) Suzuki reaction with cyclopropylboronic acid. 1 = NO2) is reduced to amine, and then N-Boc protection is performed to give 1-8.

[0225] Option 2 Scheme 2 describes an exemplary preparation of intermediate 2-6. Compound 2,6-difluoro-4-iodopyridine 2-1 reacts with amine AH (commercially available or synthesized by those skilled in the art) in the presence of a base (such as LDA) to give 2-2. 2-2 reacts with PMBOH in the presence of a base (such as NaH) to form S... N The Ar reaction yields 2-3. Compound 2-3, upon borylation, provides boric acid 2-4. Borylation is a well-documented reaction (e.g., a Pd(0)-catalyzed reaction with BPD) for those skilled in the art. The typical Suzuki reaction of borate 2-4 with iodide 2-5 (commercially available or synthesized by those skilled in the art) yields intermediate 2-6.

[0226] Option 3 Scheme 3 describes an exemplary preparation of intermediates 3-7a (R = tert-butyl) and 3-7b (R = PMB). 4-(benzyloxy)-2,6-dichloropyridine and tert -BuOK occurred S NAr reaction yields 3-1. 4-(benzyloxy)-2-(tert-butoxy)-6-chloropyridine 3-1 reacts with amine AH (commercially available or synthesized by those skilled in the art) under Buchwald-Hartwig amination conditions (PEPPSI-IPr as catalyst), or with borate ester or boric acid AB(OR)2 (commercially available or synthesized by those skilled in the art) under Suzuki reaction conditions (Pd(dppf)Cl2 as catalyst) to give “A”-substituted pyridine 3-2 (Y = Bn). Deprotection of 3-2 (Y = Bn) under Pd-catalyzed hydrogenation yields intermediate 3-3 (Y = H). Treatment of 3-3 with Tf2O in the presence of a base (e.g., pyridine) gives trifluoromethanesulfonate 3-4. Trifluoromethanesulfonate 3-4 can be converted to borate ester 3-7a (R = tert-butyl) by borylation under Pd(0) conditions. In another embodiment, intermediates 3-7a (R = tert-butyl) and 3-7b (R = PMB) can be prepared from 2,6-difluoro-4-iodopyridine. First step: 2,6-difluoro-4-iodopyridine reacts with amine AH to undergo a reaction (SH). N Ar reaction yields 3-5. Second step: Compound 3-5 passes through S... N Ar reaction occurs in the presence of a base (such as NaH) and... tert -BuOK or PMBOH reaction yields 3-6a (R = tert-butyl) and 3-6b (R = PMB). Third step: Iodides 3-6a and 3-6b can be converted to borate 7-7a and 3-7b by borylation with BPD under Pd (0) conditions, respectively.

[0227] Option 4 Scheme 4 illustrates the exemplary preparation of intermediates 4-1a, 4-1b, and 4-4. 1-1 (commercially available or synthesized by those skilled in the art) undergoes a Suzuki reaction with borate esters 2-4, 3-7a, and 3-7b in the presence of a Pd catalyst (e.g., Pd(dppf)Cl2) (Scheme 3) to yield 4-1a (R = tert-butyl) and 4-1b (R = PMB), respectively. In another embodiment, compound 1-1 (X = Cl, Br, I) reacts with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)pyridine under Suzuki reaction conditions to yield 4-2. 4-2 reacts with PMBOH in the presence of a base (e.g., LDA) under the reaction conditions... N Ar reaction yields 4-3. Compound 4-3 can be reacted at ambient temperature or high temperature by reacting with a base (such as pyridine, TEA, and...) tert -BuOK) acylation with R 4The reaction with COCl (commercially available or synthesized by those skilled in the art), or with R via a typical amide coupling reaction in the presence of a coupling agent (such as HATU, T3P, or TCFH). 4 The reaction of COOH (commercially available or synthesized by those skilled in the art) yields intermediate 4-4. In another embodiment, 4-3 undergoes a Suzuki reaction with boric acid or borate AB(OR)2 to yield 4-1b (R = PMB).

[0228] Option 5 Scheme 5 describes an exemplary preparation of intermediate 5-5. Compound 5-1 (commercially available or synthesized by those skilled in the art) reacts with borate ester 5-2 (via 2,6-difluoro-4-iodopyridine) under Suzuki reaction conditions. tert -BuOK's S N Prepared by Ar reaction, followed by typical borylation with BPD under Pd(0) conditions, to give 5-3. Compound 5-3 can be obtained by Buchwald-Hartwig cross-coupling reactions (e.g., Pd(dppf)Cl2, tert -BuONa at high temperature) and amine R 2 -NH2 (commercially available or synthesized by those skilled in the art) reacts to give 5-4. 5-4 reacts with PMBNH2 to undergo S... N Ar reaction, followed by removal of the protecting group with TFA / Et3SiH to obtain intermediate 5-5.

[0229] Option 6 Scheme 6 describes an exemplary preparation of intermediate 6-3. 1-3 undergoes a Suzuki reaction with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)pyridine to give 6-1. Compound 6-1 reacts with amine AH (commercially available or synthesized by those skilled in the art) in the presence of a base (such as DIEA) to give 6-2. 6-2 reacts with 2-(trimethylsilyl)ethanol-1-ol in the presence of a base (such as NaH) to undergo an S reaction. N Ar reaction yields intermediate 6-3.

[0230] Option 7 Scheme 7 describes an exemplary preparation of intermediates 7-1, 7-2, and 7-3. 4-1a or 4-1b is reacted with amine R. 6 -NH2 (commercially available or synthesized by those skilled in the art) in N , N' Urea is formed in the presence of -DSC to give urea 7-1. Similarly, 4-1a or 4-1b can react with alcohol R... 5-OH in N , N' The reaction in the presence of -DSC yields carbamate 7-2. Compounds 4-1a or 4-1b react in the presence of a base (such as pyridine, TEA, and...) to give carbamate 7-2. tert -BuOK) in the presence of environmental or high temperature conditions with R 4 The reaction with COCl (commercially available or synthesized by those skilled in the art), or with R in the presence of a coupling agent (such as HATU, T3P, or TCFH). 4 The reaction of COOH (commercially available or synthesized by those skilled in the art) yields amide 7-3.

[0231] Option 8 Scheme 8 illustrates an exemplary preparation of compounds of formula I (8-2 and 8-4). 1-3 undergoes a Suzuki reaction with borate esters (2-4, 3-7a, 3-7b) to give 8-1a and 8-1b (R = tert-butyl, PMB). In another embodiment, 6-2 reacts with PMBOH in an alkali (such as NaH or...) tert S occurs under the presence of -BuOK) N Ar reaction yields 8-1b (R = PMB) and 8-1a (R = tert-butyl), respectively. Compounds 8-1a (R = tert-butyl) and 8-1b (R = PMB) can be deprotected with TFA or HCl to give compound I (8-2). Compound 8-2 reacts with acryloyl chloride or vinyl sulfonyl chloride in the presence of a base (such as TEA or DIEA) to give 8-3 (W = CO, SO2). 8-3 reacts with amine NH(R... 8 )2 (commercially available or synthesized by those skilled in the art) undergoes a Michael reaction to yield compound I, 8-4).

[0232] Option 9 Scheme 9 illustrates an exemplary preparation of compound (9-3) of formula I. Compounds 4-1a and 4-1b react with acryloyl chloride in the presence of a base (such as pyridine) to give 9-1. 9-1 reacts with amine NH(R) 8 9-2 (commercially available or synthesized by those skilled in the art) was subjected to a Michael reaction to give 9-2. 9-2 was then deprotected under acidic conditions (such as TFA or HCl) to give compound I (9-3).

[0233] Option 10 Scheme 10 illustrates an exemplary preparation of compound (10-4) of formula I. Intermediates 1-3, 1-5, 1-6, and 1-8 (X = Cl, Br, I) are reacted with borate esters 2-4, 3-7a, or 3-7b under Suzuki conditions to give intermediate 10-1. Alternatively, intermediate 10-1 can be prepared by: (1) reacting chloride 2-6 with amine R 2 -NH2 (commercially available or synthesized by those skilled in the art) is prepared by Buchwald-Hatwig amination reaction conditions (e.g., using PEPPSI-IPr as a catalyst); (2) chloride 4-4 is prepared by the Suzuki reaction with borate ester or borate AB(OR)2 (commercially available or synthesized by those skilled in the art); and (3) fluoride 5-4 is prepared by the S reaction with amine AH. N Ar reaction preparation. Deprotection of 10⁻¹ under acidic conditions (such as HCl or TFA) yields compound I (10⁻⁴). In another embodiment, compounds 1-3, 1-5, 1-6, and 1-8 are boronized to yield borate ester 10⁻⁂. Boronization is a well-documented reaction (e.g., Pd(O)-catalyzed reaction with BPD). 10⁻⁂ undergoes a Suzuki reaction with bromide or iodide 3-6a or 3-6b, followed by deprotection with TFA or HCl to yield compound I (10⁻⁴). Similarly, compounds 6-4, 7-1, 7-2, and 7-3 are deprotected under acidic conditions (such as TFA or HCl) to yield compound I (10⁻⁴).

[0234] Option 11 Scheme 11 illustrates an exemplary preparation of compound I (11-3). Compound 5-5 is reacted with sulfonyl chloride (11-1, commercially available or synthesized by those skilled in the art) to give 11-2. 11-2 is deprotected under acidic conditions (such as HCl) to give compound I (11-3).

[0235] Preparation of intermediates and final compounds.

[0236] The following compounds were prepared using the synthetic procedures and methods described herein and methods known to those skilled in the art: Preparation of intermediate A1: Methyl (4-bromo-5-methylpyridin-2-yl)carbamate A solution of 4-iodo-5-methylpyridin-2-amine (25.0 g, 107 mmol) in pyridine (250 mL) was treated dropwise with methyl chloroformate (25.2 g, 267 mmol, 20.6 mL) in an ice-water bath. The mixture was stirred at 0 °C for 2 h, followed by heating the reaction mixture to room temperature for 10 h. The reaction mixture was quenched with MeOH (50 mL) and concentrated under reduced pressure. The crude product was ground at 20 °C with 50% NaHCO3 (aq, 100 mL) for 30 min. The solid was filtered, washed with water, and dried under high vacuum to give a white solid. N 4-(4-iodo-5-methyl-2-pyridyl)carbamate (A1, 30.0 g, 91%). 1 H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 3.66 (s, 3H), 2.50 (s,3H); MS (ESI) m / z: 292.8 (M+H + ).

[0237] Preparation of intermediate A2: N-(4-iodo-5-methylpyridin-2-yl)-2-methylpyrimidin-4-amine N -(4-iodo-5-methylpyridin-2-yl)-2-methylpyrimidin-4-amine A solution of 2-fluoro-4-iodo-5-methylpyridine (5.0 g, 21 mmol) and 2-methylpyrimidin-4-amine (2.8 g, 25 mmol) in DMF (80 mL) was treated with Cs₂CO₃ (21 g, 63 mmol). The mixture was heated at 100 °C for 24 h and then cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic matter was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–30% EtOAc / pet-ether) to give a yellow solid. N -(4-iodo-5-methylpyridin-2-yl)-2-methylpyrimidin-4-amine (A2, 2.0 g, 29%). 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.97(s, 1H), 7.16 (d, J = 5.6 Hz, 1H), 2.55 (s, 3H), 2.32 (s, 3H); MS (ESI) m / z:327.0 (M+H + ).

[0238] The following compounds are basically prepared by methods for preparing A1 or A2.

[0239] Preparation of intermediate A19: Methyl (4-chloro-5-cyclopropylpyridin-2-yl)carbamate Will N Methyl 4-(4-chloro-5-iodo-2-pyridyl)carbamate (A10, 0.50 g, 1.6 mmol), cyclopropylboronic acid (0.27 g, 3.2 mmol), and Na2CO3 (0.34 g, 3.2 mmol) were mixed in a mixture of 1,4-dioxane (25 mL) and H2O (5 mL) and degassed by purging with N2 for 3 min. Pd(dppf)Cl2 (0.12 g, 0.1 eq) was added, and the mixture was then heated at 80 °C under N2 atmosphere for 12 h. The mixture was cooled to room temperature and then diluted with H2O (20 mL). The mixture was filtered through a diatomaceous earth filter, and the filtrate was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–6% EtOAc / pet-ether) to give a white solid. N -(4-chloro-5-cyclopropyl-2-pyridyl)carbamate (A19, 0.16 g 44%): 1 H NMR (400 MHz, DMSO-d6): δ8.05 (s, 1H), 7.91 (s, 1H), 3.82 (s, 3H), 2.01 (m, 1H), 0.95-1.04 (m, 2H), 0.68-0.72 (m, 2H).

[0240] Preparation of intermediate A20: Methyl (4-chloro-5-(fluoromethyl)pyridin-2-yl)carbamate Will N A solution of methyl 4-chloro-5-iodo-2-pyridyl)carbamate (A10, 1.0 g, 3.2 mmol), Pd(PPh3)4 (0.37 g, 0.32 mmol), and tributyltin alkyl methanol (3.08 g, 9.60 mmol) in 1,4-dioxane (20 mL) was heated at 100 °C for 8 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was ground with MTBE (5 mL) and the resulting solid was filtered to give methyl 4-chloro-5-(hydroxymethyl)pyridyl-2-yl)carbamate (0.26 g, 38%) as a green solid. (ESI) m / z: 217.2 (M+H + ).

[0241] A solution of methyl (4-chloro-5-(hydroxymethyl)pyridin-2-yl)carbamate (0.23 g, 1.06 mmol) in DCM (4 mL) was added dropwise to DAST (0.86 g, 5.31 mmol). The reaction mixture was stirred at -70 °C for 3 h. The reaction mixture was quenched with MeOH (1 mL) and then concentrated under reduced pressure. The residue was treated with water (10 mL) and then extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground with MeOH (5 mL), and the precipitate was collected by filtration to give methyl (4-chloro-5-(fluoromethyl)pyridin-2-yl)carbamate (A20, 0.11 g, 47%) as a brown solid. MS (ESI) m / z: 219.1 (M+H + ).

[0242] Preparation of intermediate A21: ( R )- N -(4-iodo-5-methylpyridin-2-yl)-1-methylpyrrolidine-3-carboxamide Will( R )- NA mixture of 3-(4-iodo-5-methylpyridin-2-yl)pyrrolidine-3-carboxamide (A12, 0.90 g, 2.45 mmol), formaldehyde (0.40 g, 4.90 mmol), AcOH (one drop), and NaBH3CN (0.46 g, 7.34 mmol) in MeOH (18 mL) was stirred at 0 °C under a N2 atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure, followed by the addition of water (10 mL). The solution was extracted with EtOAc (3×), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–20% DCM / MeOH) to give ( R )- N -(4-iodo-5-methylpyridin-2-yl)-1-methylpyrrolidine-3-carboxamide (0.75 g, 89%). MS (ESI) m / z: 346.2 (M+H) + ).

[0243] The following compounds were prepared primarily by the method used to prepare intermediate A21.

[0244] Preparation of intermediate A23: (5-amino-4-chloropyridin-2-yl)carbamate methyl ester Treatment with Fe (0.81 g, 14.5 mmol) and NH4Cl (0.78 g, 14.5 mmol) N A solution of methyl 4-(chloro-5-nitro-2-pyridyl)carbamate (A18, 0.84 g, 3.63 mmol) in a mixture of EtOH (20 mL) and H2O (4 mL) was prepared. The mixture was stirred at 80 °C for 8 h, and the hot solution was then filtered through a diatomaceous earth filter and washed with hot EtOH (3×). The filtrate was concentrated under reduced pressure to give methyl 5-amino-4-chloropyridyl-2-yl)carbamate (A23, 1.2 g, 98%) as a reddish-brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.85 (br d, J = 2.4 Hz, 1H), 7.82 (br s,1H), 7.54-7.72 (m, 1H), 3.63 (br s, 3H); MS (ESI) m / z: 202.2 (M+H) + ).

[0245] Preparation of intermediate A24: N-(4-iodo-5-methylpyridin-2-yl)-5-methyl-1,2,4-oxadiazol-3-amine A mixture of 4-iodo-5-methylpyridin-2-amine (2.0 g, 8.55 mmol) and NaHCO3 (0.72 g, 8.55 mmol) in DCM (15 mL) and water (15 mL) was treated with a solution of thiocarbonyl dichloride (0.72 mL, 9.40 mmol) in DCM (15 mL). The reaction mixture was stirred at 0 °C under a N2 atmosphere for 2 h. The reaction mixture was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5–10% EtOAc / pet-ether) to give 4-iodo-2-isothiocyano-5-methylpyridine (0.53 g, 121%) as a yellow solid. MS (ESI) m / z: 277.1 (M+H + ).

[0246] A solution of 4-iodo-2-isothiocyano-5-methylpyridine (0.53 g, 1.92 mmol) and N,N-diethylacetamidine (0.22 g, 1.92 mmol) in DMF (20 mL) was stirred at room temperature for 1 h. Et3N (0.67 mL, 4.80 mmol) was added to the mixture, followed by the slow addition of NH2OH•HCl (0.13 g, 1.92 mmol) with stirring at room temperature. Fine powder of AgNO3 (0.42 g, 2.47 mmol) was slowly added to this suspension, and the mixture was stirred at room temperature for 4 h. The mixture was filtered through a diatomaceous earth filter and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by C-18 prep-HPLC (5-45% H2O (0.2% FA) / MeCN) to give a white solid. N -(4-iodo-5-methylpyridin-2-yl)-5-methyl-1,2,4-oxadiazol-3-amine (A24, 0.05 g, 8%). MS (ESI) m / z: 317.1 (M+H + ).

[0247] Preparation of intermediate B1: 2'-chloro-6'-fluoro-5-methyl-[4,4'-bipyridine]-2-amine A solution of 4-bromo-5-methylpyridin-2-amine (4.0 g, 21.4 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)pyridine (6.6 g, 25.7 mmol) in a mixture of 1,4-dioxane (75 mL) and water (11 mL) was treated with Cs₂CO₃ (16.0 g, 49.2 mmol). The mixture was bubbled with Ar for 2 min, followed by the addition of Pd(dppf)Cl₂ (0.94 g, 1.28 mmol). The reaction mixture was heated at 80 °C for 3 h, followed by cooling to room temperature. The mixture was diluted with DCM and filtered through a diatomaceous earth filter. The filtrate was treated with saturated NaHCO₃(aq), followed by extraction with DCM (2×). The combined organic matter was dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (0-100% H2O (0.1% FA) / MeCN) to give 2'-chloro-6'-fluoro-5-methyl-[4,4'-bipyridine]-2-amine (B1, 1.55 g, 30%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.58 (s,1H), 7.34 (d, J = 1.4 Hz, 1H), 6.44 (d, J = 1.7 Hz, 1H), 6.26 (s, 2H), 2.03(s, 3H); MS (ESI) m / z: 238.0 (M+H + ).

[0248] The following compounds were prepared primarily by the method used to prepare intermediate B1.

[0249] Preparation of intermediate C1: 4-(benzyloxy)-2-(tert-butoxy)-6-chloropyridine Add to a suspension of 4-(benzyloxy)-2,6-dichloropyridine (5.0 g, 20 mmol) in 2-methyltetrahydrofuran (30 mL) tert -BuOK (2.5 g, 22 mmol). The reaction mixture was heated at 70 °C for 2 h and then cooled to room temperature. The precipitate was filtered, and the solid was dissolved in DCM. The solution was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 4-(benzyloxy)-2-(tert-butoxy)-6-chloropyridine (4.1 g, 71%) as a colorless liquid. MS (ESI) m / z: 236.2 (M+H) + ).

[0250] Preparation of intermediate C2: ( R 2-Fluoro-4-iodo-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine Treatment with 2.0 M LDA (23 mL, 46 mmol) at -40 °C (2) R A solution of 2-(trifluoromethyl)piperidine (7.0 g, 46 mmol) in THF (100 mL) was added and stirred for 15 min. Under the same conditions, 2,6-difluoro-4-iodopyridine (10 g, 46 mmol) was added, followed by stirring at 0 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl (100 mL), and the aqueous phase was extracted with EtOAc (3×). The combined organic matter was washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–20% EtOAc / pet-ether) to give a pale yellow oil (C2, 28 g, 45%). 1 H NMR (400 MHz, DMSO-d6): δ 7.22 (s, 1H), 6.80 (d, J = 3.2 Hz,1H), 5.29 (m, 1H), 4.13 (d, J = 12.4 Hz, 1H), 2.96 (t, J = 12.8 Hz, 1H), 1.95 (s, 1H), 1.69-1.79 (m, 2H), 1.64 (d, J = 4.0 Hz, 2H), 1.44 (m, 1H).

[0251] The following compounds are basically prepared by methods for preparing C1 and C2.

[0252] Preparation of intermediate D1: ( R )-4-(benzoxy)-2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine 4-(benzyloxy)-2-(tert-butoxy)-6-chloropyridine (C1, 4.0 g, 14 mmol) and ( RA suspension of 2-trifluoromethylpiperidine (2.5 g, 16 mmol) in 1,4-dioxane (30 mL) was treated with sodium butyroxane (3.9 g, 41 mmol), followed by treatment with PEPSI-iPr (0.1 g, 0.15 mmol). The resulting reaction mixture was heated at 90 °C for 2 h, followed by concentration under reduced pressure. The residue was treated with EtOAc (30 mL), and the solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and then filtered through a silica gel filter. The filtrate was concentrated under reduced pressure to give a brown solid ( R )-4-(benzoxy)-2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine (D1, 3.8 g, 68%). 1 H NMR (400 MHz, DMSO-d6): δ 7.23-7.48 (m, 5H), 5.99 (s,1H), 5.67 (s, 1H), 5.27-5.42 (m, 1H), 5.08 (s, 2H), 3.94 (br d, J = 12.6 Hz,1H), 2.97(m, 1H), 1.98 (br d, J = 13.2 Hz, 1H), 1.64 (br s, 5H), 1.48 (s,9H); MS (ESI) m / z: 409.2 (M+H + ).

[0253] Preparation of intermediate D2: ( R )-4-iodo-2-((4-methoxybenzyl)oxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine A solution of NaH (2.8 g, 70.2 mmol, 60% in mineral oil) in 200 mL of THF was stirred under a nitrogen atmosphere. (4-methoxyphenyl)methanol (6.4 mL, 51.4 mmol) was added dropwise at 0 °C. o C. Stir the mixture for 20 minutes. Add 2-fluoro-4-iodine-6-[(2 R )-2-(trifluoromethyl)-1-piperidinyl]pyridine (17.5 g, 46.8 mmol), and at 55 oThe mixture was stirred at C for 12 h. The reaction mixture was quenched with NH4Cl (aq, 200 mL) and diluted with EtOAc (200 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc / pet-ether) to give (R)-4-iodo-2-((4-methoxybenzyl)oxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine (20.0 g, 83%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): δ7.31 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 6.52 (s,1H), 5.39 (m, 1H), 5.17 (s, 2H), MS (ESI) m / z: 493.2 (M+H + ).

[0254] The following compounds were prepared primarily by methods for preparing intermediates D1 and D2.

[0255] Preparation of intermediate E1: ( R 2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridin-4-ol Treatment with palladium / charcoal (10% moistened) (0.9 g, 8.6 mmol) R A solution of 4-(benzyloxy)-2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine (D1, 3.5 g, 8.6 mmol) in MeOH (30 mL) was prepared. The reaction mixture was hydrogenated for 2 h at 40 psi on a Parr shaker. The reaction mixture was filtered through a diatomaceous earth filter and washed with MeOH. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. R2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridin-4-ol (E1, 2.6 g, 95%). 1 H NMR (400 MHz, DMSO-d6): δ10.00 (s, 1H), 5.73 (s, 1H), 5.43 (s, 1H), 5.20-5.35 (m, 1H), 3.81 (m, 1H), 2.96 (br t, J = 12.8 Hz, 1H), 1.99 (m, 1H), 1.61-1.77 (m, 4H), 1.50 (m, 1H),1.45 (s, 9H); MS (ESI) m / z: 319.2 (M+H + ).

[0256] The following compounds are basically prepared by the method for preparing E1.

[0257] Preparation of intermediate F1: ( R 2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridin-4-yltrifluoromethanesulfonate Will( R A solution of 2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridin-4-ol (E1, 2.6 g, 8.2 mmol) in DCM (30 mL) and Et3N (2.0 mL, 15 mmol) was cooled to 0. o C. Trifluoromethanesulfonic anhydride (1.5 mL, 9.2 mmol) was added under the same conditions, and the reaction mixture was then heated to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NaHCO3(aq) solution, and the mixture was extracted with DCM (2×). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a red, viscous, lumpy substance. R 2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridin-4-yltrifluoromethane sulfonate (F1, 2.8 g, 76%). 1H NMR (400 MHz, CDCl3): δ5.99 (s, 1H), 5.94 (s, 1H), 5.12-5.37 (m, 1H), 3.81 (br d, J = 13.2 Hz, 1H), 3.20 (br t, J = 14.0 Hz, 1H), 2.13 (m, 1H), 1.70-1.89 (m, 4H), 1.56-1.59 (m,1H), 1.55 (s, 9H); MS (ESI) m / z: 450.9 (M+H + ).

[0258] The following compounds are basically prepared by the method for preparing F1.

[0259] Preparation of intermediate G1: ( R )-2-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine Will( R A mixture of 2-(tert-butoxy)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridin-4-yltrifluoromethanesulfonate (F1, 1.0 g, 2.5 mmol) and BPD (0.7 g, 2.8 mmol) in 1,4-dioxane (30 mL) was treated with KOAc (0.7 g, 7.1 mmol) followed by Pd(dppf)Cl2 (0.1 g, 0.12 mmol). The reaction mixture was stirred at 110 °C for 3 h and then cooled to room temperature. The mixture was filtered through a diatomaceous earth filter and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was filtered through a short silica gel column using EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a dark semi-solid ( R )-2-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine (G1, 0.70 g, 65%). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J = 4.4 Hz,1H), 8.02 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 4.8, 8.0 Hz, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 1.49 (s, 9H), 1.29 (s, 12H); MS (ESI) m / z: 429.0 (M+H + ).

[0260] The following compounds are basically prepared by the method for preparing G1.

[0261] Preparation of intermediate G6: 4-(6-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronecyclo-2-yl)pyridin-2-yl)-3-(trifluoromethyl)morpholine A mixture of 4-(6-tert-butoxy-2-pyridinyl)-3-(trifluoromethyl)morpholine (0.10 g, 0.33 mmol), BPD (0.42 g, 1.64 mmol), [Ir(OMe)(COD)]2 (22 mg, 0.1 eq), and 4-tert-butyl-2-(4-tert-butyl-2-pyridinyl)pyridine (18 mg, 0.2 eq) in MTBE (10 mL) was degassed with N2 and purged for 3 min. The mixture was heated in a microwave at 80 °C for 2 h. The reaction mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc / pet-ether) to give 4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronecyclo-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholine (G6, 0.35 g, crude product), which was a brown oil. 1 H NMR (400 MHz, CDCl3): δ 6.52 (s, 1H), 6.48 (s, 1H), 5.12 (m, 1H), 4.32 (d, J = 12.4 Hz, 1H), 4.02 (dd, J = 2.8, 10.4 Hz, 1H), 3.77 (m, 1H), 3.47-3.69 (m, 3H), 1.52 (s, 9H), 1.33 (s, 12H) The following compounds were prepared primarily by the method used to prepare intermediate G6.

[0262] Preparation of intermediate H1: 2'-chloro-6'-((4-methoxybenzyl)oxy)-5-methyl-[4,4'-bipyridine]-2-amine A solution of (4-methoxyphenyl)methanol (0.78 g, 5.6 mmol) in 1,4-dioxane (25 mL) was treated with LiHMDS (9.3 mL, 9.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min, followed by the addition of 2'-chloro-6'-fluoro-5-methyl-[4,4'-bipyridine]-2-amine (B1, 1.7 g, 7.2 mmol). The reaction mixture was heated at 100 °C for 24 h, followed by cooling to room temperature. The reaction mixture was diluted with DCM and saturated NaHCO3 (aq). The mixture was extracted with DCM (2×), and the combined organic matter was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give an amber oil, 2'-chloro-6'-((4-methoxybenzyl)oxy)-5-methyl-[4,4'-bipyridine]-2-amine (H1, 2.22 g, 116%). MS (ESI) m / z: 356.2 (M+H) + ).

[0263] The following compounds were prepared primarily by the method of preparing intermediate H1.

[0264] Preparation of intermediate H3: N -(2'-chloro-6'-((4-methoxybenzyl)oxy)-5-methyl-[4,4'-bipyridine]-2-yl)cyclopropaneformamide A solution of 2'-chloro-6'-((4-methoxybenzyl)oxy)-5-methyl-[4,4'-bipyridine]-2-amine (H1, 1.0 g, 2.8 mmol) in DCM (10 mL) was treated with pyridine (0.36 mL, 4.5 mmol). The mixture was stirred at room temperature, and then cyclopropanecarbonyl chloride (0.46 mL, 5.06 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure. The residue was diluted with water (30 mL), and the solution was extracted with DCM (3×). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc / pet-ether) to give a yellow solid. N-(2'-chloro-6'-((4-methoxybenzyl)oxy)-5-methyl-[4,4'-bipyridine]-2-yl)cyclopropaneformamide (1.1 g, 74%). 1 H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.26 (s,1H), 7.95 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 0.8 Hz, 1H), 6.95(d, J = 8.4 MS (ESI) m / z: 424.2(M+H + ).

[0265] Preparation of intermediate H4: 2'-(tert-butoxy)-6'-fluoro-5-methyl- N -(2-methylpyrimidin-4-yl)-[4,4'-bipyridine]-2-amine A mixture of 2-tert-butoxy-4-(2-chloro-5-methyl-4-pyridyl)-6-fluoropyridine (B5, 1.24 g, 4.21 mmol) and 2-methylpyrimidin-4-amine (1.38 g, 12.6 mmol) in 2-methylbut-2-ol (15 mL) was treated with Cs₂CO₃ (4.11 g, 12.6 mmol). The reaction mixture was degassed and purged with N₂ gas for 3 min. BINAP (0.26 g, 0.42 mmol) and rac-BINAP-Pd-G₃ (0.42 g, 0.42 mmol) were added, followed by heating the mixture at 100 °C under N₂ atmosphere for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H₂O (50 mL) and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% EtOAc / pet-ether) to give a yellow solid of 2'-(tert-butoxy)-6'-fluoro-5-methyl- N -(2-methylpyrimidin-4-yl)-[4,4'-bipyridine]-2-amine (H4, 1.23 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ10.15 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 8.24 (s, 1H), 7.66 (d, J = 6.0 Hz,1H), 7.48 (s, 1H), 6.76 (s, 1H), 6.65 (s, 1H), 2.45 (s, 3H), 2.16 (s, 3H), 1.58 (s, 9H); MS (ESI) m / z: 368.4 (M+H + ).

[0266] Preparation of intermediate I1: 6'-(tert-butoxy)-2''-chloro-5''-methyl-2-(trifluoromethyl)-3,2':4',4''-terpyridine A solution of 6-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-2'-(trifluoromethyl)-2,3'-bipyridine (G2, 8.0 g, 18.9 mmol) and 2-chloro-4-iodo-5-methylpyridine (4.8 g, 18.9 mmol) in a mixture of 1,4-dioxane (100 mL) and H2O (5 mL) was treated with Na2CO3 (4.0 g, 37.8 mmol). The reaction mixture was degassed with N2 for 3 min, followed by the addition of Pd(dppf)Cl2 (1.4 g, 1.89 mmol). The reaction mixture was heated at 90 °C under N2 atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% EtOAc / pet-ether) to give 6'-(tert-butoxy)-2''-chloro-5''-methyl-2-(trifluoromethyl)-3,2':4',4''-terpyridine (7.8 g, 83%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.78 (d,J = 3.6 Hz, 1H), 8.31 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.60 (dd, J = 4.4,8.0 Hz, 1H), 7.22 (s, 1H), 6.88 (s, 1H), 6.64 (d, J = 1.2 Hz, 1H), 2.28 (s, 3H), 1.61 (s, 9H).

[0267] The following compounds were prepared primarily by the method of preparing intermediate I1.

[0268] Preparation of intermediate J1: 6'-(tert-butoxy)-5''-methyl-2-(trifluoromethyl)-[3,4':2',4''-terpyridine]-2''-amine A suspension of 2'-(tert-butoxy)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-2-(trifluoromethyl)-3,4'-bipyridine (G2, 3.5 g, 8.3 mmol) and 4-iodo-5-methylpyridin-2-amine (2.5 g, 11 mmol) in a mixture of EtOH (45 mL) and water (5 mL) was treated with K2CO3 (2.5 g, 18.1 mmol). The reaction mixture was degassed and purged with N2 gas for 3 min, followed by the addition of XPhos-Pd-G2 (0.040 g, 0.051 mmol). The reaction mixture was heated at 100 °C for 2 h, followed by cooling to room temperature. The mixture was concentrated under reduced pressure, and the residue was treated with DCM (200 mL). The solids were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% MeOH / DCM) to give 6'-(tert-butoxy)-5''-methyl-2-(trifluoromethyl)-[3,4':2',4''-terpyridine]-2''-amine (2.6 g, 78%) as a green foamy solid. MS (ESI) m / z: 403.2 (M+H) + ).

[0269] The following compounds were prepared primarily by the method used to prepare intermediate J1.

[0270] Preparation of intermediate J7: ( R )-2'-((4-methoxybenzyl)oxy)-6'-(2-(methoxymethyl)pyrrolidone-1-yl)-5-methyl-[4,4'-bipyridine]-2-amine Treatment with LiHMDS (3.5 mL, 3.5 mmol) RA solution of 2-(methoxymethyl)pyrrolidine (0.22 mL, 1.8 mmol) in 1,4-dioxane (4.4 mL) was prepared. The reaction mixture was stirred at room temperature for 5 min. 2'-fluoro-6'-((4-methoxybenzyl)oxy)-5-methyl-[4,4'-bipyridine]-2-amine (H2, 0.3 g, 0.88 mmol) was added, and the reaction mixture was stirred at 165 °C for 45 min. The reaction mixture was cooled to room temperature and then quenched with saturated NaHCO3(aq). The mixture was extracted with DCM (2×), and the combined organic matter was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give a clear amber oil. R 2'-((4-methoxybenzyl)oxy)-6'-(2-(methoxymethyl)pyrrolidone-1-yl)-5-methyl-[4,4'-bipyridine]-2-amine (0.20 g, 53%). MS (ESI) m / z: 435.2 (M+H + ).

[0271] Preparation of intermediate J8: 6-amino-5'-methyl-2'-((2-methylpyrimidin-4-yl)amino)-[4,4'-bipyridine]-2(1 H )-ketone 2'-(tert-butoxy)-6'-fluoro-5-methyl N A solution of 6'-(tert-butoxy)-2-amine (0.50 g, 1.36 mmol) in (4-methoxyphenyl)methylamine (5 mL) was heated at 110 °C for 36 h. The reaction mixture was cooled to room temperature and then quenched with 1.0 M HCl (adjusted to pH 6). The solution was extracted with EtOAc (3×), and the combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–50% EtOAc / pet-ether) to give a yellow solid of 6'-(tert-butoxy)- N 2' -(4-methoxybenzyl)-5-methyl- N 2 -(2-methylpyrimidin-4-yl)-[4,4'-bipyridine]-2,2'-diamine (0.68 g, 79%). 1H NMR (400 MHz, CDCl3): δ8.35 (d, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.52 (d, J = 6.0 Hz, 1H), 7.30 (d, J= 8.4 Hz, 2H), 7.25 (br s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4Hz, 2H), 5.95 (s, 1H), 5.85 (s, 1H), 4.70 (br t, J = 4.4 Hz, 1H), 4.45 (d, J= 5.6 Hz, 2H), 3.82 (s, 3H), 2.61 (s, 3H), 2.19 (s, 3H), 1.59 (s, 9H).

[0272] To 6'-(tert-butoxy)- N 2' -(4-methoxybenzyl)-5-methyl- N 2 0.44 g (0.91 mmol) of 6-amino-5'-methyl-2'-((2-methylpyrimidin-4-yl)amino)-[4,4'-bipyridine]-2,2'-diamine was added to a solution of 6-amino-5'-methyl-2'-((2-methylpyrimidin-4-yl)amino)-[4,4'-bipyridine]-2(1-diamine) in TFA (5 mL), and Et3SiH (0.29 mL, 2 eq) was added. The mixture was stirred at 40 °C for 3 h and then concentrated under reduced pressure. The crude product was ground with EtOAc and the solid was filtered to give a light green solid of 6-amino-5'-methyl-2'-((2-methylpyrimidin-4-yl)amino)-[4,4'-bipyridine]-2(1-diamine) H )-Keto-TFA salt (0.38 g, 77%). 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.49 (br s, 1H), 8.49 (d, J = 6.8 Hz, 1H), 8.33 (s, 1H), 7.91 (br m, 1H), 7.43 (br m, 1H), 6.11–6.41 (m, 2H), 5.38 (s, 1H), 5.33 (s, 1H), 2.60 (s, 3H), 2.22 (s, 3H), with one NH₃ in solvent; MS (ESI) m / z: 309.3 (M+H₂) + ).

[0273] Preparation of intermediate K1: ( S 2'-(2'-fluoro-5-methyl-6'-(2-methylpiperidin-1-yl)-[4,4'-bipyridine]-2-yl)carbamate Treatment with DIEA (0.50 mL, 2.86 mmol) at 0 °C (2) S A solution of 2-methylpiperidine (0.17 mL, 1.43 mmol) in DMSO (10 mL). Add... N methyl 4-[4-(2,6-difluoro-4-pyridyl)-5-methyl-2-pyridyl]carbamate (B3, 0.40 g, 1.43 mmol) was added, followed by heating the mixture at 80 °C for 5 h. The reaction mixture was cooled and then quenched with water. The resulting solid was filtered to give a gray solid. S 2'-(2'-fluoro-5-methyl-6'-(2-methylpiperidin-1-yl)-[4,4'-bipyridin]-2-yl)carbamate (0.50 g, crude product). MS (ESI) m / z: 359.2 (M+H) + ).

[0274] The following compounds are basically prepared by the same method used to prepare K1.

[0275] Preparation Example L1: ( R 5-Methyl-2'-oxo-6'-(2-(trifluoromethyl)-4-(vinylsulfonyl)piperazin-1-yl)-1',2'-dihydro-[4,4'-bipyridine]-2-yl)carbamate Towards N -[5-methyl-4-[2-[(2 S )-2-methylpiperazine-1-yl]-6-oxo-1 H Methyl pyridin-4-yl]-2-pyridyl]carbamate (45, 0.1 g, 0.25 mmol) was added to a solution of DCM (1 mL), along with one drop of DMF and 0.07 mL of Et3N. DCM (1 mL) containing ethylene sulfonyl chloride (0.03 g, 0.25 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure to give ( R 5-Methyl-2'-oxo-6'-(2-(trifluoromethyl)-4-(vinylsulfonyl)piperazin-1-yl)-1',2'-dihydro-[4,4'-bipyridin]-2-yl)carbamate (L1, crude product), which was used in the next step without further purification. MS (ESI) m / z: 448.6 (M+H) + ).

[0276] Preparation Example 1: ( R 5-Methyl-2'-oxo-6'-(2-(trifluoromethyl)piperidin-1-yl)-1',2'-dihydro-[4,4'-bipyridine]-2-yl)carbamate 12221 (4-Iodo-5-methylpyridin-2-yl)carbamate (A1, 2.04 g, 6.98 mmol) and ( R A mixture of 2-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6-(2-(trifluoromethyl)piperidin-1-yl)pyridine (G3, 4.27 g, 6.98 mmol) in 1,4-dioxane (75 mL) and H2O (15 mL). The reaction mixture was degassed with N2 for 3 min, followed by degassed with Pd(dppf)Cl2 (0.50 g, 0.70 mmol). The mixture was heated at 80 °C under N2 atmosphere for 3 h, followed by cooling to room temperature. The reaction mixture was diluted with water (200 mL), and the aqueous phase was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc / pet-ether) to give a yellow solid ( R 2'-(tert-butoxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridine]-2-yl)carbamate (2.9 g, 79%). 1 H NMR: (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.15 (s,1H), 7.86 (s, 1H), 6.06 (s, 1H), 6.00 (d, J = 0.8 Hz, 1H), 5.34 (m, 1H), 3.92(m, 1H), MS (ESI) m / z: 467.1 (M+H + ).

[0277] Treat with HCl / EtOAc (20 mL) R1.82 g (3.90 mmol) of methyl carbamate (2'-(tert-butoxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridin]-2-yl)carbamate was added. The mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL) and NaHCO3 (0.07 mL, 1.72 mmol) was added, followed by stirring at room temperature for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was ground with MeCN and stirred at room temperature for 20 min to give a white solid ( R 5-Methyl-2'-oxo-6'-(2-(trifluoromethyl)piperidin-1-yl)-1',2'-dihydro-[4,4'-bipyridine]-2-yl)carbamate (1, 0.40 g, 62%). 1 ¹H NMR: (400 MHz, DMSO-d⁶): δ 10.16 (br s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 6.24 (s, 1H), 5.87 (s, 1H), 5.48 (m, 1H), 4.11 (br d, J = 12.4 Hz, 1H), 3.65 (s, 3H), 2.98 (t, J = 12.6 Hz, 1H), 2.15 (s, 3H), 1.97 (br d, J = 13.6 Hz, 1H), 1.59–1.83 (m, 4H), 1.45 (m, 1H), ¹NH₃ in solvent; MS (ESI) m / z: 411.1 (M+H₂) + ).

[0278] Preparation Example 2: ( R )-5'-methyl-2'-((6-methylpyrazin-2-yl)amino)-6-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridine]-2(1 H )-Ketone 13741 A mixture of 6-methylpyrazine-2-amine (0.037 g, 0.31 mmol) and (R)-2-chloro-2'-((4-methoxybenzyl)oxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-4,4'-bipyridine (I2, 0.15 g, 0.31 mmol) in DMF (15 mL) was treated with Cs2CO3 (0.20 g, 0.61 mmol). The mixture was degassed and purged with N2 gas for 3 min, followed by the addition of Pd2(dba)3 (0.028 g, 0.1 eq) and Xantphos (0.35 g, 0.2 eq). The reaction mixture was stirred at 100 °C for 6 h and then quenched at room temperature with NH4Cl (20 mL) / water (50 mL). The solution was extracted with EA (3×), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc / pet-ether) to give (R)-2'-((4-methoxybenzyl)oxy)-5-methyl-N-(6-methylpyrazin-2-yl)-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridine]-2-amine (0.18 g, 84%) as a gray solid.

[0279] A solution of (R)-2'-((4-methoxybenzyl)oxy)-5-methyl-N-(6-methylpyrazin-2-yl)-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridine]-2-amine (0.18 g, 0.32 mmol) in HCl / EtOAc (6 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C-18 prep-HPLC (25-55% H2O (0.05% NH3H2O ​​+ 10 mM NH4HCO3) / MeCN) to give a white solid (0.067 g, 47%). 1H NMR: (400MHz, DMSO-d6): δ 10.40 (br s, 1H), 9.91 (s, 1H), 8.94 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.50 (s, 1H), 6.26 (s, 1H), 5.90 (s, 1H), 5.48 (m, 1H), 4.14 (br d, J = 11.2 Hz, 1H), 2.99 (br t, J = 12.8 Hz, 1H), 2.36 (s, 3H), 2.15 (s,3H), 1.97 (br d, J = 13.2 Hz, 1H), 1.62-1.80 (m, 4H), 1.46 (m, 1H); MS (ESI)m / z: 445.1 (M+H + ).

[0280] Preparation Example 3: ( R )- N -(5-Methyl-2'-oxo-6'-(2-(trifluoromethyl)piperidin-1-yl)-1',2'-dihydro-[4,4'-bipyridin]-2-yl)-2-(1-methylazacyclobutane-3-yl)acetamide 13692 A solution of 2-(1-tert-butoxycarbonylazycyclobutan-3-yl)acetic acid (0.23 g, 1.06 mmol) in DMF (5 mL) was treated with NMI (0.25 mL, 3.17 mmol) and TCFH (0.44 g, 1.59 mmol), followed by the addition of 4-[2-[(4-methoxyphenyl)methoxy]-6-[(2 R [-2-(trifluoromethyl)-1-piperidinyl]-4-pyridinyl]-5-methylpyridin-2-amine (0.5 g, 1.06 mmol) was stirred at room temperature for 2 h. The reaction mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-45% EtOAc / pet-ether) to give a white solid ( R 3-(2-((2'-((4-methoxybenzyl)oxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridin]-2-yl)amino)-2-oxoethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.60 g, 85%). MS (ESI) m / z: 670.4 (M+H) + ).

[0281] Towards( R0.40 g (0.60 mmol) of tert-butyl 3-(2-((2'-((4-methoxybenzyl)oxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridin]-2-yl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate (DCM) in a solution of tert-butyl 3-(2-(2'-(4-methoxybenzyl)oxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridin]-2-yl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate (DCM) in 15 mL solution was added slowly, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a white solid. R )-2-(azacyclobutane-3-yl)- N -(2'-(4-methoxyphenoxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridin]-2-yl)acetamide (0.37 g, crude product). MS (ESI) m / z: 570.4 (M+H) + ).

[0282] Towards( R )-2-(azacyclobutane-3-yl)- N -(2'-(4-methoxyphenoxy)-5-methyl-6'-(2-(trifluoromethyl)piperidin-1-yl)-[4,4'-bipyridin]-2-yl)acetamide (0.34 g, 0.60 mmol) was added to a solution in DCE (5 mL), followed by the addition of HCHO (0.13 mL, 1.79 mmol, 37% purity, 3.0 eq), and the mixture was stirred at room temperature for 0.5 h. NaBH3CN (0.056 g, 1.5 eq) was then added, and the mixture was stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure, followed by the addition of water (10 mL). The mixture was extracted with EtOAc (3×), and the combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. N -[4-[2-[(4-methoxyphenyl)methoxy]-6-[(2 R [2-(trifluoromethyl)-1-piperidinyl]-4-pyridinyl]-5-methyl-2-pyridinyl]-2-(1-methylazacyclobutane-3-yl)acetamide (0.55 g, crude product). MS (ESI) m / z: 584.3 (M+H) + ).

[0283] Treat with TFA (0.5 mL) N -[4-[2-[(4-methoxyphenyl)methoxy]-6-[(2 RA solution of 0.50 g (0.86 mmol) of 2-(trifluoromethyl)-1-piperidinyl]-4-pyridinyl]-5-methyl-2-pyridinyl]-2-(1-methylazacyclobutane-3-yl)acetamide in DCM (10 mL) was obtained. The reaction mixture was stirred at room temperature for 0.5 h and then concentrated under reduced pressure. The residue was purified by C-18 prep-HPLC (20-50% H2O (10 mM NH4HCO3) / MeCN) to give a white solid. R )- N -(5-methyl-2'-oxo-6'-(2-(trifluoromethyl)piperidin-1-yl)-1',2'-dihydro-[4,4'-bipyridine]-2-yl)-2-(1-methylazacyclobutane-3-yl)acetamide (77, 0.053 g, 13%). 1 H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 10.01 (br s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 6.22 (s,1H), 5.85 (s, 1H), 5.48 (m, 1H), 4.10 (br d, J = 12.8 Hz, 1H), 3.27-3.30 (m,2H), 2.98 (br t, J = 12.8 Hz, 1H), 2.74-2.79 (m, 2H), 2.60-2.67 (m, 3H), 2.16(s, 3H), 2.15 (s, 3H), 1.97 (m, 1H), 1.60-1.81 (m, 4H), 1.46 (m, 1H); MS(ESI) m / z: 464.1 (M+H + ).

[0284] Preparation Example 4: (5''-methyl-6'-oxo-4-(trifluoromethyl)-1',6'-dihydro-[3,2':4',4''-terpyridine]-2''-yl)carbamate 13821 A solution of 6'-((4-methoxybenzyl)oxy)-5''-methyl-4-(trifluoromethyl)-[3,2':4',4''-terpyridine]-2''-amine (J4, 0.27 g, 0.58 mmol) in pyridine (5 mL) was prepared and cooled to 0 °C. Methyl chloroformate (0.18 mL, 2.3 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give methyl (6'-((4-methoxybenzyl)oxy)-5''-methyl-4-(trifluoromethyl)-[3,2':4',4''-terpyridine]-2''-yl)carbamate (0.31 g, 100%) as a clear amber solid.

[0285] A solution of methyl 6'-((4-methoxybenzyl)oxy)-5''-methyl-4-(trifluoromethyl)-[3,2':4',4''-terpyridine]-2''-yl)carbamate (0.31 g, 0.58 mmol) in MeOH (5 mL) was treated with TFA (3.5 mL, 45 mmol). The reaction mixture was heated to 60 °C for 16 h and then concentrated under reduced pressure. The residue was treated with MeCN (5 mL) and sonicated for 10 min. The resulting solid was filtered and washed with MeCN to give methyl 5''-methyl-6'-oxo-4-(trifluoromethyl)-1',6'-dihydro-[3,2':4',4''-terpyridine]-2''-yl)carbamate (78 g, 0.11 g, 44%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.99 (br s, 1H), 10.23(s, 1H), 8.87-8.99 (m, 2H), 8.20 (s, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.74 (s,1H), 6.48 (s, 2H), 3.66 (s, 3H), 2.20 (s, 3H); MS (ESI) m / z: 405.0 (M+H + ).

[0286] The following compounds were prepared primarily by the methods described in Examples 1, 2, 3 and 4.

[0287] Preparation Example 96: 2,4-Difluoro- N -(5'-Methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-oxo-1,6-dihydro-[4,4'-bipyridine]-2-yl)benzenesulfonamide 14016 To a solution of 6-amino-4-[5-methyl-2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one TFA salt (J8, 0.20 g, 0.47 mmol) in pyridine (3 mL), 2,4-difluorobenzenesulfonyl chloride (0.06 mL, 0.47 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL), and the solution was extracted with EtOAc (3×). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C-18 prep-HPLC (30-60% H2O (0.05% NH3H2O-10mM NH4HCO3) / MeCN) to give 2,4-difluoro- N -(5'-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-oxo-1,6-dihydro-[4,4'-bipyridine]-2-yl)benzenesulfonamide (81, 0.050 g, 22%). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 8.30 (d, J = 6.0 Hz,1H), 8.21 (s, 1H), 8.04 (m, 1H), 7.59 (m, 1H), 7.55 (m, 2H), 7.33 (m, 1H), 6.40 (d, J = 1.2 Hz, 1H), 6.25 (br s, 2H), 6.22 (d, J = 0.8 Hz, 1H), 2.46 (s,3H), 2.12 (s, 3H); MS (ESI) m / z: 485.1 (M+H) + ).

[0288] The following compounds were prepared essentially by the method of Preparation Example 96.

[0289] Biochemical analysis of VPS34 VPS34 kinase activity was determined using an ADP-Glo ​​kinase activity assay (Promega Corp). Analysis was performed in 384-well plates (5 μL analysis volume) using 25 nM VPS34 (ThermoFisher Scientific), 100 μg / μL PI:3PS lipid kinase substrate (Promega Corp.), and 1 mM ATP in kinase buffer. Inhibition of VPS34 was measured by adding serially diluted test compounds (final analytical concentration 0.1% DMSO) followed by incubation at 37°C for 1 h. ADP-Glo ​​reagent (5 mL) was then added, followed by incubation at room temperature for 40 min. Kinase assay reagent (10 mL) was then added, followed by incubation at room temperature for 60 min. Luminescence was then detected. RLU at each compound concentration was converted to percentage of inhibition using controls (i.e., no reaction with test compounds and reactions with known inhibitors), and IC50 was calculated by fitting a four-parameter sigmoid curve to the data using GeneData Screener software. 50 value.

[0290] VPS34 protein sequence (full length with GST tag) Table 1. Inhibition of the biochemical activity of VPS34 by exemplary compounds (“Example No.”).

[0291] For Table 1, "++++" refers to ICs less than or equal to 100 nM. 50； "+++" refers to ICs with a value greater than 100 nM and less than or equal to 500 nM. 50 "++" refers to an IC with a current greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "+" indicates an IC value greater than 1000 nM and less than or equal to 10000 nM. 50 .

[0292] Lipid kinase selective panel The compounds of the present invention were tested in a standard lipid kinase selectivity group: Sixteen other lipid kinases (Reaction Biology, Malvern, PA, USA) were tested under conditions of non-disclosure, non-transmission, and non-use. In summary, lipid kinases, including PI3Kα, PI3Kβ, and PI3Kδ, were repeatedly tested with single doses of 1 μM (see Table 2), and the reactions were performed at 10 mM ATP.

[0293] Table 2. Percentage of inhibition relative to DMSO control of PI3K family members.

[0294] equivalent Although specific embodiments have been described, the above description is exemplary and not restrictive. Many variations of the embodiments will be apparent to those skilled in the art upon reading this description. The full scope of the disclosure, its equivalents, and the full scope of this description and these variations should be determined with reference to the claims.

[0295] Unless otherwise indicated, all figures used in this specification and claims to represent the quantities of components, reaction conditions, etc., should in all cases be understood to be modified by the term "about". Therefore, unless indicated to the contrary, the numerical parameters described in this specification and the appended claims are approximate values ​​that may vary depending on the desired properties being sought.

Claims

1. A compound represented by formula (I): Equation (I), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned therein are optionally substituted each time they appear by one or more of the following groups that appear independently: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

2. A compound represented by formula (IA): Equation (IA), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is a heterocyclic group; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned therein are optionally substituted each time they appear by one or more of the following groups that appear independently: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

3. A compound represented by formula (IB): Formula (IB), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is a heteroaryl group; Q is selected from: H, -NHR 2 and -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned therein are optionally substituted each time they appear by one or more of the following groups that appear independently: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

4. The compound of claim 2 or 3, wherein Q is selected from: -NHR 2 and -NHC(O)LR 4 .

5. A compound represented by formula (IC): Formula (IC), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is -NHR 2 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 2 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; and R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned therein are optionally substituted each time they appear by one or more of the following groups that appear independently: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

6. A compound represented by formula (ID): Formula (ID), Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 Selected from: CH and N; A is selected from: cycloalkyl, heterocyclic, aryl, heteroaryl, and -NHSO2R. 3 ; Q is -NHC(O)LR 4 ; R 1 Selected from: alkyl, haloalkyl, halogen, cycloalkyl, and amino groups; R 3 Selected from: alkyl, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 4 Selected from: H, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, amino, O-cycloalkyl, O-heterocyclic, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocyclic, NH-aryl, and NH-heteroaryl; and L is selected from: bonds and alkyl groups. The cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned therein are optionally substituted each time they appear by one or more of the following groups that appear independently: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclic, or heteroaryl.

7. The compound according to any one of claims 1-6, wherein X 1 For CH.

8. The compound according to any one of claims 1-6, wherein X 1 Let N be the number of elements in the array.

9. The compound according to any one of claims 1-8, wherein R 1 Selected from: alkyl, halogen, and amino groups.

10. The compound according to any one of claims 1-9, wherein R 1 It is CH3.

11. The compound according to any one of claims 1-9, wherein R 1 It is -NH2.

12. The compound according to any one of claims 1-9, wherein R 1 Selected from: F and Cl.

13. The compound according to any one of claims 1-4 and 7-12, wherein Q is -NHR 2 .

14. The compound according to any one of claims 1-5 and 7-13, wherein R 2 It is a heteroaryl group.

15. The compound according to any one of claims 1-5 and 7-14, wherein R 2 for ; It can be a single bond or a double bond; X 11 Selected from: N, CR 11 NR 21 S and O; X 12 Selected from: N, CR 12 NR 22 S and O; X 13 Selected from: N, CR 13 NR 23 S and O; X 14 Selected from: N, CR 14 NR 24 S and O; and among them R 11 R 12 R 13 R 14 R 21 R 22 R 23 and R 24 Each is independently selected from: H, amino, halogen, cyano, alkyl, cycloalkyl, and alkylamino.

16. The compound according to any one of claims 1-5 and 7-15, wherein R 11 R 12 R 13 R 14 R 21 R 22 R 23 and R 24 Each is independently selected from: H, C1-C6 alkyl and C1-C6 alkylamino.

17. The compound according to any one of claims 1-5 and 7-16, wherein R 11 R 12 R 13 R 14 R 21 R 22 R 23 and R 24 Each is independently selected from: H, CH3 and -(CH2)2N(CH3)2.

18. The compound according to any one of claims 1-5 and 7-17, wherein R 2 Selected from: and .

19. The compound according to any one of claims 1-5 and 7-14, wherein R 2 for ; X 5 Selected from: N and CR 15 ; X 6 Selected from: N and CR 16 ; X 7 Selected from: N and CR 17 ; X 8 Selected from: N and CR 18 ; X 9 Selected from: N and CR 19 ; Where X 5 X 6 X 7 X 8 and X 9 No more than three of them are nitrogen; and among them R 15 R 16 R 17 R 18 and R 19 Each group is independently selected from: H, amino, halogen, and cyano.

20. The compound according to any one of claims 1-5, 7-14 and 19, wherein R 15 R 16 R 17 R 18 and R 19 Each is independently selected from: H and C1-C6 alkyl groups.

21. The compound according to any one of claims 1-5, 7-14 and 19-20, wherein R 15 R 16 R 17 R 18 and R 19 Each is independently selected from: H and CH3.

22. The compound according to any one of claims 1-5, 7-14 and 19-21, wherein R 2 Selected from: and .

23. The compound according to any one of claims 1-5 and 7-14, wherein R 2 Selected from: and .

24. The compound of any one of claims 1-4 and 6-12, wherein L is selected from: bonds and alkyl groups.

25. The compound according to any one of claims 1-4, 7-12 and 24, wherein Q is NHC(O)LR 4 .

26. The compound according to any one of claims 1-4, 6-12 and 24-25, wherein R 4 Selected from: alkyl, alkoxy, amino, alkylamino, cycloalkyl, heterocyclic, aryl, heteroaryl and O-heterocyclic.

27. The compound according to any one of claims 1-4, 6-12 and 24-26, wherein L is a bond.

28. The compound according to any one of claims 1-4, 6-12 and 24-27, wherein R 4 Selected from: alkyl, alkoxy, amino, cycloalkyl, heterocyclic, heteroaryl and O-heterocyclic, wherein each of the heterocyclic, heteroaryl and O-heterocyclic groups is optionally substituted by one or more substituents independently selected from alkyl and halogens.

29. The compound according to any one of claims 1-4, 6-12 and 24-28, wherein LR 4 Selected from: methyl, methoxy, -N(H)CH3, and .

30. The compound according to any one of claims 1-4, 6-12 and 24-29, wherein LR 4 Selected from: methyl, methoxy and .

31. The compound of any one of claims 1-4, 6-12 and 24-26, wherein L is an alkyl group.

32. The compound according to any one of claims 1-4, 6-12, 24-26 and 31, wherein R 4 Selected from: alkoxy, amino, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from alkyl and halogen.

33. The compound according to any one of claims 1-4, 7-12, 24-26 and 31-32, wherein R 4 Selected from: amino and heterocyclic groups.

34. The compound according to any one of claims 1-4, 7-12, 24-26 and 31-33, wherein LR 4 Selected from: and .

35. The compound of any one of claims 1 and 5-34, wherein A is selected from: aryl, heteroaryl, heterocyclic and -NHSO2R. 3 .

36. The compound of any one of claims 1 to 5-35, wherein A is -NHSO2R 3 And R 3 For optional use by R, which appears one or more times 33 Substituted phenyl, wherein R 33 Each time it appears, it is independently selected from: H, amino, and halogen.

37. The compound of any one of claims 1 and 5-35, wherein A is selected from aryl and heteroaryl groups.

38. The compound according to any one of claims 1, 5-35 and 37, wherein A is ,in: n = 0, 1, 2, or 3; and R 22 Each time it appears, it is independently selected from: alkyl, haloalkyl, cycloalkyl, and sulfonamide.

39. The compound according to any one of claims 1, 5-35 and 37-38, wherein A is 。 40. The compound of any one of claims 1, 5-35, and 37, wherein A is selected from: and ,in: n = 0, 1, 2, or 3; and R 23 Each time it appears, it is independently selected from: alkyl, haloalkyl, and cycloalkyl.

41. The compound of any one of claims 1, 5-35, 37 and 40, wherein A is selected from: and .

42. The compound of any one of claims 1, 5-35, 37 and 40-41, wherein A is selected from: and .

43. The compound of any one of claims 1 and 5-35, wherein A is a heterocyclic group.

44. The compound of any one of claims 1, 5-35 and 43, wherein A is selected from: and ,in: n = 0, 1, 2 or 3; R 24 Each time it appears, it is independently selected from: alkyl, haloalkyl, and cycloalkyl; and R 25 Selected from: alkyl, cycloalkyl, C(O)-R 26 SO2-R 27 ; R 26 Selected from: alkyl, cycloalkyl, aryl, and heteroaryl; and R 27 Selected from: alkyl, cycloalkyl, aryl and heteroaryl.

45. The compound of any one of claims 1, 5-35, and 43-44, wherein A is selected from: and .

46. ​​The compound of any one of claims 1, 5-35, and 43-45, wherein A is selected from: and .

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

48. A pharmaceutical composition comprising a compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

49. A method of treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the cancer is selected from: breast cancer (such as triple-negative breast cancer), bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, gastrointestinal stromal tumor, esophageal cancer, gastric cancer, glioma, glioblastoma, ovarian cancer, head cancer, neck cancer, urothelial carcinoma, uterine cancer, prostate cancer, hepatic cancer, osteosarcoma, sarcoma, multiple myeloma, metastatic bone cancer and papillary thyroid carcinoma, and hypoxic tumors.

51. The method of claim 50, further comprising radiotherapy.

52. The compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, for the treatment or prevention of disease.

53. The compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, for the treatment of cancer.

54. A compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, for the treatment of cancer, wherein the cancer is selected from: breast cancer (such as triple-negative breast cancer), bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, gastrointestinal stromal tumor, esophageal cancer, gastric cancer, glioma, glioblastoma, ovarian cancer, head cancer, neck cancer, urothelial carcinoma, uterine cancer, prostate cancer, hepatic cancer, osteosarcoma, sarcoma, multiple myeloma, metastatic bone cancer and papillary thyroid carcinoma, and hypoxic tumors.

55. A compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, for the treatment of cancer, wherein the cancer treatment further comprises radiotherapy.

56. Use of any compound of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof in the preparation of a medicament for treating cancer.

57. Use of any compound of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof in the preparation of a medicament for treating cancer, wherein the cancer is selected from: breast cancer (such as triple-negative breast cancer), bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma, lung cancer, gastrointestinal stromal tumor, esophageal cancer, gastric cancer, glioma, glioblastoma, ovarian cancer, head cancer, neck cancer, urothelial carcinoma, uterine cancer, prostate cancer, hepatic cancer, osteosarcoma, sarcoma, multiple myeloma, metastatic bone cancer, papillary thyroid carcinoma, and hypoxic tumors.

58. A method for treating cancer in a patient in need, the method comprising: (i) administering to the patient a therapeutically effective amount of the compound of any one of claims 1-47 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof; and (ii) administering to the patient a therapeutically effective amount of the STING agonist; Compared to any increase in the expression of at least one chemokine caused by administration of the compound alone to the patient, administration of the therapeutically effective amount of the STING agonist and the compound caused an increase in the expression of at least one chemokine in the patient.

59. A method for upregulating at least one chemokine in cells, the method comprising contacting a cell sample with: (i) a compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, an enantiomer, a stereoisomer or a tautomer; and (ii) a STING agonist in an amount sufficient to increase the expression of the at least one chemokine in the cells.

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